Ahead of print articles
PULSE PRESSURE AS A PREDICTOR OF ALZHEIMER’S DISEASE BIOMARKERS AND COGNITIVE DECLINE: THE MODERATING ROLE OF APOE Ε4
Joon Hyung Jung, Nayeong Kong, Seunghoon Lee, A4 and LEARN Study Teams
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BACKGROUND: Elevated pulse pressure (PP), indicative of arterial stiffness, has been implicated in cognitive impairment and Alzheimer’s disease (AD) pathology. However, its role in preclinical AD and interactions with genetic risk factors like apolipoprotein E ε4 (APOE4) remain unclear.
OBJECTIVES: To investigate the association between baseline PP and AD biomarkers (amyloid-beta (Aβ) and tau) and cognitive decline, and to determine whether APOE4 carrier status moderates these relationships.
DESIGN: Prospective cohort study and secondary analysis of the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s (A4) randomized clinical trial
SETTING: Multicenter observational cohort and randomized clinical trial conducted at 67 sites across the United States, Canada, Australia, and Japan.
PARTICIPANTS: This study included 1690 cognitively unimpaired older adults from the A4 and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) studies. Participants underwent baseline PP assessment, Aβ and tau PET imaging, and cognitive testing with longitudinal follow-up over 240 weeks.
MEASUREMENTS: Blood pressure was measured at baseline, with PP calculated as the difference between systolic and diastolic pressures. AD pathologies were assessed through Aβ PET imaging using 18F-Florbetapir, and regional tau deposition in inferior temporal and meta-temporal regions using 18F-Flortaucipir PET imaging. Cognitive performance was measured using the Preclinical Alzheimer Cognitive Composite (PACC).
RESULTS: Higher baseline PP was significantly associated with increased Aβ (β = 0.078; p = 0.001), inferior temporal tau (β = 0.110; p = 0.032), and meta-temporal tau deposition (β = 0.116; p = 0.022). In longitudinal analyses, elevated PP predicted greater decline in PACC scores (β = −0.020; p < 0.001). APOE4 status moderated these associations, with significant effects of PP on tau deposition and cognitive decline observed exclusively among APOE4 carriers. Mediation analysis indicated that tau deposition significantly mediated the association between PP and cognitive decline (indirect effect β = −0.068; 95 % CI [−0.126, −0.011]).
CONCLUSIONS: Elevated PP is associated with increased AD biomarker burden and accelerated cognitive decline in cognitively unimpaired older adults, particularly among APOE4 carriers. Our study suggests that arterial stiffness may contribute to AD pathogenesis and progression via tau pathology. These results highlight the potential of vascular health management as an early intervention target for AD prevention, especially in genetically at-risk populations.
CITATION:
Joon Hyung Jung ; Nayeong Kong ; Seunghoon Lee ; A4 and LEARN Study Teams (2025): Pulse pressure as a predictor of Alzheimer’s disease biomarkers and cognitive decline: The moderating role of APOE ε4. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100363
ALZHEIMER’S DISEASE PREVENTION BY FLAVONOLS AND THEIR ANALOGS
George Uhl, Balaji Kannan, Joungil Choi, Ian Henderson
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Four studies now document reduced incidence of Alzheimer’s disease (AD) or dementia diagnoses in aging individuals who report higher dietary intake of flavonols (or their glycosides) years prior to diagnosis vs those with lower intake. These effects are large, almost 50 %, for individuals at higher genetic risk for AD, providing a robust gene x environment interaction. They display a specific structure-activity relationship. These benefits are driven by modest-to-moderate differences in the quantity of flavonol (glycoside) consumed. These data contrast with the failure of late life supplementation with flavonol-rich ginko extract to alter progression to AD in groups of individuals who are not selected for genotype or dietary pattern. Studies of mouse AD models support benefits of the flavonol quercetin. In vitro and in vivo results add the receptor type protein tyrosine phosphatase PTPRD to the list of oxidative and other targets or mechanisms to which flavonol benefits are attributed. The magnitude of flavonol protection for individuals who would otherwise be especially vulnerable to AD, the ease of supplementation strategies with currently-available nutraceuticals and the opportunities for development of improved flavonol analogs all support further exploration of flavonol-based strategies for reducing the incidence of AD with aging.
CITATION:
George Uhl ; Balaji Kannan ; Joungil Choi ; Ian Henderson (2025): Alzheimer’s disease prevention by flavonols and their analogs. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100361
A CRITICAL REVIEW AND CLASSIFICATION OF DEMENTIA RISK ASSESSMENT TOOLS TO INFORM DEMENTIA RISK REDUCTION
Md Hamidul Huque, Ranmalee Eramudugolla, Meiwei Li, Kim M. Kiely, Ruth Peters, Kaarin J. Anstey
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Addressing modifiable dementia risk factors requires reliable risk assessment methods. We aimed to synthesise knowledge on risk scores for all cause dementia, Alzheimer’s disease (AD) and vascular dementia, classify them according to target population, evaluate their content, cost, appropriateness of validation studies, and suitability for implementing risk reduction guidelines. A systematic search was conducted of PubMed, Cochrane Collaboration, ProQuest, Scopus, Embase, and PsycINFO databases using a pre-registered protocol. Data on risk factors, target population, predictive validity, cost, and alignment with WHO guidelines were extracted. Random-effects meta-analysis was performed. Of 45 risk scores identified, 29 were for all-cause dementia, including 11 based on late-life cohorts, 6 on midlife, and 7 covering mid to late-life. The pooled C-statistic across development and validation studies of dementia risk scores was 0.69 (95 % CI: 0.67, 0.71). Development study AUCs were higher than validation study AUCs and dropped from 0.74 to 0.66 for risk scores developed for clinical samples and from 0.79 to 0.71 for AD specific scores (which include functional indicators non-independent of disease). There were no validated risk scores for vascular dementia. Dem-NCD, CogDrisk, ANU-ADRI and LIBRA risk scores incorporated most WHO-recommended risk factors and demonstrated accuracy comparable to the overall pooled C-statistic. We conclude that across the field, there are methodological limitations relating to validation, and inappropriate comparison of tools designed for different purposes or target populations. However, there are now several validated, risk scores for all-cause dementia and AD that assess modifiable factors and offer cost-effective dementia risk assessment and risk reduction advice.
CITATION:
Md Hamidul Huque ; Ranmalee Eramudugolla ; Meiwei Li ; Kim M. Kiely ; Ruth Peters ; Kaarin J. Anstey (2025): A critical review and classification of dementia risk assessment tools to inform dementia risk reduction. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100333
A PHASE 2 RANDOMIZED, PLACEBO-CONTROLLED STUDY ON THE EFFICACY AND SAFETY OF AR1001, A PHOSPHODIESTERASE-5 INHIBITOR, IN PATIENTS WITH MILD-TO-MODERATE ALZHEIMER’S DISEASE
David Greeley, Marshall Nash, Brad Herskowitz, Fred Kim, James Rock, Neils Prins, SangYun Kim, Tianyang Xi, Jonathan A. Busam, Benoit Tete, Jai Jun Choung, Sharon J. Sha
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BACKGROUND: AR1001 is a phosphodiesterase-5 inhibitor that produces improved cognitive performance and reduces amyloid-β and phosphorylated tau burdens in preclinical models of Alzheimer’s disease (AD).
OBJECTIVES: To evaluate the safety and efficacy of AR1001 in participants with mild-to-moderate Alzheimer’s disease (AD).
DESIGN: Randomized, double-blind, placebo-controlled phase 2 trial conducted at 21 sites in the United States.
PARTICIPANTS: Adults aged 55–80 years with mild-to-moderate dementia as determined by National Institutes of Aging-Alzheimer’s Association (NIA-AA) stage 4 or 5 and Mini-mental State Exam (MMSE) score 16-26.
INTERVENTION: Once daily oral administration of placebo, 10 mg AR1001, or 30 mg AR1001 for 26 weeks followed by 26 weeks optional extension.
MEASUREMENTS: Co-primary efficacy endpoints were changes from baseline at Week 26 in Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-Cog 13) and Alzheimer’s Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC). Secondary endpoints included measures of cognition, daily living, and depression. Levels of plasma biomarkers pTau-181, pTau-217, Aβ42/40 ratio, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) were also examined.
RESULTS: A total of 210 participants were enrolled and 82% completed 26 weeks of treatment. AR1001 10 mg and 30 mg were well-tolerated with a similar safety profile compared to placebo. After 26 weeks, there were no differences in ADAS-Cog13, ADCS-CGIC, or in secondary efficacy endpoints between groups. Levels of plasma biomarkers pTau-181, pTau-217, and GFAP were improved in the 30 mg AR1001 group compared to placebo.
CONCLUSION: AR1001 was safe and well tolerated. Although primary efficacy endpoints were not met after 26 weeks of treatment, participants receiving 30 mg AR1001 showed favorable changes in AD-related plasma biomarkers compared to placebo.
CITATION:
David Greeley ; Marshall Nash ; Brad Herskowitz ; Fred Kim ; James Rock ; Neils Prins ; SangYun Kim ; Tianyang Xi ; Jonathan A. Busam ; Benoit Tete ; Jai Jun Choung ; Sharon J. Sha (2025): A phase 2 randomized, placebo-controlled study on the efficacy and safety of AR1001, a phosphodiesterase-5 inhibitor, in patients with mild-to-moderate Alzheimer’s disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100337
PRECLINICAL DETECTION OF AL-ZHEIMER’S DISEASE PATHOLOGY USING CONCEPTUAL DISCRIMINATION ABILITIES
Lara Huyghe, Yasmine Salman, Lise Colmant, Thomas Gérard, Vincent Malotaux, Gabriel Besson, Emma Delhaye, Christine Bastin, Quentin Dessain, Laurence Dricot, Renaud Lhommel, Adrian Ivanoiu, Lisa Quenon, Bernard Hanseeuw
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BACKGROUND: Performance on the Conceptual Matching Task (CMT), a measure of discrimination between conceptually confusable items, has been suggested as a cognitive marker of rhinal cortex atrophy, one of the first brain regions affected by Alzheimer’s disease (AD) pathology.
OBJECTIVES: We aimed to determine whether CMT can detect preclinical AD, and whether CMT performance is related to regional deposition of tau protein or other AD-associated lesions including amyloid (Aβ) accumulation and white matter hyperintensities (WMH).
DESIGN, SETTING AND PARTICIPANTS: This cross-sectional study include 101 participants from the UCL2016–121 cohorts in Brussels, Belgium, classified as 56 Aβ-negative cognitively unimpaired (Aβ-CU), 25 Aβ-positive CU (Aβ+CU, preclinical AD), and 20 Aβ-positive mildly cognitively impaired (Aβ+MCI, prodromal AD) individuals.
MEASUREMENTS: Participants underwent CMT and a standard neuropsychological assessment that included the Preclinical Alzheimer Cognitive Composite (PACC5), an Aβ status examination, a 3D-T1 MRI and a [18F]MK-6240 tau-PET scan.
RESULTS: CMT performance was lower among Aβ+MCI and Aβ+CU than Aβ-CU individuals. The effect of Aβ on CMT performance was stronger in the presence of WMH, but rhinal tau burden did not explain CMT performance beyond the effects of Aβ and WMH. CMT performance correlated with executive, memory, and language performance. Finally, CMT was more sensitive than PACC5 to detect CU individuals with Aβ or tau pathology.
CONCLUSION: Given that impaired performance is observed earlier in the CMT than in standard neuropsychological tests, this test shows promise as an early diagnostic tool for AD and may offer significant utility in the context of clinical trials.
CITATION:
Lara Huyghe ; Yasmine Salman ; Lise Colmant ; Thomas Gérard ; Vincent Malotaux ; Gabriel Besson ; Emma Delhaye ; Christine Bastin ; Quentin Dessain ; Laurence Dricot ; Renaud Lhommel ; Adrian Ivanoiu ; Lisa Quenon ; Bernard Hanseeuw (2025): Preclinical detection of Alzheimer’s disease pathology using conceptual discrimination abilities. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100332
PREVALENCE AND CO-OCCURRENCE OF DEMENTIA RISK FACTORS IN DENMARK: A NATIONWIDE STUDY
Janet Janbek, Thomas Munk Laursen, Kasper Jørgensen, Martin Mejlby Jensen, Marie Holm Eliasen, Anne Illemann Christensen, Sebastian Walsh, Andrew Sommerlad, Carol Brayne, Gunhild Waldemar
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BACKGROUND: The clustering of dementia risk factors is common and has implications for policies targeting risk reduction.
OBJECTIVES: To estimate the prevalence of 16 dementia risk factors and their co-occurrence.
DESIGN: Cross-sectional based on a closed cohort on 1 January 2022 with nationwide data on risk factors from 1969/1977.
SETTING: Denmark.
PARTICIPANTS: Whole population; closed cohort of individuals ≥65 years on 1 January 2022, and a subpopulation of responders in the 2010/2013 Danish National Health Survey.
INERTVENTION (EXPOSURES): Sixteen dementia risk factors: hypertension, cardiovascular disease, diabetes, hypercholesterolemia, obesity, smoking, alcohol, physical inactivity, depression, hearing loss, vision impairment, traumatic brain injury, sleep disorders, hospital-diagnosed infections, social isolation, and low education.
MEASUREMENTS: Period and point prevalence proportions of the dementia risk factors and of all possible combinations of factors (those occurring in ≥10 % of individuals). The prevalence estimates reflect a population-level view of persons who have experienced, were diagnosed, or were treated for the risk factors assessed.
RESULTS: In the whole population (N = 1,214,286) and the subpopulation (N = 88,565), 5 % had no risk factors, 12 % had only one, and 82 % had multiple. Hypertension was the most prevalent (57 %), and vision impairment the least (2 %). Men, individuals ≥85 years, and those with low education had the highest prevalence of risk factors (with exceptions).
CONCLUSIONS: Clustering of risk factors is very common, and findings emphasize the need to focus on multidomain interventions for dementia risk reduction that account for the clustering of risk.
CITATION:
Janet Janbek ; Thomas Munk Laursen ; Kasper Jørgensen ; Martin Mejlby Jensen ; Marie Holm Eliasen ; Anne Illemann Christensen ; Sebastian Walsh ; Andrew Sommerlad ; Carol Brayne ; Gunhild Waldemar (2025): Prevalence and co-occurrence of dementia risk factors in Denmark: A nationwide study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100365
APOE ε4-RELATED DIFFERENCES IN BRAIN STRUCTURE, FUNCTION, AND CONNECTIVITY AT MIDLIFE: A SCOPING REVIEW
Rikki Lissaman, Sidra Anjum, Andrea Quaiattini, M. Natasha Rajah
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BACKGROUND: The apolipoprotein E (APOE) ε4 allele is a major genetic risk factor for late-onset Alzheimer’s disease (AD), yet there is little consensus about how and when the allele exerts its influence on the brain.
METHODS: In this scoping review, we synthesized research examining APOE ε4-related differences on MRI-derived measures of brain structure, function, and connectivity in cognitively unimpaired, middle-aged adults (aged 40–65 years). Four online databases (Ovid MEDLINE, Ovid Embase, Ovid PsycINFO, Scopus) were searched on July 11, 2024, and forward/backward reference searching was conducted on identified studies. We extracted data on sample characteristics, methods, and key APOE ε4-related results.
RESULTS: Our pre-registered search strategy identified 30 relevant studies. Overall, we found little evidence of robust, consistent differences between APOE ε4 carriers and non-carriers at midlife, especially in relation to brain structure. However, among the studies identified, small samples were common, and limited consideration was afforded to factors such as sex and ethnocultural diversity.
CONCLUSIONS: Overall, the existing literature indicates that APOE ε4 exerts little, if any, influence on brain structure at midlife, while differences in brain function and connectivity remain poorly characterized.
CITATION:
Rikki Lissaman ; Sidra Anjum ; Andrea Quaiattini ; M. Natasha Rajah (2025): APOE ε4-related differences in brain structure, function, and connectivity at midlife: A scoping review. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100364
EARLY ALZHEIMER’S DISEASE (MILD COGNITIVE IMPAIRMENT OR MILD DEMENTIA): PREVALENCE, DIAGNOS-TICS, TREATMENT OPTIONS, AND GUIDELINES IN ASIA, AUSTRALASIA, AND PACIFIC NATIONS COUNTRIES
Jung-Lung Hsu, Kee Hyung Park, Peter K. Panegyres, Yao Hsien Huang, Young In Eom, Vinay Prusty, Lolita Stephanie Tan, Yat Fung Shea
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Early diagnosis of mild cognitive impairment (MCI) and Alzheimer’s disease (AD) with mild dementia is becoming increasingly important to enable patients to receive appropriate treatment with available amyloid-targeting therapies. Reviews of AD prevalence and diagnostic and treatment patterns typically focus on global or western populations, but the situation in Asia, Australasia, and Pacific Nations (AAPN) countries is less clear. We performed a narrative review of literature for AD in several AAPN countries, focusing on patients with MCI or mild dementia who may benefit from early treatment. Published information regarding AD incidence and prevalence and current practice in AAPN countries is limited and the nature of available information differs between countries. However, AAPN countries include some of the most rapidly aging populations and show the associated increasing trend of all-cause dementia prevalence observed globally. Although lecanemab and donanemab are now approved for AD with MCI and mild dementia in several AAPN countries, the most appropriate diagnostic pathway for patients with MCI and early AD is not established. Even though the AAPN region includes countries with routine access to advanced technologies, concerns have already been raised about the ability of healthcare systems in Australia, New Zealand, and Korea to respond to approvals of new AD therapies, including the need to ensure availability of biomarker testing and dementia specialists to allow patients to receive the early diagnosis required to enable appropriate treatment. Guidelines and national policies also need updating to differentiate between dementia subtypes and include amyloid-targeting therapies for eligible patients with early AD.
CITATION:
Jung-Lung Hsu ; Kee Hyung Park ; Peter K. Panegyres ; Yao Hsien Huang ; Young In Eom ; Vinay Prusty ; Lolita Stephanie Tan ; Yat Fung Shea (2025): Early Alzheimer’s disease (mild cognitive impairment or mild dementia): Prevalence, diagnostics, treatment options, and guidelines in Asia, Australasia, and Pacific nations countries. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100362
ASSOCIATIONS BETWEEN TRAUMATIC BRAIN INJURY AND THE PREVALENCE OF ALZHEIMER’S DISEASE DEMENTIA AND BEHAVIORAL AND PSYCHOLOGICAL SYMPTOMS OF DEMENTIA: A RETROSPECTIVE COHORT STUDY
Han-Kyeol Kim, Sojeong Park, Sung-Woo Kim, Yeonju Jin, Hokyung Lee, Jin Yong Hong, Ickpyo Hong, Min Seok Baek
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BACKGROUND: Traumatic brain injury is an environmental risk factor that may accelerate the progression of Alzheimer’s disease and behavioral and psychological symptoms of dementia in patients with mild cognitive impairment.
OBJECTIVES: To investigate whether traumatic brain injury in patients with mild cognitive impairment is associated with an increased risk of progression to Alzheimer’s disease dementia and behavioral and psychological symptoms of dementia.
DESIGN: A retrospective cohort study using the Korean National Health Insurance Service database.
SETTING: National-level health data covering healthcare utilization, diagnoses, prescriptions, and procedures in South Korea from January 2012 to December 2021.
PARTICIPANTS: Patients diagnosed with mild cognitive impairment between January 1, 2013, and December 31, 2016, were followed until Alzheimer’s disease dementia diagnosis, behavioral and psychological symptoms of dementia occurrence, death, or December 31, 2021. These patients were classified into two groups according to the presence of traumatic brain injury during the follow-up period.
MEASUREMENTS: Age at the time of mild cognitive impairment diagnosis, sex, income level, the presence of several chronic conditions, presence of traumatic brain injury, progression of Alzheimer’s disease dementia, and behavioral and psychological symptoms of dementia
RESULTS: We assessed 452,718 patients (mean age: 67.16 years). Traumatic brain injury was significantly associated with an increased risk of Alzheimer’s disease dementia progression (hazard ratio = 1.252, 95 % confidence interval: 1.206–1.301), particularly among patients aged <65 years (hazard ratio = 1.560, 95 % confidence interval: 1.391–1.749), and was linked to a higher risk of behavioral and psychological symptoms of dementia following Alzheimer’s disease dementia diagnosis (hazard ratio = 1.300, 95 % confidence interval: 1.181–1.431).
CONCLUSIONS: Our results underscore the importance of traumatic brain injury prevention in patients with mild cognitive impairment for mitigating the progression and neuropsychiatric complications of Alzheimer’s disease.
CITATION:
Han-Kyeol Kim ; Sojeong Park ; Sung-Woo Kim ; Yeonju Jin ; Hokyung Lee ; Jin Yong Hong ; Ickpyo Hong ; Min Seok Baek (2025): Associations between traumatic brain injury and the prevalence of Alzheimer’s disease dementia and behavioral and psychological symptoms of dementia: A retrospective cohort study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100360
ASSOCIATION BETWEEN CEREBRAL MICROBLEEDS AND COGNITION IN A MEMORY CLINIC POPULATION
Young Min Choe, Hyewon Baek, Min Soo Byun, Dahyun Yi, Hyejin Ahn, Gijung Jung, Chul-Ho Sohn, Dong Young Lee
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BACKGROUND: The cognitive consequences of cerebral microbleeds (CMBs) in memory clinic population with a diverse cognitive spectrum remain unclear.
OBJECTIVES: This study aimed to investigate how CMBs at different locations are associated with cognitive performance in a memory clinic population and whether these associations are independent of related small vessel disease (SVD) markers.
DESIGN: A cross-sectional study.
SETTING: A university hospital memory clinic. Data were collected from December 2004 to September 2014 and analyzed in June 2024.
PARTICIPANTS: A total of 910 participants, composed of 64 individuals with subjective cognitive decline, 399 with mild cognitive impairment (MCI), 339 with Alzheimer disease dementia (AD), 58 with vascular dementia and mixed dementia, and 50 with other types of dementia, were included.
MAIN OUTCOMES AND MEASURES: Summary scores for global cognition, memory, language, visuospatial function, and executive function measured by the Consortium to Establish a Registry for Alzheimer’s disease (CERAD) neuropsychological battery.
RESULTS: In the overall population, the presence of deep/infratentorial CMBs was significantly associated with executive dysfunction; however, this association was attenuated after adjusting for related SVD markers. When stratified by diagnostic subgroup, strictly lobar CMBs were significantly associated with impairments in global cognition and memory in the MCI group, independent of related SVD markers. In contrast, no significant associations between CMBs and cognitive domains were observed in the AD group.
CONCLUSIONS: These findings, based on memory clinic population with a broad cognitive spectrum, suggest that CMBs, depending on their location, may have different implications for cognitive function.
CITATION:
Young Min Choe ; Hyewon Baek ; Min Soo Byun ; Dahyun Yi ; Hyejin Ahn ; Gijung Jung ; Chul-Ho Sohn ; Dong Young Lee (2025): Association between cerebral microbleeds and cognition in a memory clinic population. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100340
LETTER TO THE EDITOR: REEVALUATING THE NEUROPROTECTIVE PROMISE OF DIETARY NITRATE: COMMENTARY ON RAJENDRA ET AL. (2025)
Parth Aphale, Himanshu Shekhar, Shashank Dokania
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CITATION:
Parth Aphale ; Himanshu Shekhar ; Shashank Dokania (2025): Letter to the Editor: Reevaluating the neuroprotective promise of dietary nitrate: Commentary on Rajendra et al. (2025). The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100339
REPLY TO LETTER TO THE EDITOR: “REEVALUATING THE NEUROPROTECTIVE PROMISE OF DIETARY NITRATE: COMMENTARY ON RAJENDRA ET AL. (2025)
Catherine Bondonno
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CITATION:
Catherine Bondonno (2025): Reply to letter to the editor: “Reevaluating the Neuroprotective promise of dietary nitrate: Commentary on Rajendra et al. (2025). The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100338
BRAIN LYMPHATIC DRAINAGE PATHWAYS, DEEP CERVICAL LYMPHATIC SURGERY, AND CURRENT INSIGHTS: A SYSTEMATIC REVIEW
Theodore Lahmar, Francois Thuau, Gaelle Pinard, Claire Boutoleau-Bretonniere, Pierre Perrot, Ugo Lancien
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The discovery of the glymphatic system and the later rediscovery of the meningeal lymphatic network have significantly changed our understanding of central nervous system (CNS) waste clearance. Aging is linked to a gradual decline in these clearance pathways, resulting in waste buildup. As a result, therapeutic strategies targeting cerebral lymphatic function have garnered growing interest, with lymphatic surgery emerging as a promising option.
We conducted a review until July 2025, providing an overview of the potential of lymphatic surgical techniques to enhance CNS metabolic waste clearance pathways as a therapeutic approach for brain lymphatic system disorders.
Currently available data are limited, nine publications addressing this approach. These studies explore an innovative technique involving lymphatico-venous anastomoses (LVA) targeting deep cervical lymphatic vessels to promote clearance for the treatment of Alzheimer’s or Parkinson’s diseases.
Cerebral lymphatic drainage is critical for effective brain waste elimination such as amyloid-β, phosphorylated tau, and α-synuclein, which are linked to neurodegenerative diseases. Viewing these lymphatic dysfunctions as a form of “cerebral lymphedema,” LVA, already used in treating peripheral lymphedema, shows potential as a therapeutic approach. Although clinical evidence is still limited, lymphatic supermicrosurgery presents promising therapeutic possibilities for neurodegenerative diseases and other conditions related to impaired CNS lymphatic outflow.
CITATION:
Theodore Lahmar ; Francois Thuau ; Gaelle Pinard ; Claire Boutoleau-Bretonniere ; Pierre Perrot ; Ugo Lancien (2025): Brain lymphatic drainage pathways, deep cervical lymphatic surgery, and current insights: A systematic review. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100335
PLASMA AND NEUROSTRUCTURAL BIOMARKERS IN THE CLINICAL-BIOLOGICAL CHARACTERIZATION OF EARLY STAGES OF THE ALZHEIMER\'S DISEASE CONTINUUM: FINDINGS FROM THE COMPOSTELA AGING STUDY
Montserrat Zurrón, Arturo Xosé Pereiro, Ana Isabel Rodriguez-Perez, Santiago Galdo-Álvarez, Juan José Ansede, Cristina Lojo-Seoane, Mónica Lindín, David Facal, Miguel Ángel Rivas-Fernández, María Campos-Magdaleno, Ángel Carracedo, José Luis Labandeira-Garcia, Fernando Díaz
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Recent technical advances in peripheral blood analysis have enabled precise quantification of Alzheimer´s Disease (AD) biomarkers in the early stages of the AD continuum, in an economical, non-invasive and safe manner. The main objective of this study was to contribute to the clinical-biological characterization of the initial stages of cognitive impairment by measurement of blood and neurostructural AD biomarkers in groups of participants classified according to their cognitive clinical phenotype.
Plasma concentrations of p-tau217, p-tau181, total tau, neurofilament light chain and amyloid-β 42/40 ratio biomarkers were measured along with APOE gene variants, hippocampal volume and cortical thickness of the AD signature regions. The cohort of 329 participants included Cognitively Unimpaired (CU), Subjective Cognitive Decline (SCD), single-domain amnestic Mild Cognitive Impairment (sd-aMCI), multidomain aMCI (md-aMCI), and single-domain non-amnestic MCI (sd-naMCI) groups.
P-tau217 concentrations were significantly higher in the md-aMCI and sd-aMCI groups than in the CU, SCD and sd-naMCI groups. P-tau181 concentrations were significantly higher in md-aMCI group than in CU, SCD and sd-naMCI groups. Hippocampal volume and AD signature cortical thickness were significantly lower in the md-aMCI group than in the CU, SCD and sd-naMCI groups. No across group differences were found in the distribution of carriers/non-carriers of APOE-ε4. Mediation analysis revealed that hippocampal volume and AD signature cortical thickness mediated the relationship between p-tau217 and p-tau181 levels and cognitive performance.
Sd-aMCI and md-aMCI represent two distinct and sequential clinical-biological stages of the AD continuum. Conversely, sd-naMCI does not appear to be associated with AD pathology. Finally, the SCD group does not seem to display a higher risk of progression along the AD continuum than the CU group.
CITATION:
Montserrat Zurrón ; Arturo Xosé Pereiro ; Ana Isabel Rodriguez-Perez ; Santiago Galdo-Álvarez ; Juan José Ansede ; Cristina Lojo-Seoane ; Mónica Lindín ; David Facal ; Miguel Ángel Rivas-Fernández ; María Campos-Magdaleno ; Ángel Carracedo ; José Luis Labandeira-Garcia ; Fernando Díaz (2025): Plasma and neurostructural biomarkers in the clinical-biological characterization of early stages of the Alzheimer's disease continuum: findings from the Compostela Aging Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100331
A PRELIMINARY ECONOMIC EVALUATION OF A POTENTIAL PROGRAM FOR THE PRIMARY PREVENTION OF ALZHEIMER’S DISEASE
Soeren Mattke, Jiahe Chen, Eric M Reiman
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INTRODUCTION: We evaluated the potential cost-effectiveness of a hypothetical primary prevention screening and treatment program to avert the biological and clinical onset of Alzheimer’s disease (AD) in cognitively unimpaired older adults.
METHODS: This hypothetical program would use an amyloid plaque-clearing antibody therapy monthly in the first six months and annually thereafter in cognitively unimpaired 55–79 year-old APOE4 carriers and 60–79 year-old non-carriers with a negative AD blood test (sensitivity and specificity of 0.9), averting the onset of moderately frequent neuritic amyloid plaques by 75 %. Lifetime hypothetical treatment outcomes were compared to natural history outcomes to estimate cost-effectiveness.
RESULTS: The program would be cost-effective up to a per-dose price of $1173 in APOE4 carriers and $307 in non-carriers or a lifetime cost of $20,167 and $5146, respectively.
DISCUSSION: Primary AD prevention could be cost-effective in older adults, especially in those at higher risk. Our findings and assumptions need to be confirmed with actual data.
CITATION:
Soeren Mattke ; Jiahe Chen ; Eric M Reiman (2025): A preliminary economic evaluation of a potential program for the primary prevention of Alzheimer’s disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100334
DEMENTIA RISK PREDICTION: A COMPARATIVE ANALYSIS OF THE ANU-ADRI, CAIDE, COGDRISK, LIBRA, AND LIBRA2 INDICES IN THE HUNT STUDY
Josephine Stubs, Ellen Melbye Langballe, Gill Livingston, Kaarin J. Anstey, Kay Deckers, Fiona E. Mathews, Mika Kivimäki, Bjørn Heine Strand, Anne-Marie Rokstad, Steinar Krokstad, Geir Selbæk
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BACKGROUND/OBJECTIVE:Dementia is a major global health concern, necessitating effective risk assessment tools and early intervention. This study compared the performance of five modifiable dementia risk indices – ANU-ADRI, CAIDE, CogDrisk, LIBRA, and LIBRA2 and a “demographics-only” (age, education) model.
METHODS: We analyzed data from 5247 Norwegian participants in the Trøndelag Health Study (HUNT4 70+, 2017–2019) and dementia risk indices from baseline data in HUNT3 (2006–2008). Logistic regression models assessed associations between standardized index scores and all-cause dementia and Alzheimer’s disease (AD) across age group (<65 vs. ≥65 years), sex, and APOE4 status.
RESULTS: During the mean follow-up of 10.6 (9.3–12.3) years (SD=0.74), all indices significantly predicted dementia and AD, though none outperformed the demographics-only model. CogDrisk showed significantly better discriminative ability than all other indices (0.76, 95 % CI:0.74–0.78; DeLong p < 0.05), followed by LIBRA (0.75, 95 % CI:0.72–0.77) and ANU-ADRI (0.74, 95 % CI:0.72–0.76). LIBRA2 (0.69, 95 % CI:0.66–0.71) and CAIDE (0.59, 95 % CI:0.56–0.61) had significantly lower accuracy (DeLong p < 0.001). Removing demographics maintained rank order but reduced accuracy across all indices. Stratified analyses showed stronger performance in those ≥65 years and females at HUNT3, while APOE4 status did not affect performance.
CONCLUSION: All indices were associated with dementia risk, with CogDrisk performing best across all conditions, and LIBRA2 and CAIDE performing weakest. No index outperformed a model including age and education only. Future research should refine risk indices for age- and sex-specific applications and assess whether simpler demographic models may suffice in some contexts.
CITATION:
Josephine Stubs ; Ellen Melbye Langballe ; Gill Livingston ; Kaarin J. Anstey ; Kay Deckers ; Fiona E. Mathews ; Mika Kivimäki ; Bjørn Heine Strand ; Anne-Marie Rokstad ; Steinar Krokstad ; Geir Selbæk (2025): Dementia risk prediction: A comparative analysis of the ANU-ADRI, CAIDE, CogDrisk, LIBRA, and LIBRA2 indices in the HUNT study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100326
CARDIOVASCULAR-KIDNEY-METABOLIC HEALTH, GENETIC SUSCEPTIBILITY, AND THE RISK OF DEMENTIA: A PROSPECTIVE COHORT STUDY
Yi-Peng Zhang, Jing-Wei Gao, Guang-Hong Liao, Qing-Yuan Gao, Ze-Gui Huang, Chuan-Rui Zeng, Yang-Wei Cai, Yong-Xiang Ruan, Zhi-Teng Chen, Yang-Xin Chen, Jing-Feng Wang
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BACKGROUND: The joint effect of cardiovascular-kidney-metabolic (CKM) health and genetic susceptibility on dementia remains unclear.
METHODS: This prospective cohort study utilized data from the UK Biobank. CKM syndrome was characterized by the presence of metabolic risk factors, cardiovascular disease, and chronic kidney disease. We employed Cox proportional hazards models to examine the association between CKM syndrome and dementia incidence, while also investigating the influence of genetic risk via polygenic risk score (PRS) and apolipoprotein E (APOE) ε4 status. We also examined the association between CKM syndrome and cognitive function via linear regression model.
RESULTS: Among 331,731 participants (mean ± SD age, 56.53 ± 8.1 years; 156,762 [47.26 %] male), 4413 (1.33 %) developed dementia during a mean follow-up of 12.8 years. Advanced CKM syndrome correlated with higher risk of dementia; compared to stage 0, HRs for dementia were 1.19 (95 % CI 1.01–1.39, P = 0.036), 1.26 (95 % CI 1.09–1.45, P = 0.002), and 2.06 (95 % CI 1.77–2.39, P < 0.001) for stages 1, 2, and 3–4, respectively. Genetic susceptibility further strengthened this association, and the synergistic effect of CKM syndrome, dementia PRS, and APOE ε4 status surpasses the individual contributions of any single factor. These findings remained robust in a series of subgroups and sensitivity analyses. Individuals in the later stages of CKM syndrome demonstrated poorer performance on cognitive function tests.
CONCLUSIONS: Poor CKM health was independently associated with cognitive impairment and an increased risk of dementia. The association between CKM syndrome and risk of dementia could be further strengthened by genetic susceptibility.
CITATION:
Yi-Peng Zhang ; Jing-Wei Gao ; Guang-Hong Liao ; Qing-Yuan Gao ; Ze-Gui Huang ; Chuan-Rui Zeng ; Yang-Wei Cai ; Yong-Xiang Ruan ; Zhi-Teng Chen ; Yang-Xin Chen ; Jing-Feng Wang (2025): Cardiovascular-kidney-metabolic health, genetic susceptibility, and the risk of dementia: A prospective cohort study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100325
ASSESSMENT OF DEMENTIA RISK SCORES IN PREDICTING MILD COGNITIVE IMPAIRMENT: A COMPARISON OF COGDRISK, CAIDE, LIBRA, AND ANU-ADRI
Md Hamidul Huque, Kaarin J. Anstey
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BACKGROUND: Given the lack of widely accessible dementia treatments, identifying individuals at high risk of dementia is vital for prevention. No prior study has compared multiple validated dementia risk tools for predicting mild cognitive impairment (MCI) across multiple datasets. We assess the performance of the CogDrisk, ANU-ADRI, CAIDE, and LIBRA in predicting MCI.
METHOD: Data were obtained from the ARIC, Whitehall II, and PATH Through Life cohorts. Participants without dementia or MCI at baseline were included. Risk scores were computed using available risk factors and analysed using logistic regression, with Area Under the Curve (AUC) estimates. Multiple imputation was used to evaluate the impact of missing data.
RESULTS: The ARIC (n = 5778), Whitehall II (n = 6387), and PATH (n = 2115) cohorts had mean baseline ages of 51.9, 55.8, and 62.5 years, with follow-ups of 28.2, 15.7, and 11.2 years, respectively. AUCs for MCI prediction were generally similar across tools and datasets. Dementia prevalence following MCI was highest in ARIC (23.6%), followed by Whitehall II (14.1%) and PATH (7.0%). In ARIC, CogDrisk showed slightly better AUCs for predicting MCI cases that progressed to dementia. Whitehall II and PATH showed mixed results, with wider confidence intervals for progressing MCI cases, and higher AUCs for non-progressing MCI cases using CogDrisk and ANU-ADRI. All tools performed consistently when predicting dementia without prior MCI.
DISCUSSION: Dementia risk scores demonstrated comparable performance of MCI prediction and are more sensitive for identifying cases that progress to dementia, supporting their greater utility for informing risk reduction strategies.
CITATION:
Md Hamidul Huque ; Kaarin J. Anstey (2025): Assessment of dementia risk scores in predicting mild cognitive impairment: A comparison of CogDrisk, CAIDE, LIBRA, and ANU-ADRI. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100324
A NOVEL EARLY IMAGING BIOMARKER FOR GLYMPHATIC FUNCTION: CEREBRAL CORTICAL ARTERIAL PULSATILITY INDEX FROM 2-MINUTE PHASE-CONTRAST MRI
Sung-Hye You, Byungjun Kim, Byungjun Kim, Kyung-Sook Yang, Hye-Won Park, InSeong Kim, SuGil Kim, Kyung Min Kim, Bo Kyu Kim, Jae Ho Shin
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BACKGROUND: Arterial pulsatility is one of the driving forces of glymphatic flow.
OBJECTIVES: To evaluate the feasibility of the pulsatility index (PI) of cortical arteries in the centrum semiovale (PICSO) as a novel non-invasive imaging biomarker for Alzheimer’s disease (AD) in the context of glymphatic function.
DESIGN: Retrospective cross-sectional study.
SETTING: Single tertiary academic center equipped with both 3.0 T MRI systems.
PARTICIPANTS: A total of 160 individuals were enrolled: 50 healthy volunteers, 46 cognitively normal controls, and 64 AD patients who underwent diffusion tensor imaging (DTI) and 2D phase-contrast MRI.
MEASUREMENTS: Diffusion Tensor Imaging Analysis along the Perivascular Space (DTI-ALPS) index and PICSO were assessed using 2D phase-contrast MRI. Correlations with age, DTI-ALPS index, and Mini-Mental State Examination (MMSE) scores were analyzed.
RESULTS: PICSO was significantly higher in the AD group than those in healthy volunteers (P<0.001) and cognitively normal aging (P=0.001) groups. PICSO correlated positively with age (rho=0.613, P<0.001) and negatively with both the DTI-ALPS index (rho=-0.439, P<0.001) and MMSE scores (rho=-0.486, P<0.001) in total group.
CONCLUSION: PICSO derived from 2D phase-contrast 3.0T MRI may serve as a novel imaging biomarker for Alzheimer’s disease in relation to glymphatic function.
CITATION:
Sung-Hye You ; Byungjun Kim ; Moonjung Hwang ; Kyung-Sook Yang ; Hye-Won Park ; InSeong Kim ; SuGil Kim ; Kyung Min Kim ; Bo Kyu Kim ; Jae Ho Shin (2025): A novel early imaging biomarker for glymphatic function: Cerebral cortical arterial pulsatility index from 2-Minute phase-contrast MRI. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100323
ASSOCIATION BETWEEN ALCOHOLIC BEVERAGE CONSUMPTION AND CEREBRAL SMALL VESSEL DISEASE BURDEN
Ben-Bo Xiong, Zi-Jie Wang, Zhi-Ming Li, Tian-Nan Yang, Xiang-Yu Li, Meng-Jie Lu, Qi Li
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BACKGROUND: The relationship between alcohol consumption and cerebral small vessel disease (CSVD) remains uncertain, particularly regarding drinking patterns and beverage types. We investigated how total alcohol intake, drinking frequency, and beverage-specific consumption are associated with CSVD burden using cross-sectional data.
METHODS: We included 27,326 UK Biobank (UKB) participants with MRI data, among whom 21,130 were current drinkers with full alcohol intake data. Alcohol consumption (frequency and beverage type) was self-reported. CSVD burden was measured via normalized white matter hyperintensity volume (WMHV) on T2-FLAIR MRI. Multivariable linear regression models adjusted for demographics, lifestyle, and vascular risk factors were used to examine associations.
RESULTS: Compared with non-drinkers, alcohol consumers had greater CSVD burden (Beta = 0.07; 95 % CI, 0.00–0.15). Among them, higher drinking frequency (≥5 times/week) was associated with increased CSVD burden (Beta = 0.10; 95 % CI, 0.07–0.13). High consumption of red wine, white wine/champagne, and spirits (≥7 servings/week) correlated positively with CSVD burden. In contrast, low-to-moderate beer/cider intake (≤3 servings/week) was inversely associated with burden. A dose-response relationship between total ethanol intake and CSVD burden was observed, with minimal intake (<1.97 g/day) showing a mild negative association, and higher levels increasing risk.
CONCLUSION: Greater frequency and volume of alcohol intake, especially from wine and spirits, are linked with higher CSVD burden. Conversely, low beer/cider consumption may be inversely associated with CSVD burden. These findings underscore the importance of moderating alcohol consumption to maintain cerebrovascular health.
CITATION:
Ben-Bo Xiong ; Zi-Jie Wang ; Zhi-Ming Li ; Tian-Nan Yang ; Xiang-Yu Li ; Meng-Jie Lu ; Qi Li (2025): Association between alcoholic beverage consumption and cerebral small vessel disease burden. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100322
IDENTIFYING THE OPTIMAL COMBINATIONS OF MODIFIABLE DEMENTIA RISK FACTORS TO TARGET IN MULTIDOMAIN INTERVENTION – THREE-YEAR LONGITUDINAL FINDINGS FROM THE CANADIAN LONGITUDINAL STUDY ON AGING Æ
Surim Son, Mark Speechley, Guangyong Zou, Manuel Montero-Odasso
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BACKGROUND: Recent multidomain prevention trials for dementia have shifted toward more targeted approaches, focusing on specific combinations of risk factors and interventions at certain times. However, the optimal combinations of modifiable risk factors that can be targeted to maximize intervention effect remain unclear. Identifying risk factor combinations with the highest prevalence and largest effect sizes can enhance efficiency of trial design.
OBJECTIVES: To identify risk factor combinations that are both highly prevalent and have the most detrimental effect on cognition, and to assess their interaction effect and synergism.
DESIGN: Longitudinal analysis of Canadian Longitudinal Study on Aging (CLSA).
SETTING: Community. PARTICIPANTS: 30,097 adults aged 45 to 85 at baseline.
MEASUREMENTS: The five most prevalent dyad, triad, and tetrad combinations of 12 modifiable risk factors were identified. Cognition was assessed with a composite Z-score from a neuropsychological test battery. Linear mixed effect models were used to examine the association between the identified combinations and 3-year cognitive changes. Interaction was assessed on additive scale, and synergism was explored.
RESULTS: The combinations that were both highly prevalent and had the most detrimental effect on global cognition were: hearing loss and physical inactivity for the dyad (mean difference in change score = -0.07 SD; 95 % CI: -0.09 to -0.06; p < 0.001; effect size = -0.28), hearing loss, physical inactivity, and hypertension for the triad (mean difference in change score = -0.07; 95 % CI: -0.09 to -0.06; p < 0.001; effect size = -0.28), and hearing loss, physical inactivity, hypertension, and sleep disturbance for the tetrad (mean difference in change score = -0.05; 95 % CI: -0.07 to -0.03; p < 0.001; effect size = -0.20). Similar patterns were observed for memory and executive function. A significant synergistic interaction was observed between hearing loss and physical inactivity for global cognition (p = 0.005).
CONCLUSIONS: The combined effect of multiple risk factors varied by its combinations. The combination of hearing loss and physical inactivity offers a greater potential benefit than other dyad combinations. Hypertension and sleep disturbance can be further included for triad and tetrad combinations. Auditory health and exercise should be prioritized for multidomain interventions.
CITATION:
Surim Son ; Mark Speechley ; Guangyong Zou ; Manuel Montero-Odasso (2025): Identifying the optimal combinations of modifiable dementia risk factors to target in multidomain intervention – Three-year longitudinal findings from the Canadian longitudinal study on aging. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100321
DIETARY INDEX FOR GUT MICROBIOTA (DI-GM) AND COGNITIVE FUNCTION: NHANES FINDINGS AND VALIDATION IN A HONG KONG COHORT WITH METAGENOMIC DATA
Hui Jiang, Jiashuo Zhang, Shuyi Li, Timothy Kwok, Siew C Ng, Allen Ting Chun Lee, Zhilu Xu
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BACKGROUND: The diet-gut-microbiota-brain axis is critical for maintaining brain health. The Dietary Index for Gut Microbiota (DI-GM), comprising beneficial and unfavorable components, may serve as a proxy for this connection, yet its association with cognition remains underexplored.
METHODS: This study examined the relationship between DI-GM, its components, and cognitive function in older adults using data from the National Health and Nutrition Examination Survey (NHANES). Findings were validated in an independent Hong Kong osteoporosis cohort (OS cohort) with gut metagenomic data to assess of microbiota’s mediating role in diet-cognition relationship. Cognitive assessment in NHANES utilized the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD), Animal Fluency Test (AFT), and Digit Symbol Substitution Test (DSST), while the OS cohort employed the Hong Kong version of the Montreal Cognitive Assessment (HK-MoCA). DI-GM was calculated from 24-hour dietary recalls. The diet-cognition associations were assessed by weighted multivariate regressions, supplemented by restricted cubic spline (RCS), subgroup, correlation network, and mediation analyses.
RESULTS: Higher DI-GM was significantly associated with better performance on DSST (OR=0.90; 95 % CI: 0.82, 0.99; p = 0.033). The beneficial-to-gut-microbiota score (BGMS) associated with lower psychometric mild cognitive impairment (p-MCI) risk (OR=0.88; 95 % CI: 0.80, 0.98; p = 0.022) and better CERAD immediate and delayed recall and DSST (all p < 0.05). The beneficial-to-gut-microbiota components like dietary fiber demonstrated protective effects across cognitive domains, while refined grains was associated with poorer cognition. In the OS cohort, higher dietary fiber intake correlated with higher HK-MoCA score (p < 0.05) and increased abundance of fermenting bacteria. Among these species, Eubacterium ventriosum mediated the beneficial effect of dietary fiber intake on dementia risk reduction, with an indirect effect of -0.014 (95 % CrI: -0.040, -0.001), accounting for approximately 12.7 % of the total effect.
CONCLUSION: Higher adherence to beneficial-to-gut-microbiota dietary patterns, as reflected by DI-GM, was associated with better cognitive function in older adults. These findings highlight the importance of a gut-microbiota-targeted diet in maintaining cognitive health.
CITATION:
Hui Jiang ; Jiashuo Zhang ; Shuyi Li ; Timothy Kwok ; Siew C Ng ; Allen Ting Chun Lee ; Zhilu Xu (2025): Dietary index for gut microbiota (DI-GM) and cognitive function: NHANES findings and validation in a Hong Kong cohort with metagenomic data. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100319
PROPORTION OF LIFE SPENT IN THE UNITED STATES AND COGNITIVE FUNCTIONING IN SPANISH-SPEAKING MIGRANTS: FINDINGS FROM THE BOSTON LATINO AGING STUDY
Isabel Solis, Randy Medrano, Lusiana Martinez, Nadeshka J. Ramirez, Nikole A. Bonillas Felix, Jorge Alcina, Averi Giudicessi, Jairo E. Martinez, Clara Vila-Castelar, Liliana A. Ramirez-Gomez, Marta Gonzalez Catalan, Daniel G. Saldana, Yakeel T. Quiroz
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Latino migrants are at increased risk for cognitive decline, yet the influence of immigration-related factors, such as time lived in the United States (U.S.), remains poorly understood. In the Boston Latino Aging Study (BLAST), 130 older Latino migrants completed a comprehensive neuropsychological assessment. We examined whether the proportion of years lived in the U.S. was associated with cognitive performance, adjusting for age, education, and acculturation. Greater time in the U.S was significantly associated with lower phonemic fluency, while no associations were found for other domains. Notably, 16 % of phonemic fluency errors involved English intrusions during a Spanish-language task, suggesting cross-linguistic interference. These findings underscore the importance of considering language dynamics and sociocultural context in studies of Latino cognitive aging.
CITATION:
Isabel Solis ; Randy Medrano ; Lusiana Martinez ; Nadeshka J. Ramirez ; Nikole A. Bonillas Felix ; Jorge Alcina ; Averi Giudicessi ; Jairo E. Martinez ; Clara Vila-Castelar ; Liliana A. Ramirez-Gomez ; Marta Gonzalez Catalan ; Daniel G. Saldana ; Yakeel T. Quiroz (2025): Proportion of life spent in the United States and cognitive functioning in Spanish-speaking migrants: Findings from the Boston Latino Aging Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100320
DIFFERENTIAL EFFECTS OF SOLUBLE AND PLAQUE AMYLOID ON LATE-LIFE DEPRESSION: THE MODERATING ROLE OF TAU PATHOLOGY
Gihwan Byeon, Suhyung Kim, Sunghwan Kim, Yoo Hyun Um, Sheng-Min Wang, Seunggyun Ha, Sonya Youngju Park, Yeong Sim Choe, Donghyeon Kim, Hyun Kook Lim, Chang Uk Lee, Dong Woo Kang
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BACKGROUND: Late-life depression frequently co-occurs with Alzheimer’s disease (AD); however, the interactive effects of amyloid-beta (Aβ) species and tau pathology on depressive symptoms remain unclear. Soluble oligomeric Aβ (OAβ) and amyloid plaques may differentially influence depression depending on tau burden.
OBJECTIVES: To examine how plasma OAβ and PET-measured amyloid plaque burden are associated with depressive symptoms across varying levels of tau pathology.
DESIGN: Cross-sectional analysis using generalized linear models with interaction terms, supported by stratified subgroup analyses and Johnson–Neyman procedures.
SETTING: Memory disorder clinic at a university-affiliated hospital.
PARTICIPANTS: A total of 103 individuals, including cognitively normal controls (n = 24), patients with mild cognitive impairment (n = 54), and amyloid-positive dementia (n = 25), all of whom underwent plasma biomarker testing and tau and amyloid PET imaging.
MEASUREMENTS: Depression was evaluated using the Cornell Scale for Depression in Dementia (CSDD), Hamilton Depression Rating Scale (HAM-D), and Geriatric Depression Scale–Short Version (GDS-SV). Plasma OAβ was measured by Multimer Detection System (MDS), and PET quantified amyloid and tau burden.
RESULTS: MDS-OAβ showed a significant negative interaction with tau PET SUVR on depression scores (FDR-adjusted p < 0.05). Higher OAβ levels were linked to greater depression severity in low-tau individuals, but inversely related in high-tau individuals. Amyloid plaque burden was associated with depression only in those with advanced tau pathology.
CONCLUSIONS: The association between amyloid pathology and depression differs depending on tau burden. Soluble OAβ may be a key contributor to depressive symptoms in early AD stages, while plaque effects become prominent later. These findings underscore the potential utility of OAβ as an early neuropsychiatric biomarker in AD and highlight the need to consider tau pathology when evaluating amyloid-related mood disturbances.
CITATION:
Gihwan Byeon ; Suhyung Kim ; Sunghwan Kim ; Yoo Hyun Um ; Sheng-Min Wang ; Seunggyun Ha ; Sonya Youngju Park ; Yeong Sim Choe ; Donghyeon Kim ; Hyun Kook Lim ; Chang Uk Lee ; Dong Woo Kang (2025): Differential effects of soluble and plaque amyloid on late-life depression: The moderating role of tau pathology. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100318
PSYCHIATRY MEETS NEURODEGENERATION – A COLLABORATIVE APPROACH TO DEMENTIA PREVENTION
Carolin Kurz, Martin Haupt, Stefanie Auer, Nicola Lautenschlager, Alexander Kurz
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The advent of amyloid-targeting therapies and biomarker-based risk stratification has transformed the understanding of Alzheimer’s disease and related disorders. These conditions are now recognized as chronic, detectable and modifiable, often presenting decades before clinical symptoms appear. While this paradigm shift enables earlier intervention, it also raises ethical and psychological challenges that necessitate a redefined role for psychiatry. Instead of merely supporting late-stage care, psychiatry is well-placed to facilitate risk communication, promote resilience, and encourage adaptive behavior in individuals navigating preclinical or prodromal neurodegeneration. This article outlines an ethical, stepwise communication framework, clarifies the distinction between diagnosis and probabilistic risk, and explores psychiatric contributions—from motivational models to lifestyle-based prevention—that bridge the gap between biological insight and subjective experience. By reinterpreting risk as a chance for intervention rather than resignation, psychiatry broadens the therapeutic scope and helps safeguard independence, dignity and quality of life—making it a pivotal participant in dementia prevention and individualized, person-centered care.
CITATION:
Carolin Kurz ; Martin Haupt ; Stefanie Auer ; Nicola Lautenschlager ; Alexander Kurz (2025): Psychiatry meets neurodegeneration – A collaborative approach to dementia prevention. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100317
ASSOCIATION OF SUGAR INTAKE WITH INCIDENT DEMENTIA IN THE UK BIOBANK: A PROSPECTIVE COHORT STUDY
Yue Che, Wenming Wei, Tingting Mao, Lina Qin, Hanchi Wang, Yijia Li, Weixuan Da, Jin Feng, Li Liu, Bolun Cheng, Huan Liu, Yan Wen, Yumeng Jia, Feng Zhang
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BACKGROUND: Excessive sugar intake has been implicated in increased dementia risk; however, existing studies are constrained by small sample sizes and a primary focus on total sugar, with limited investigation into specific sugar subtypes. This study explores the relationship between sugar intake, its subtypes, and the incidence of dementia.
METHODS: We analyzed 172,516 participants from the UK Biobank who completed at least one 24-hour dietary recall (Oxford WebQ). Cox proportional hazards models estimated the hazard ratios (HRs) and 95 % confidence intervals (95 % CIs) for total sugar and its subtypes (free sugar, fructose, glucose, sucrose, maltose, lactose, and other sugars) about the risk of dementia. Sex-stratified analyses were also performed.
RESULTS: Higher intakes of total sugar (HR = 1.292, 95 % CI = 1.148–-1.453) and free sugar intake (HR = 1.254, 95 % CI = 1.117–-1.408) were significantly associated with increased dementia risk. Positive associations were also observed for non-milk extrinsic sugars (HR = 1.321, 95 % CI = 1.175–-1.486) and sucrose (HR = 1.291, 95 % CI = 1.147–-1.452). These associations were evident in women, with higher intakes of total sugars, free sugars, glucose, sucrose, and non-milk extrinsic sugars independently linked to increased dementia risk, whereas no significant associations were found in men.
CONCLUSION: Higher consumption of total sugars, free sugars, sucrose, and non-milk extrinsic sugars confers increased dementia risk, particularly among women.
CITATION:
Yue Che ; Wenming Wei ; Tingting Mao ; Lina Qin ; Hanchi Wang ; Yijia Li ; Weixuan Da ; Jin Feng ; Li Liu ; Bolun Cheng ; Huan Liu ; Yan Wen ; Yumeng Jia ; Feng Zhang (2025): Association of sugar intake with incident dementia in the UK Biobank: a prospective cohort study. The Journal of Prevention of Alzheimer’s Disease (JPAD).https://doi.org/10.1016/j.tjpad.2025.100311
BLOOD PRESSURE AND ALZHEIMER’S DISEASE BIOMARKERS IN COGNITIVELY UNIMPAIRED ADULTS: A MULTICENTER STUDY
Mariona Osset-Malla, Aitana Martínez-Velasco, Gonzalo Sánchez-Benavides, Mariateresa Buongiorno, Alejandro de la Sierra, Mahnaz Shekari, Carolina Minguillon, Gwendlyn Kollmorgen, Clara Quijano-Rubio, Henrik Zetterberg, Kaj Blennow, David Vállez García, Marc Suárez-Calvet, Juan Domingo Gispert, Oriol Grau-Rivera, ALFA Study
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BACKGROUND: Hypertension is a modifiable risk factor for dementia, potentially influencing Alzheimer's disease (AD) pathology. Understanding this relationship is essential for developing interventions to reduce dementia risk.
OBJECTIVES: We investigated cross-sectional and longitudinal associations between blood pressure and AD biomarkers in cerebrospinal fluid (CSF) and amyloid (Aβ) positron emission tomography (PET) in cognitively unimpaired adults.
DESIGN: Prospective observational study.
SETTING: We analyzed data from cognitively unimpaired participants from three observational prospective European studies: ALFA+ (NCT02485730), EPAD-LCS (NCT02804789), and AMYPAD PNHS (EudraCT: 2018–002,277–22).
MEASUREMENTS: ALFA+ participants had either CSF biomarkers (CSF Aβ42, Aβ40, p-tau181, t-tau) and/or Aβ PET data. EPAD participants had CSF biomarkers (CSF Aβ42, p-tau181, t-tau), and AMYPAD participants had Aβ PET data. All participants had available data about diabetes, use of hypertensive medication, and waist-to-hip ratio. Multivariable linear regression models were used to analyze cross-sectional associations between systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure (PP) with CSF biomarkers or Aβ PET (Centiloid units, CL); longitudinal associations were tested by means of delta CL scores between baseline and follow-up to assess Aβ PET changes over time.
RESULTS: We included 405 participants from ALFA+ (mean age 61.1 years; 60 % female), 1104 from EPAD (mean age 64.8 years; 59.1 % female), and 340 from AMYPAD (mean age 71.8 years; 60 % female). In ALFA+, DBP was negatively associated with CSF Aβ40 (p = 0.016) and p-tau181 (p = 0.050), while there was a non-significant trend towards a positive association between SBP and CL over time (p = 0.058). In EPAD, DBP was negatively associated with CSF Aβ42 (p < 0.001) and p-tau181 (p = 0.014), while PP was positively associated with CSF Aβ42 (p = 0.024). In AMYPAD, SBP (p = 0.002) and PP (p = 0.003) were positively associated with CL at baseline, with a similar non-significant trend being found for DBP (p = 0.089). Higher DBP (p = 0.042) was significantly associated to increased CL over time, with a similar non-significant trend being found for SBP (p = 0.072). We did not find significant associations between blood pressure and longitudinal changes in CSF biomarkers.
CONCLUSIONS: Elevated blood pressure was associated with increased Aβ PET accumulation in cognitively unimpaired individuals. Further research is warranted to elucidate potential mechanisms underlying the negative associations between DBP and CSF biomarkers, which do not reflect the typical AD molecular signature. These findings highlight the relevance of high blood pressure as a potential risk factor for cognitive decline.
CITATION:
Mariona Osset-Malla ; Aitana Martínez-Velasco ; Gonzalo Sánchez-Benavides ; Mariateresa Buongiorno ; Alejandro de la Sierra ; Mahnaz Shekari ; Carolina Minguillon ; Gwendlyn Kollmorgen ; Clara Quijano-Rubio ; Henrik Zetterberg ; Kaj Blennow ; David Vállez García ; Marc Suárez-Calvet ; Juan Domingo Gispert ; Oriol Grau-Rivera ; ALFA Study (2025): Blood pressure and Alzheimer’s disease biomarkers in cognitively unimpaired adults: a multicenter study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100304
MEDICAL RISK FACTORS, APOE HAPLOTYPE, AND ALZHEIMER’S DISEASE: A LARGE-SCALE ANALYSIS
Uri Elias, Lidor Gazit, Roei Zucker, Amos Stern, Michal Linial, Gilles Allali, Tamir Ben-Hur, Gad A. Marshall, Shahar Arzy
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BACKGROUND: The multifactorial nature of Alzheimer’s disease (AD) has become increasingly evident. In addition to well-established features like neurodegeneration, amyloid-beta and tau deposition, or glial changes, other processes—such as metabolic, circulatory, and inflammatory factors—may also play a key role in driving or accelerating AD-related pathology and cognitive decline. These factors represent important targets for slowing disease progression.
OBJECTIVES: Although many studies have examined individual risk factors and meta-analyses have been performed, a large-scale, comprehensive comparison using formal medical data from a single, unified cohort is needed.
DESIGN: A retrospective case-control study leveraging comprehensive health database.
SETTING: Data were obtained from the UK-Biobank, a large (∼500 K people) population-based biomedical database in the United Kingdom.
PARTICIPANTS: The study included participants aged 40-69 at enrollment between 2006 and 2010, comprising 3,843 individuals who were clinically diagnosed with AD by August 2022 and 387,275 individuals without dementia or cognitive-impairment diagnoses.
MEASUREMENTS: ICD-10-coded diagnoses, recorded at least 10 years prior to AD diagnosis, were analyzed. Logistic regression was used to estimate the impact and significance of various medical conditions and their interactions with genetic risk factors, while accounting for demographic determinants.
RESULTS: The analysis identified 45 medical factors (96 ICD-10 entities) across multiple systems—particularly metabolic, circulatory, gastrointestinal, and sensorimotor—that significantly differentiated individuals with clinical AD from cognitively unimpaired individuals. Interaction analyses revealed that circulatory and metabolic factors had a weaker influence on AD risk in Apolipoprotein E ε4 carriers, suggesting a gene-environment interaction in disease susceptibility.
CONCLUSIONS: These findings enhance the understanding of system-level risk factors for clinical AD, highlight the relevance of less frequently reported factors in the AD prevention literature—such as gastrointestinal and sensorimotor disorders—and underscore the complex interplay between genetic susceptibility and vascular risk factors.
CITATION:
Uri Elias ; Lidor Gazit ; Roei Zucker ; Amos Stern ; Michal Linial ; Gilles Allali ; Tamir Ben-Hur ; Gad A. Marshall ; Shahar Arzy (2025): MEDICAL RISK FACTORS, APOE HAPLOTYPE, AND ALZHEIMER’S DISEASE: A LARGE-SCALE ANALYSIS. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100301
THE ROLE OF TAU, AMYLOID-Β AND NEUROINFLAMMATION IN THE ASSOCIATION BETWEEN COGNITION AND WHITE MATTER HYPERINTENSITIES IN A SOUTHEAST ASIAN COHORT
Gurveen Kaur Sandhu, Ashwati Vipin, Jacklyn Leonardo, Fatin Zahra Zailan, Pricilia Tanoto, Faith Phemie Hui En Lee, Xin Ying Sim, Smriti Ghildiyal, Yi Jin Leow, Shan Yao Liew, Gursimar Bhalla, Rasyiqah Binte Shaik Mohamed Salim, Bocheng Qiu, Nagaendran Kandiah
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BACKGROUND: Elevated Glial Fibrillary Acidic Protein (GFAP) is associated with increased Phosphorylated Tau 181 (pTau181) induced neurodegeneration in Alzheimer’s Disease.
OBJECTIVES: However, the role of GFAP and pTau181 in vascular/mixed dementias requires elucidation within the Southeast Asian context, where their burden is considerable.
DESIGN: Population based cross-sectional study.
SETTING: Biomarkers and Cognition Study, Singapore (BIOCIS).
PARTICIPANTS: Baseline data from n = 583 (40.3 % male), non-demented but at risk, Southeast Asian community participants, were included in this analysis. All participants displayed cognitive symptoms on the Subjective Memory Complaints Questionnaire, although they may or may not have objective cognitive deficits and did not meet the criteria for dementia as per the DSM – 5.
METHODS: Neuropsychological assessments for executive function evaluation, volumetric White Matter Hyperintensities (WMH) measurement and plasma biomarker expression, were determined in non-demented but at risk, Southeast Asian research participants. Partial correlation analysis demonstrated variable associations. Simple moderation analysis revealed the ability for plasma biomarkers to influence the relationship between executive function and WMH.
RESULTS: WMH burden positively correlated to Neurofilament-Light (NfL) and pTau181. Executive function and processing speed negatively correlated to WMH burden. GFAP positively correlated to pTau181 and negatively correlated to executive function. NfL, GFAP, pTau181, and Amyloid beta 42/Amyloid beta 40 (Aβ42/Aβ40) ratio independently moderated, the relationship between executive function/processing speed and WMH burden.
CONCLUSIONS: Inflammatory mechanisms represented by GFAP were linked to tau pathology and WMH and also moderated the association between WMH on cognitive performance.
CITATION:
Gurveen Kaur Sandhu ; Ashwati Vipin ; Jacklyn Leonardo ; Fatin Zahra Zailan ; Pricilia Tanoto ; Faith Phemie Hui En Lee ; Xin Ying Sim ; Smriti Ghildiyal ; Yi Jin Leow ; Shan Yao Liew ; Gursimar Bhalla ; Rasyiqah Binte Shaik Mohamed Salim ; Bocheng Qiu ; Nagaendran Kandiah (2025): The role of Tau, amyloid-β and neuroinflammation in the association between cognition and white matter hyperintensities in a southeast Asian cohort. The Journal of Prevention of Alzheimer’s Disease (JPAD).https://doi.org/10.1016/j.tjpad.2025.100300
TEMPORAL ASSOCIATIONS OF NEUROPSYCHIATRIC SYMPTOMS, DEMOGRAPHICS AND AMYLOID WITH SUBSEQUENT TAU BURDEN IN OLDER ADULTS
Pablo Aguilar-Dominguez, Eleni Palpatzis, Muge Akinci, Anna Canal-Garcia, Joana B. Pereira, Alexandre Bejanin, Eider M. Arenaza-Urquijo, Alzheimer’s Disease Neuroimaging Initiative
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BACKGROUND: Psychiatric symptoms are increasingly recognized as early manifestations of Alzheimer’s disease (AD). These symptoms may reflect or contribute to underlying neurobiological changes, including tau burden, which represents more advanced AD pathology. Understanding factors associated with tau burden may help identify individuals at elevated risk and improve early detection strategies.
OBJECTIVES: To investigate the temporal relationships between neuropsychiatric symptoms, demographic factors, and tau burden, by examining amyloid (Aβ)-dependent, -independent, and interactive associations.
DESIGN: Retrospective cohort study.
SETTING: Alzheimer’s Disease Neuroimaging Initiative.
PARTICIPANTS: We included 681 participants without dementia (mean age = 71.2 years, 51.8 % female).
MEASUREMENTS: The participants underwent tau PET scanning with prior amyloid PET and Neuropsychiatric Inventory (NPI) interview assessments clustered around three time periods relative to tau PET: closest (0 − 2 years), mid (3 − 5 years), and furthest (6 − 8 years). Linear regression analyses, adjusting for age and APOE ε4 alleles, examined associations of NPI scores, sex, education, and their Aβ-status interactions with tau burden.
RESULTS: Higher total NPI scores up to 2 years prior to tau PET were associated with greater tau burden independently of Aβ status, whereas anxiety symptoms demonstrated an Aβ-dependent relationship with tau. (NPI: β=0.117, 95 % CI: 0.049 to 0.185, p = 0.001, Anxiety: β=0.249, 95 % CI: 0.073 to 0.424, p = 0.006). NPI measured up to 5 years prior to tau PET interacted with Aβ on tau burden (0–2 years: β=0.272, 95 % CI: 0.136 to 0.407, p < 0.001, 3–5 years: β=0.336, 95 % CI: 0.127 to 0.544, p = 0.002). Sex and education showed minimal associations with tau at uncorrected statistical levels.
CONCLUSIONS: Neuropsychiatric symptoms were associated with tau burden up to two years before tau sampling, independently of Aβ, and interacted with Aβ status up to five years prior, suggesting that neuropsychiatric symptoms are related to tau in the short term and may represent manifestations of advancing AD pathology. Demographic factors showed minimal associations. These findings highlight the importance of evaluating neuropsychiatric and anxiety symptoms as potential indicators of increased tau pathology.
CITATION:
Pablo Aguilar-Dominguez ; Eleni Palpatzis ; Muge Akinci ; Anna Canal-Garcia ; Joana B. Pereira ; Alexandre Bejanin ; Eider M. Arenaza-Urquijo ; Alzheimer’s Disease Neuroimaging Initiative (2025): Temporal associations of neuropsychiatric symptoms, demographics and amyloid with subsequent tau burden in older adults. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100294
PREGNANCY HYPERTENSION IS ASSOCIATED WITH HIGHER P-TAU217 IN HEALTHY MIDLIFE WOMEN
Eu-Leong Yong, Beverly Wen Xin Wong, Darren Yuen Zhang Tan, Liang Shen, Benecia Wan Qing Thia, Joyce Ruifen Chong, Christopher Li-Hsian Chen
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INTRODUCTION: There is very limited knowledge on the relationship between pregnancy hypertension and the occurrence of pre-clinical Alzheimer's disease (AD).
METHODS: Community-dwelling midlife women without dementia were enrolled from well-woman clinics of the National University Hospital, Singapore. Sociodemographic parameters and history of pregnancy hypertension were obtained. Cognition was assessed using the Montreal Cognitive Assessment-Basic tool. Fasted blood samples were stored for batched analysis of renal function, APOE genotyping and p-tau217 levels using Simoa® ALZpath p-tau217 Advantage PLUS (Quanterix, MA, USA). General linear modelling was used to examine the association between pregnancy hypertension and p-tau217.
RESULTS: Among 743 women (mean age 62.9 ± 6.0; range: 50.7 to 76.6 years) enrolled, 68 (9.2%) reported pregnancy hypertension. General linear modelling showed that an older age [mean difference: 0.002 (95% CI: 0.001, 0.003)], mild cognitive impairment [0.016 (0.001, 0.032)], lower BMI [0.068 (0.027, 0.109)], eGFR<60 mL/min/1.73 m2 [0.132 (0.072, 0.193)] and the APOE4 carrier genotype [0.038 (0.018, 0.058)] were independently associated with higher serum p-tau217 levels. History of pregnancy hypertension remained significantly associated with subsequent higher serum p-tau217 [0.040 (0.013, 0.067)], after adjustment for age, mild cognitive impairment, hypertension, BMI, renal function, and APOE4 genotype status.
DISCUSSION: Pregnancy hypertension was associated with AD pathology with mean differences similar to high risk APOE4 carrier genotypes. Information on pregnancy hypertension could help physicians to identify women who might benefit from early p-tau217 screening for Alzheimer’s disease, allowing for early clinical intervention.
CITATION:
Eu-Leong Yong ; Beverly Wen Xin Wong ; Darren Yuen Zhang Tan ; Liang Shen ; Benecia Wan Qing Thia ; Joyce Ruifen Chong ; Christopher Li-Hsian Chen (2025): Pregnancy hypertension is associated with higher p-tau217 in healthy midlife women. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100316
CHOLINERGIC BASAL FOREBRAIN ATROPHY ACCELERATES COGNITIVE DECLINE VIA CORTICAL THINNING: THE MODERATING ROLE OF AMYLOID-Β PATHOLOGY IN PRECLINICAL ALZHEIMER’S DISEASE
Si Cen, Lijuan Wang, Meiling Qiu, Zhongqiang Xu, Li Xu, Rui Bao, Xiaolei Tang, Juanyu Gong, Jinting Wu, Zhiding Shao, Tonghua Zhang, Fan Yang, Wencai Ding, on behalf of the Harvard Aging Brain Study (HABS)
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BACKGROUND: Cholinergic basal forebrain (cBF) atrophy is a critical early marker of neurodegeneration in Alzheimer’s disease (AD). While cBF degeneration is linked to cognitive decline, the role of cortical thinning in this process, especially during the preclinical phase of AD, remains underexplored. Additionally, the impact of amyloid-β (Aβ) pathology on these relationships warrants further examination.
METHODS: We analyzed longitudinal structural MRI and PIB-PET data from 230 cognitively normal older adults enrolled in the Harvard Aging Brain Study, with a mean follow-up of six years. cBF volume and cortical thickness were quantified using FreeSurfer. Cognitive performance was assessed with the Preclinical Alzheimer Cognitive Composite-5 (PACC5). Linear mixed-effects models were used to investigate the longitudinal associations between cBF atrophy, cortical thinning, and cognitive decline. Mediation analyses explored whether cortical thinning mediated the relationship between cBF degeneration and cognitive decline, and the moderating role of Aβ burden was examined.
RESULTS: Progressive cortical thinning in multiple cognition-related regions was significantly associated with cBF atrophy. Mediation analysis revealed that cortical thinning accounted for approximately 44 % of the relationship between cBF degeneration and cognitive decline. These associations were more pronounced in individuals with elevated Aβ, suggesting a synergistic interaction between amyloid pathology and cholinergic system degeneration.
CONCLUSIONS: Our findings suggest that cBF atrophy accelerates cognitive decline through its impact on cortical thinning, with Aβ pathology further exacerbating these effects. These results highlight the potential of cBF and cortical thinning as early biomarkers for preclinical AD and underscore the importance of targeting cholinergic dysfunction in early intervention strategies.
CITATION:
Si Cen ; Lijuan Wang ; Meiling Qiu ; Zhongqiang Xu ; Li Xu ; Rui Bao ; Xiaolei Tang ; Juanyu Gong ; Jinting Wu ; Zhiding Shao ; Tonghua Zhang ; Fan Yang ; Wencai Ding ; on behalf of the Harvard Aging Brain Study (HABS) (2025): Cholinergic basal forebrain atrophy accelerates cognitive decline via cortical thinning: The moderating role of amyloid-β pathology in preclinical Alzheimer’s disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100315
DIETARY SUGAR INTAKE, GENETIC SUSCEPTIBILITY, AND RISK OF DEMENTIA: A PROSPECTIVE COHORT STUDY
Yu An, Limin Cao, Gang Zheng, Yashu Liu, Honghao Yang, Liangkai Chen, Yuhong Zhao, Xiaopeng Zhang, Yang Xia
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BACKGROUND: Sugar intake has been identified as a risk factor for incident dementia; however, the role of genetic susceptibility in such association remains unclear.
METHODS: This cohort study involved 158,408 participants from the UK Biobank to explore the effect of genetic susceptibility on the association between dietary sugar intake and dementia risk. Data on sugar intake were evaluated using repeated web-based 24-hour dietary recalls. Polygenic risk scores (PRS) for sugar metabolism (Triglyceride Glucose, TyG), gut microbiota, and disease susceptibility (Alzheimer's disease) were generated based on genome-wide association studies.
RESULTS: Over a median follow-up period of 9.94 years, 1,219 dementia cases (0.7%) were documented. There were significant positive dose-response relationships between sugar intake and dementia risk (non-free sugar: HR, 95% CI, Quartile 4 vs. Quartile 1 = 1.26, 1.04–1.52; free sugar: 1.43, 1.20–1.70). Genetic susceptibility, including TyG-PRS, gut microbiota, and disease susceptibility, showed a combined effect on the association between sugar intake and dementia risk. Notably, significant interactions were observed between sugar intake, PRS for Ruminococcaceae UCG-014 and dementia, as well as between free sugar, PRS for Oscillospira and dementia. Participants with lower PRS of Ruminococcaceae UCG-014, or higher PRS of Oscillospira, posed a higher risk of dementia due to sugar intake.
CONCLUSION: Both free and non-free sugar intake are independent risk factors for dementia incidence. The role of genetic susceptibility among such association cannot be ignored. These results underscore the importance of personalized nutritional interventions targeting both dietary habits and genetic risk profiles in dementia prevention strategies.
CITATION:
Yu An ; Limin Cao ; Gang Zheng ; Yashu Liu ; Honghao Yang ; Liangkai Chen ; Yuhong Zhao ; Xiaopeng Zhang ; Yang Xia (2025): Dietary sugar intake, genetic susceptibility, and risk of dementia: A prospective cohort study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100312
DISCLOSURE OF ALZHEIMER’S DISEASE BLOOD-BASED BIOMARKER RESULTS IN A PRIMARY CARE SETTING: OPPORTUNITIES AND CHALLENGES
Corey J. Bolton, Ayda Rostamzadeh, Nathaniel Chin, Nicole R. Fowler, Judith Heidebrink, Annalise Rahman-Fillipiak, Raymond R. Romano III, Lindsay R. Clark, Advisory Group on Risk Evidence Education in Dementia (AGREEDementia)
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Blood-based biomarkers (BBMs) for Alzheimer’s disease (AD) have advanced rapidly and may be a critical tool for broad community-based screening for AD and detection of AD pathology in individuals with cognitive impairment. To meet the impending demand for AD diagnosis, BBMs could be implemented in a primary care setting to maximize accessibility and efficiency. However, this primary care implementation would be associated with numerous challenges, including issues related to disclosure of test results to patients. In this perspective article, we highlight the need for and potential challenges of AD BBM results disclosure in a primary care setting. Drawing from existing studies of AD risk disclosure, we highlight key areas of consideration to maximize patient safety and comprehension of results. Resources are suggested to aid health systems in implementing BBM testing in primary care settings. Finally, we emphasize the need for further research on the accuracy of BBMs and the practice of disclosure in primary care settings.
CITATION:
Corey J. Bolton ; Ayda Rostamzadeh ; Nathaniel Chin ; Nicole R. Fowler ; Judith Heidebrink ; Annalise Rahman-Fillipiak ; Raymond R. Romano III ; Lindsay R. Clark ; Advisory Group on Risk Evidence Education in Dementia (AGREEDementia) (2025): Disclosure of Alzheimer’s disease blood-based biomarker results in a primary care setting: Opportunities and challenges. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100310
CORTICAL MICROSTRUCTURE IN FAMILIAL FRONTOTEMPORAL DEMENTIA ASSOCIATED WITH MAPT, GRN, AND C9ORF72 PATHOGENIC VARIANTS: LOOKING BEYOND ATROPHY
Lijuan Wang, Si Cen, Li Zhao, Junfeng Tang, Pengcheng Xu, Pusheng Quan, Wencai Ding, ARTFL-LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) Research Consortium
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BACKGROUND: This study aimed to evaluate cortical mean diffusivity (cMD) as a sensitive biomarker for early neurodegenerative changes in familial frontotemporal lobar degeneration (FTLD) associated with C9orf72, GRN, and MAPT mutations. We compared cMD with cortical thickness (cTH) in detecting subtle microstructural alterations and examined its association with clinical severity and neurofilament light chain (NFL) concentrations.
METHODS: We analyzed data from 322 participants, including symptomatic carriers of C9orf72 (n = 85), GRN (n = 56), and MAPT (n = 58) mutations, along with 123 healthy controls. Cortical microstructure was assessed using both cTH and cMD. Clinical severity was evaluated with the CDR plus NACC FTLD scale, and plasma NFL was measured as a marker of neuroaxonal injury.
RESULTS: C9orf72 carriers exhibited the most widespread cortical thinning and increased cMD, while GRN and MAPT carriers showed more regionally restricted alterations. Across all mutation groups, cMD demonstrated higher sensitivity than cTH in detecting early changes. Furthermore, cMD values were significantly correlated with CDR plus NACC FTLD scores and NFL concentrations, underscoring its relevance to disease progression.
CONCLUSION: Cortical mean diffusivity outperforms cortical thickness in detecting early microstructural changes in familial FTLD. Its strong association with both clinical severity and neurodegeneration biomarkers highlights its potential utility for early diagnosis, disease monitoring, and individualized therapeutic strategies in FTLD.
CITATION:
Lijuan Wang ; Si Cen ; Li Zhao ; Junfeng Tang ; Pengcheng Xu ; Pusheng Quan ; Wencai Ding ; ARTFL-LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) Research Consortium (2025): Cortical microstructure in familial frontotemporal dementia associated with MAPT, GRN, and C9orf72 pathogenic variants: Looking beyond atrophy. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100306
COMPARATIVE ANALYSIS OF THE BURDEN OF YOUNG-ONSET AND LATE-ONSET DEMENTIA IN CHINA FROM 1990 TO 2021: A STUDY BASED ON GBD 2021 DATA
Ke-qiang Lu, Ke-jia Lu, Zheng-jun Ji
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BACKGROUND: Most epidemiological studies on dementia in China have focused on the elderly population, with a lack of systematic comparisons between the burden of young-onset dementia (YOD) and late-onset dementia (LOD).
METHODS: Based on data from the Global Burden of Disease (GBD) study, this research systematically evaluated changes in the burden of YOD and LOD in China over different time periods. The analysis employed average annual percentage change (AAPC), Bayesian age-period-cohort (BAPC) modeling, decomposition analysis, risk factor attribution analysis, health inequality analysis, and frontier analysis.
RESULTS: AAPC analysis showed that the growth rate of YOD has significantly outpaced that of LOD since 2012. Forecasting results indicated that the age-standardized rates for both YOD and LOD are expected to continue rising in the future. Decomposition analysis revealed that between 1990 and 2021, the main drivers of the increasing YOD burden shifted from population growth to epidemiological changes and population aging, whereas population growth remained the dominant driver for LOD. Risk factor analysis indicated that the impact of high BMI on both YOD and LOD has become increasingly pronounced. Health inequality and frontier analyses suggested that, although disparities in YOD and LOD burden across different SDI regions were not significant, there remains substantial room for improvement in managing both conditions in China.
CONCLUSION: In recent years, YOD has exhibited a more rapid increase compared to LOD, with its driving forces gradually shifting from population-related factors to epidemiological transitions. This highlights the need to strengthen identification and intervention strategies targeting younger and middle-aged populations. Tobacco use, high fasting plasma glucose, and high BMI are key modifiable risk factors shared by both YOD and LOD, with particular attention needed on the sustained impact of high BMI. Although international disparities in health inequality are not pronounced, China still holds considerable potential for improvement in the prevention and control of both YOD and LOD. Future interventions should be more forward-looking, systematic, and tailored to specific population groups.
CITATION:
Ke-qiang Lu ; Ke-jia Lu ; Zheng-jun Ji (2025): Comparative analysis of the burden of young-onset and late-onset dementia in China from 1990 to 2021: A study based on GBD 2021 data. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100307
SYSTEMATIC REVIEW AND META-ANALYSIS OF RURAL-URBAN DISPARITIES IN ALZHEIMER’S DISEASE DEMENTIA PREVALENCE
Abe Mollalo, Mackenzie Kramer, Maxwell Cutty, Benyamin Hoseini
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BACKGROUND: The prevalence of Alzheimer’s disease (AD) dementia varies between rural and urban areas worldwide, with studies reporting mixed patterns. In this study, we conducted a systematic review and meta-analysis to pool the odds ratio (OR) of rural-to-urban prevalence and explored contributing regional and socioeconomic factors.
METHODS: We performed comprehensive searches in PubMed, MEDLINE, CINAHL, Web of Science, and Scopus (January 2000-August 2024) for peer-reviewed studies reporting individual-level AD dementia prevalence comparisons between rural and urban settings. A random-effects model was used to calculate pooled OR at a 95 % confidence interval (CI). Prespecified subgroup analyses examined variations by WHO-defined regions, healthcare expenditure, income level, and educational attainment.
RESULTS: The meta-analysis incorporated 19 studies (22 datasets, N = 584,863) and found significantly higher AD dementia prevalence in rural areas (pooled OR = 1.247, 95 % CI: 1.059–1.468), with considerable between-study heterogeneity (I2=95.5 %). Regional subgroup analyses revealed marked disparities in the Western Pacific (OR = 1.416, 95 % CI: 1.083–1.851) and Southeast Asia (OR = 1.382, 95 % CI: 1.058–1.805), contrasting with nonsignificant findings in the Americas (OR = 0.989, 95 % CI: 0.785–1.247). Socioeconomic stratification showed pronounced rural disadvantages in: (1) lower healthcare expenditure regions (≤7.5 % GDP: OR = 1.268, 95 % CI: 1.043–1.542) and (2) among lower-middle to upper-middle income countries (OR = 1.260, 95 % CI: 1.030–1.542). This disparity attenuated in high-income settings (OR = 1.206, 95 % CI: 0.979–1.486) and in regions with healthcare expenditure >7.5 % GDP (OR = 1.16, 95 % CI: 0.87–1.53). Educational stratification revealed significant rural-urban disparities in regions with lower educational attainment (≤8.1 mean schooling years: OR=1.43, 95 % CI: 1.15–1.79). In contrast, regions with higher educational attainment (>8.1 years) showed no significant difference (OR=1.05, 95 % CI: 0.89–1.25).
CONCLUSION: This review provides useful evidence that AD dementia prevalence is higher in rural areas than in urban areas, particularly in resource-limited settings. Our findings call for targeted rural interventions in vulnerable regions and further research into how healthcare infrastructure and education jointly influence AD dementia disparities.
CITATION:
Abe Mollalo ; Mackenzie Kramer ; Maxwell Cutty ; Benyamin Hoseini (2025): Systematic review and meta-analysis of rural-urban disparities in Alzheimer’s disease dementia prevalence. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100305
CHILDHOOD MALTREATMENT CONFERS LONG-TERM RISK FOR COGNITIVE IMPAIRMENT: A PROSPECTIVE INVESTIGATION
Stephanie Assuras, Kellie Courtney, Molly Maxfield, Shaina Shagalow, Sara Sherer, Jennifer J. Manly, Cathy Spatz Widom
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IMPORTANCE: Childhood maltreatment has been associated with greater risk for Alzheimer's disease and related dementias. Better understanding of this association will have implications for prevention and intervention efforts.
OBJECTIVE: To determine whether individuals with documented histories of childhood maltreatment and matched controls differ in cognitive functioning in late midlife and whether maltreatment leads to higher rates of cognitive impairment.
DESIGN: Prospective cohort design.
SETTING: Metropolitan Midwestern county area.
PARTICIPANTS: Children with documented maltreatment histories and demographically matched controls were followed up into late midlife (N = 447, Mage = 59.4). Control group children were matched to maltreated children on age, sex, race and ethnicity, and approximate family social class during the time the cases were processed.
EXPOSURE: Children with documented cases of physical and sexual abuse and neglect during 1967 to 1971 in the county juvenile (family) or adult criminal courts. Cases were restricted to children ages 0–11 at the time of the maltreatment to ensure that the temporal direction of consequences was clear.
MAIN OUTCOME AND MEASURES: Using a comprehensive neuropsychological assessment battery, multiple tests of cognitive functioning and the Functional Activities Questionnaire were administered. Participants were categorized as having cognitive impairment with no dementia (CIND) or dementia.
RESULTS: Individuals with histories of childhood maltreatment performed worse on all 12 neuropsychological tests, compared to matched controls (Cohen’s d 0.28 to 0.42) and had significantly higher risk for CIND [AOR = 1.86), amnestic CIND [AOR = 1.68) and non-amnestic [AOR = 1.48). About 13 % of maltreated individuals met criteria for amnestic CIND. Few met criteria for dementia. Males, females, Blacks, Whites, older and younger individuals, and those physically or sexually abused or neglected showed the effects of maltreatment.
CONCLUSIONS AND RELEVANCE: Cognitive repercussions of childhood maltreatment continue into late midlife. Findings reinforce the importance of early detection and preventive interventions that may decrease risks associated with childhood maltreatment in later adulthood. Because we use documented court cases from childhood, this design reduces potential biases associated with reliance on retrospective self-reports of childhood adversities. To our knowledge, this is the first study to examine long-term consequences of childhood neglect for cognitive impairment.
CITATION:
Stephanie Assuras ; Kellie Courtney ; Molly Maxfield ; Shaina Shagalow ; Sara Sherer ; Jennifer J. Manly ; Cathy Spatz Widom (2025): Childhood maltreatment confers long-term risk for cognitive impairment: A prospective investigation. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100303
ORGAN-SPECIFIC PROTEOMIC AGING AND COGNITIVE PERFORMANCE: IMPLICATIONS FOR RISK PREDICTION OF ALZHEIMER’S DISEASE AND RELATED DEMENTIAS IN OLDER ADULTS
Sujin Kang, Susan Baker, Benedict Hayhoe, Geraint Price, Gerald Novak, Janice Wong, Lefkos Middleton, Oliver Robinson
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BACKGROUND AND OBJECTIVES: Biological aging, characterized by cellular and molecular changes, may play a key role in neurodegenerative diseases. While recent proteomic advancements have introduced new aging clocks, widespread validation remains necessary. This study evaluated organ-specific and cognition-enriched proteomic clocks in relation to chronological age and cognitive change.
METHODS: We analyzed plasma proteomic data from the CHARIOT PRO SubStudy (N = 409), measured using the SomaScan assay (version 4.1) at four time points over three years (months 0, 12, 24, and 36). Using published proteomic organ age weights, we calculated conventional, organ-specific, and cognition-enriched biological ages and compared them with chronological age. Adjusted multilevel regression analyses assessed associations between baseline proteomic AgeGaps (biological−chronological age differences) and cognitive performance over 54 months.
RESULTS: The cohort (mean age: 71.8 ± 5.5 years; 50.1 % female) showed moderate to strong correlations between proteomic ages and chronological age (r = 0.37–0.80; MAE = 4.2–2.7). Over three years, AgeGaps increased across the conventional, organismal, muscle, liver, artery, and immune systems, ranging from 2.1 ± 1.9 to 1.0 ± 2.3 years. The artery AgeGap was most strongly associated with cognitive decline, with conventional and organismal AgeGaps showing similar patterns. Higher baseline AgeGap z-scores (i.e., greater biological age) in the artery and brain were associated with poorer cognition, as measured by the Repeatable Battery for the Assessment of Neuropsychological Status Total Scores (Coeff. −3.0, 95 % CI: −3.4, −2.5; and −1.1, 95 % CI: −1.5, −0.6) and the Preclinical Alzheimer's Cognitive Composite (Coeff. −0.5, 95 % CI: −0.6, −0.4; and −0.14, 95 % CI: −0.3, −0.03).
CONCLUSIONS: These findings highlight the interplay between neurological function and cardiovascular aging in cognitive decline. Organ-specific biological age assessments may aid in the early detection of age-related changes, informing personalized interventions. Our study underscores the importance of proteomic aging signatures in elucidating Alzheimer’s disease mechanisms and other neurodegenerative conditions, advocating for an integrated approach to brain and cardiovascular health.
CITATION:
Sujin Kang ; Susan Baker ; Benedict Hayhoe ; Geraint Price ; Gerald Novak ; Janice Wong ; Lefkos Middleton ; Oliver Robinson (2025): Organ-specific proteomic aging and cognitive performance: Implications for risk prediction of Alzheimer’s disease and related dementias in older adults. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100274
JPAD Volume 12, N°08 - 2025
EDITORIAL: BRAIN-PENETRANT ANTIBODIES FOR ALZHEIMER’S DISEASE: THE NEXT GENERATION?
C.H. van Dyck
J Prev Alz Dis 2025;8(12)
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CITATION:
C.H. van Dyck (2025): Editorial: Brain-penetrant antibodies for Alzheimer’s disease: The next generation?. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100314
EDITORIAL : TARGETING TAU FOR ALZHEIMERS DISEASE THROUGH OGA INHIBITION
Michael S. Rafii
J Prev Alz Dis 2025;8(12)
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CITATION:
Michael S. Rafii (2025): Editorial: Targeting tau for Alzheimers disease through OGA inhibition. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100309
EDITORIAL: GENE AND GENETIC THERAPIES IN ALZHEIMER’S DISEASE AND OTHER DEMENTIAS
Robert C. Alexander
J Prev Alz Dis 2025;8(12)
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CITATION:
Robert C. Alexander (2025): Editorial: Gene and genetic therapies in Alzheimer’s disease and other dementias. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100313
EDITORIAL : STRUCTURAL EQUATION MODELING CONFIRMS INTERACTION OF ALZHEIMER’S DISEASE AND VASCULAR DISEASE IN HIPPOCAMPAL INJURY
Gary A. Rosenberg
J Prev Alz Dis 2025;8(12)
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CITATION:
Gary A. Rosenberg (2025): Editorial: Structural equation modeling confirms interaction of Alzheimer’s disease and vascular disease in hippocampal injury. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100255
BISPECIFIC BRAIN-PENETRANT ANTIBODIES FOR TREATMENT OF ALZHEIMER’S DISEASE
Dag Sehlin, Greta Hultqvist, Wojciech Michno, Ximena Aguilar, Amelia D Dahlén, Enrica Cerilli, Nadja M Bucher, Sara Lopes van den Broek, Stina Syvänen
J Prev Alz Dis 2025;8(12)
Show summaryHide summaryThe emerging class of bispecific antibodies represents a significant advancement in Alzheimer’s disease (AD) immunotherapy by addressing the limited brain concentrations achieved with conventional monoclonal antibodies. The majority of bispecific antibodies developed for AD treatment utilize transferrin receptor (TfR1)-mediated transcytosis to enhance blood-brain barrier (BBB) penetration, resulting in higher and more uniform brain concentrations compared to conventional antibodies. This improved delivery has demonstrated superior efficacy in reducing brain amyloid-beta (Aβ) burden. Additionally, TfR1-mediated delivery may help mitigate adverse effects such as amyloid-related imaging abnormalities (ARIA). This is likely achieved by a reduction in antibody accumulation at vascular Aβ deposits, resulting from the combined effects of lower dosing and a different brain entry route when using bispecific antibodies. Besides targeting Aβ, bispecific antibodies have been engineered to address other key pathological features of AD, including tau pathology and neuroinflammatory targets, which are critical drivers of disease progression. These antibodies also show promise in diagnostic applications, particularly as radioligands for antibody-based positron emission tomography (immunoPET), leveraging their rapid brain delivery and efficient and specific target engagement. Moreover, the principles of bispecific antibody technology have been adapted for use beyond immunotherapy. The incorporation of TfR1-binding domains into enzymes, antisense oligonucleotides, or viral vectors such as adeno-associated viruses broadens their therapeutic potential. These approaches may enable more efficient treatment strategies, not only for AD but also for other neurological disorders, by facilitating the delivery of diverse therapeutic agents across the BBB.
CITATION:
Dag Sehlin ; Greta Hultqvist ; Wojciech Michno ; Ximena Aguilar ; Amelia D Dahlén ; Enrica Cerilli ; Nadja M Bucher ; Sara Lopes van den Broek ; Stina Syvänen (2025): Bispecific brain-penetrant antibodies for treatment of Alzheimer’s disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2025.8
RESULTS OF THE FIRST-IN-HUMAN, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, SINGLE- AND MULTIPLE-ASCENDING DOSE STUDY OF BIIB113 IN HEALTHY VOLUNTEERS
Flavia C. Nery, Maciej Kaliszczak, Ben Suttle, Lori Jones, Shuang Wu, Jing Xie, Gioacchino Curiale, Esin Yesilalan, Beth Hirschhorn, Denisa Wilkes, Dave Singh, Martin Bolin, Sangram Nag, Andrea Varrone, Per Stenkrona, Anton Forsberg Morén, Christer Halldin, Jeffrey Yachnin, H. Moore Arnold, Szofia Bullain, Jaren Landen, Diana Gallagher, Heike Hering
J Prev Alz Dis 2025;8(12)
Show summaryHide summaryBACKGROUND: Preclinical studies have demonstrated that inhibition of the O-linked β-N-acetylglucosaminidase enzyme increases tau O-linked β-N-acetylglucosaminylation and may attenuate tau pathology in Alzheimer’s disease.
OBJECTIVES: To examine the safety, tolerability, pharmacokinetics, and target occupancy of single- and multiple-ascending oral doses of the small-molecule O-linked β-N-acetylglucosaminidase inhibitor, BIIB113.
DESIGN: Study 276HV101 was a first-in-human, multicenter, Phase 1, randomized, double-blind, placebo-controlled, single- and multiple-ascending dose trial.
SETTING: 72 participants were enrolled from February 2022 through July 2023.
PARTICIPANTS: Adult healthy female and infertile/vasectomized male participants.
INTERVENTION: In the single-ascending dose substudy, participants received a single dose of placebo or BIIB113 0.5, 3, 15, or 50 mg. In the 14-day multiple-ascending dose substudy, participants received placebo or BIIB113 15 or 50 mg once daily. In the target occupancy substudy, participants received either a single dose of BIIB113 0.5 or 3 mg or a once-daily dose of BIIB113 0.5 mg.
MEASUREMENTS: Safety and tolerability were measured by incidence of adverse events. Pharmacokinetic and concentration-time profiles were assessed. Target occupancy was evaluated using the carbon-11 BIO-1819,578 radioligand.
RESULTS: BIIB113 was generally well tolerated. Pharmacokinetics were linear over the dose range, with a half-life of approximately 30 h. Administration with food decreased the rate but did not affect the extent of absorption. There were no clinically meaningful differences in pharmacokinetics between elderly and nonelderly participants. Multiple once-daily doses of BIIB113 0.5 mg maintained a target occupancy of ≥90 % up to 48 h.
CONCLUSIONS: BIIB113 was well tolerated and achieved high levels of target occupancy.
CITATION:
Flavia C. Nery ; Maciej Kaliszczak ; Ben Suttle ; Lori Jones ; Shuang Wu ; Jing Xie ; Gioacchino Curiale ; Esin Yesilalan ; Beth Hirschhorn ; Denisa Wilkes ; Dave Singh ; Martin Bolin ; Sangram Nag ; Andrea Varrone ; Per Stenkrona ; Anton Forsberg Morén ; Christer Halldin ; Jeffrey Yachnin ; H. Moore Arnold ; Szofia Bullain ; Jaren Landen ; Diana Gallagher ; Heike Hering (2025): Results of the first-in-human, randomized, double-blind, placebo-controlled, single- and multiple-ascending dose study of BIIB113 in healthy volunteers. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100302
CTAD TASKFORCE: GENETIC THERAPIES IN ALZHEIMER’S DISEASE
D. Jakabek, A.M. Isaacs, B. De Strooper, M. Tuszynski, R. Lane, O. Uspenskaya, E. McDade, M.S. Rafii, C.J. Mummery
J Prev Alz Dis 2025;8(12)
Show summaryHide summaryThere are an increasing number of genetic approaches to treating Alzheimer’s disease and other dementias, with some promising results from early-phase trials. This prompted the convention of the first EU-US CTAD Task Force on genetic therapies in Alzheimer’s disease in October 2024. Preclinical studies and clinical trials of genetic therapies in Alzheimer’s disease and other dementias are presented here with key lessons for the field. Importantly, there are several challenges and opportunities unique to neurogenetic therapies which were reviewed and discussed, including means of genetic manipulation, adverse events, monitoring, timing of therapy, and the importance of patient involvement in trial design. Continued collaboration across disciplines will accelerate development of neurogenetic therapeutics.
CITATION:
D. Jakabek ; A.M. Isaacs ; B. De Strooper ; M. Tuszynski ; R. Lane ; O. Uspenskaya ; E. McDade ; M.S. Rafii ; C.J. Mummery (2025): CTAD taskforce: genetic therapies in Alzheimer’s disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100269
CEREBROVASCULAR DISEASE IN ALZHEIMER\'S DISEASE: BRAIN STRUCTURE AS A CRITICAL MEDIATOR OF COGNITIVE DECLINE
Chao Tang, Yaqi Ding, Jiaxin Yang, Dian He
J Prev Alz Dis 2025;8(12)
Show summaryHide summaryBACKGROUND: The co-occurrence of Alzheimer's disease and cerebrovascular disease is increasingly prevalent in aging populations, yet the mechanisms of their interaction remain incompletely understood. This study aims to investigate the associations between CVD and AD and their composite effects on cognitive function, identifying key mediating pathways in these relationships.
METHODS: Participants underwent standardized clinical evaluations, detailed neuropsychological testing, and comprehensive neuropathological examinations. Structural equation modeling with multiple mediation analyses was employed to disentangle direct and indirect effects of vascular pathology on cognition and identify key mediating pathways. Relationships between specific cognitive domain assessments and whole brain and hippocampal volumes were analyzed, while interactions between traditional AD biomarkers (amyloid, tau) and vascular factors were examined.
RESULTS: CVD substantially increased AD risk. Structural equation modeling revealed that vascular factors influence cognitive performance primarily through hippocampal atrophy, APOE genotype, and cerebral atrophy. Participants with concomitant AD +CVD pathology displayed a distinctive hybrid pattern of brain-cognition relationships, with stronger correlations between hippocampal atrophy and cognitive performance compared to pure AD or CVD cases. Pathway-specific analysis demonstrated that hippocampal atrophy served as the strongest mediator of vascular effects on cognition, followed by cerebral atrophy and APOE genotype.
CONCLUSION: Our findings demonstrate that cerebrovascular disease significantly increases the risk of Alzheimer's disease and substantially influences its clinical expression through multiple pathways, with structural brain changes serving as critical mediators of vascular effects on cognition. These results highlight the importance of addressing vascular health as an integral component of strategies to prevent and treat Alzheimer's disease and related cognitive disorders.
CITATION:
Chao Tang ; Yaqi Ding ; Jiaxin Yang ; Dian He (2025): Cerebrovascular disease in Alzheimer's disease: Brain structure as a critical mediator of cognitive decline. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100209
THE EFFECT OF MODIFIED DONANEMAB TITRATION ON AMYLOID-RELATED IMAGING ABNORMALITIES WITH EDEMA/EFFUSIONS AND AMYLOID REDUCTION: 18-MONTH RESULTS FROM TRAILBLAZER-ALZ 6
Hong Wang, Emel Serap Monkul Nery, Paul Ardayfio, Rashna Khanna, Diana Otero Svaldi, Sergey Shcherbinin, Wen Xu, Scott W. Andersen, Paula M. Hauck, Dawn A. Brooks, Emily C. Collins, Stephen Salloway, Mark A. Mintun, John R. Sims
J Prev Alz Dis 2025;8(12)
Show summaryHide summaryThe TRAILBLAZER-ALZ 6 study (NCT05738486) evaluated the effect of different donanemab dosing regimens on amyloid-related imaging abnormalities with edema/sulcal effusions (ARIA-E). The modified titration arm met the primary outcome and significantly reduced ARIA-E frequency compared with the standard dosing while maintaining a similar pharmacodynamic effect on amyloid reduction at 24 weeks. Primary outcome and 52-week data were previously published. Completed study results at 76 weeks are reported here. ARIA-E frequencies were 15.6 % and 24.2 % in the modified titration and standard arms, respectively. ARIA-E radiographic severity was significantly lower (p = 0.015) with modified titration than with standard dosing. Additionally, symptomatic ARIA-E frequency was lower with modified titration versus standard dosing (2.8 % vs 4.8 %). The frequency of serious adverse events was comparable between the modified titration and standard dosing arms. A more gradual titration of donanemab dosing significantly reduced ARIA-E risk versus standard dosing.
CITATION:
Hong Wang ; Emel Serap Monkul Nery ; Paul Ardayfio ; Rashna Khanna ; Diana Otero Svaldi ; Sergey Shcherbinin ; Wen Xu ; Scott W. Andersen ; Paula M. Hauck ; Dawn A. Brooks ; Emily C. Collins ; Stephen Salloway ; Mark A. Mintun ; John R. Sims (2025): The effect of modified donanemab titration on amyloid-related imaging abnormalities with edema/effusions and amyloid reduction: 18-month results from TRAILBLAZER-ALZ 6. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100266
THE ALZHEIMER’S DISEASE COOPERATIVE STUDY – ACTIVITIES OF DAILY LIVING DEPENDENCE SCORE: REVISION AND VALIDATION OF AN ALGORITHM EVALUATING PATIENT DEPENDENCE ACROSS THE SPECTRUM OF AD SEVERITY
Julie M. Chandler, Claire J. Lansdall, Wenyu Ye, Fiona McDougall, Mark Belger, Balazs Toth, Xiaojuan Mi, Kaycee M. Sink, Alexandra S. Atkins
J Prev Alz Dis 2025;8(12)
Show summaryHide summaryBACKGROUND: Increasing dependence on informal and formal caregivers in Alzheimer’s disease (AD) contributes to high societal cost. Treatments that delay time to increased dependence/care needs would be clinically meaningful, but these outcomes are rarely collected in early AD clinical trials. The 2015 ADCS-ADL dependence algorithm was created to estimate level of dependence in AD.
OBJECTIVES: To revise the original dependence algorithm to improve accuracy of dependence scores (DS) across AD severity, including early symptomatic AD.
DESIGN: Secondary data analysis.
SETTING: Community cohort; randomized clinical trial.
PARTICIPANTS: 14,000 participants enrolled across GERAS-EU observational study and 12 AD clinical trials.
MEASUREMENTS: Three-phase algorithm revision: 1) reassess ADCS-ADL items to identify those appropriate for assessing dependence; 2) (a) assign individual item responses to degrees of assistance and (b) to operationalize assignment of DS based on extent of total assistance needed; and 3) validate revised algorithm in multiple datasets across AD severity from mild cognitive impairment due to AD to moderate-severe AD.
RESULTS: The revised DS (0-6) algorithm classified most participants with early symptomatic AD as independent or moderately independent (DS<3) at baseline. With disease progression over time, the proportion of participants who were mildly to fully dependent (DS≥3) increased across AD severity. Increased DS was associated with incremental worsening of clinical outcomes.
CONCLUSIONS: The revised ADCS-ADL DS algorithm provides a supplementary approach to evaluate the impact of emerging treatments on independence/care needs in AD and may be useful in clinical trials where the ADCS-ADL has been collected.
CITATION:
Julie M. Chandler ; Claire J. Lansdall ; Wenyu Ye ; Fiona McDougall ; Mark Belger ; Balazs Toth ; Xiaojuan Mi ; Kaycee M. Sink ; Alexandra S. Atkins (2025): The Alzheimer’s Disease Cooperative Study – Activities of Daily Living dependence score: revision and validation of an algorithm evaluating patient dependence across the spectrum of AD severity. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100261
BRIDGING THE GAP: A CONVERSION FRAMEWORK FOR CDR-SB AND MOCA SCORES IN ALZHEIMER\'S DISEASE AND RELATED DEMENTIA
Babak Haji, Quanwu Zhang, Amir Abbas Tahami Monfared
J Prev Alz Dis 2025;8(12)
Show summaryHide summaryBACKGROUND: Accurate assessment of cognitive impairment is essential to effective Alzheimer’s disease (AD) management and research. However, the absence of validated methods to translate scores between widely used instruments—such as the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) in trials and the Montreal Cognitive Assessment (MoCA) in clinical practice—poses a significant barrier. This limits data harmonization, impedes cross-study comparability, and complicates the integration of clinical and research evidence. Bridging this gap is critical for consistent staging, longitudinal monitoring, and data-driven decision-making in AD and related dementias.
OBJECTIVES: To develop and validate bidirectional score conversion tables between CDR-SB and MoCA using a large, diverse cohort spanning the full spectrum of cognitive function.
DESIGN: Retrospective, cross-sectional analysis using equipercentile equating with log-linear smoothing. Optimal smoothing parameters were selected by minimizing mean squared error, Akaike Information Criterion, and Bayesian Information Criterion. Concordance was assessed using Spearman’s rank correlation and Bland-Altman plots.
SETTING: National Alzheimer’s Coordinating Center (NACC), aggregating standardized assessments from 35 U.S.-based Alzheimer’s Disease Research Centers.
PARTICIPANTS: 23,717 individuals (59,871 visits) with same-day CDR-SB and MoCA assessments from January 2015 to September 2024, spanning normal cognition, mild cognitive impairment (MCI), and dementia.
INERVENTION: None; this was a secondary analysis of existing data.
MEASUREMENTS: Primary measures included CDR-SB (0–18; higher = greater impairment) and MoCA (0–30; higher = better cognition). Bidirectional crosswalk tables were derived using equipercentile equating.
RESULTS: CDR-SB and MoCA scores showed strong inverse correlation (Spearman’s ρ = –0.68; p < 0.001). Crosswalk tables demonstrated good agreement across the cognitive spectrum and performed consistently in the full cohort and an AD-specific subgroup.
CONCLUSIONS: This study provides the first validated, bidirectional CDR-SB–MoCA crosswalk, supporting data harmonization and consistent interpretation of cognitive severity across research and clinical settings.
CITATION:
Babak Haji ; Quanwu Zhang ; Amir Abbas Tahami Monfared (2025): Bridging the gap: A conversion framework for CDR-SB and MoCA scores in Alzheimer's disease and related dementia. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2025.8
NEW-GENERATION ANTIDIABETIC MEDICATIONS AND DEMENTIA RISK IN OLDER ADULTS WITH TYPE 2 DIABETES: A RETROSPECTIVE COHORT STUDY
Avi Cohen, Stephen Z Levine, Gabriel Vainstein, Michal Schnaider Beeri, Galit Weinstein
J Prev Alz Dis 2025;8(12)
Show summaryHide summaryBACKGROUND: New-generation antidiabetic medications may have therapeutic potential for dementia, beyond their glycemic effects. However, information from observational studies exploring the association between new-generation antidiabetic use and dementia risk is limited.
OBJECTIVES: To examine the association between new-generation antidiabetic medication use and dementia risk.
DESIGN: Retrospective cohort study using electronic health records of a large non-profit health maintenance organization.
PARTICIPANTS: 84,798 dementia-free individuals aged ≥65y with type 2 diabetes.
MEASUREMENTS: Antidiabetic medication exposure was based on purchased prescriptions and was used as a time-varying variable. Exposure periods were defined as periods in which either dipeptidyl peptidase-4 inhibitors (DPP-4i), sodium-glucose cotransporter-2 inhibitors (SGLT-2i), or glucagon-like peptide-1 analogs (GLP-1a) or their combinations were used, otherwise unexposed. Dementia classification was based on the International Classification of Diseases, Ninth Revision codes or antidementia medication prescriptions. Cox regression models were fitted to quantify the association between antidiabetic medication use and incident dementia. Models were adjusted for 13 potential sources of confounding using inverse-probability weighting.
RESULTS: Among 84,798 individuals with a mean diabetes onset age of 66.4 ± 7.5 years, the median follow-up for dementia risk was 8.7 years (Q1-Q3: 5.4–12.8). Dementia was diagnosed in 11,642 (13.7%) individuals. New-generation medication use was associated with reduced dementia risk (HR = 0.69; 95% CI, 0.66–0.73) and by drug classes (DPP-4i, HR 0.67 [95% CI 0.63–0.71]; SGLT-2i, 0.63 [95% CI 0.56–0.70], GLP-1a, 0.61 [95% CI 0.54–0.69].
CONCLUSION: The results of this large-scale study suggest that new-generation antidiabetic medication use may be associated with lower dementia risk in older adults with T2D.
CITATION:
Avi Cohen ; Stephen Z Levine ; Gabriel Vainstein ; Michal Schnaider Beeri ; Galit Weinstein (2025): New-generation antidiabetic medications and dementia risk in older adults with type 2 diabetes: A retrospective cohort study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100199
A MODELLING APPROACH TO DERIVE POPULATION-SPECIFIC CUTOFF FOR PLASMA P-TAU217
Tau Ming Liew, Alzheimer\'s Disease Neuroimaging Initiative
J Prev Alz Dis 2025;8(12)
Show summaryHide summaryPlasma pTau-217 shows promise for detecting Alzheimer’s disease, but needs population-specific cutoffs for effective use. Conventional cutoff determination relies on invasive or costly gold-standards, limiting scalability. This study evaluated Finite Mixture Modelling (FMM) for establishing cutoffs without gold-standards. FMM was applied to derive cutoffs for Lumipulse plasma p-Tau217 and p-Tau217/Aβ42 ratio among 1039 ADNI participants, with validation conducted in a subset with amyloid PET data (n = 711). Additionally, simulations were conducted to determine the minimum sample size for reliable FMM estimation. The results showed that FMM-derived cutoffs effectively classified participants into brain amyloid-negative, -positive, and -indeterminate groups, with an indeterminate proportion <20 %, negative and positive predictive values near or above 90 %, and with p-Tau217/Aβ42 outperforming p-Tau217. These FMM-derived cutoffs demonstrated test performance that surpassed several previously-established cutoffs, including the recent FDA-approved cutoff. At least 900 samples were needed for reliable cutoff estimation. In conclusion, this study demonstrated the effectiveness of a modelling approach for estimating plasma p-Tau217 cutoffs without reliance on gold-standards. This approach simplifies the determinating of population-specific cutoffs and facilitates adoption of plasma p-Tau217 in communities lacking access to gold-standards, including some LMICs.
CITATION:
Tau Ming Liew ; Alzheimer's Disease Neuroimaging Initiative (2025): A modelling approach to derive population-specific cutoff for plasma p-Tau217. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100264
IMPACT OF CARDIOVASCULAR RISK FACTORS ON PLASMA BIOMARKERS IN PREDICTION OF ALZHEIMER\'S AND CEREBROVASCULAR NEUROPATHOLOGY
Camilo Bermudez, Jeremy A. Syrjanen, Nikki H. Stricker, Alicia Algeciras-Schimnich, Naomi Kouri, Walter K. Kremers, Ronald C. Petersen, Clifford R. Jack Jr, David S. Knopman, Dennis W. Dickson, Darren M. Rothberg, Christina M. Moloney, Baayla D.C. Boon, Aivi T. Nguyen, R. Ross Reichard, Melissa E. Murray, Michelle M. Mielke, Prashanthi Vemuri, Jonathan Graff-Radford
J Prev Alz Dis 2025;8(12)
Show summaryHide summaryBACKGROUND: Plasma biomarkers for Alzheimer’s disease and neurodegeneration have shown accurate prediction of underlying neuropathology. However, chronic cardiovascular risk factors such as diabetes and hypertension are associated with plasma biomarker levels and can influence the accurate prediction of underlying neuropathologic changes.
OBJECTIVE: To understand the interaction between plasma biomarkers of Alzheimer’s disease and neurodegeneration with cardiovascular risk factors in relation to neuropathologic change in a heterogenous population to ascertain a more accurate utilization of these biomarkers.
DESIGN: Retrospective, case-control study.
SETTING: Population-based, Olmstead county, Minnesota, USA.
PARTICIPANTS: Three-hundred and fifty-one participants (aged 87.4 ± 7.5 years) with brain autopsy and antemortem plasma biomarker testing.
MEASUREMENTS: Plasma biomarker testing for Aβ42/40, p-tau181, GFAP, and NfL using Quanterix Simoa assays. Cardiovascular risk factors were quantified by a composite score of cardiovascular metabolic conditions (CMC) consisting of a binary history of diabetes, congestive heart failure, stroke, coronary artery disease, atrial fibrillation, hypertension, or dyslipidemia. Plasma biomarkers and cardiovascular metabolic conditions score were Z-scored and neuropathologic scales were binarized into high and low categories. Outcomes included elevated microvascular (Kalaria) and macrovascular (Strozyk) neuropathologic scales as well as Alzheimer’s disease neuropathologic change (ADNC), Thal phase, Braak stage, and neuritic plaque score. Multivariate logistic regression models incorporated interaction terms between plasma biomarkers and CMC while controlling for age, sex, cognitive impairment, and BMI.
RESULTS: We observed that at higher cardiovascular metabolic conditions score, the association between GFAP and overall ADNC (OR = 0.61 [0.42, 0.89]), Thal phase (OR = 0.48 [0.33, 0.71]), and Braak Stage (OR = 0.56 [0.37, 0.84]), became weaker, while the association with Strozyk score (OR = 1.65 [1.11, 2.46]) was stronger with higher CMC. Meanwhile, at higher CMC Aβ42/40 became more strongly negative with high Braak stage (OR = 0.63 [0.47, 0.85]), neuritic plaque score (OR 0.70 [0.52, 0.95]), Kalaria score (OR = 0.71 [0.57, 0.88]), and Strozyk score (OR = 0.60 [0.43, 0.83]). The association between p-tau181 and Thal phase (OR = 1.43 [1.00, 2.04]) was stronger at higher CMC while the association between p-tau181 and Strozyk score (OR = 0.47 [0.31, 0.71]) was weaker at higher CMC. There was no interaction between NfL and CMC score for any metric of neuropathologic change.
CONCLUSION: Understanding how cardiovascular risk factors can modulate plasma biomarkers is important for their interpretation with respect to underlying pathology and their clinical application in screening, diagnosis, and prognosis of neurodegenerative diseases.
CITATION:
Camilo Bermudez ; Jeremy A. Syrjanen ; Nikki H. Stricker, ; Alicia Algeciras-Schimnich ; Naomi Kouri ; Walter K. Kremers ; Ronald C. Petersen ; Clifford R. Jack Jr ; David S. Knopman ; Dennis W. Dickson ; Darren M. Rothberg ; Christina M. Moloney ; Baayla D.C. Boon ; Aivi T. Nguyen ; R. Ross Reichard ; Melissa E. Murray ; Michelle M. Mielke ; Prashanthi Vemuri ; Jonathan Graff-Radford (2025): Impact of cardiovascular risk factors on plasma biomarkers in prediction of Alzheimer's and cerebrovascular neuropathology. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.1002248
EARLY DETECTION OF ALZHEIMER’S DISEASE USING SMALL RNAS. RESULTS FROM THE EPAD COHORT
Tobias Sikosek, Marco Heuvelman, Jagoda Mika, Mustafa Kahraman, Julia Jehn, Maurice Frank, Alberto Daniel-Moreno, Jessika Ceiler, Jasmin Skottke, Marta Sanchez-Delgado, Patrick Neubert, Christina Rudolf, Kaja Tikk, Rastislav Horos, Jeffrey L. Cummings, Josie Butchart, Craig Ritchie, Jean Manson, Bruno R. Steinkraus, the EPAD consortium
J Prev Alz Dis 2025;8(12)
Show summaryHide summaryBACKGROUND: Alzheimer's disease (AD) is the most common form of dementia, and early diagnosis is crucial to enable effective interventions. Currently, Alzheimer's disease is diagnosed through cognitive assessments, brain imaging and fluid biomarkers focused on determining amyloid (A) and, tau (T) protein levels as well as neurodegeneration (N) in the AT(N) framework. Prognostic biomarkers for predicting cognitive decline within the amyloid positive (Aβ+) individuals would further strengthen the framework.
OBJECTIVES: This study evaluated small RNAs as novel auxiliary biomarkers, independent of the AT(N) framework, either alone or in combination with established protein markers, for detecting the earliest cognitive decline in AD.
DESIGN: The European Prevention of Alzheimer’s Disease (EPAD) clinical trial platform is a prospective, multi-center study designed to investigate biomarkers for preclinical and prodromal AD.
SETTING: Peripheral whole blood RNA sequencing was performed on participants across Europe with no cognitive impairment or very mild cognitive impairment (MCI), stratified by cerebrospinal fluid amyloid levels.
PARTICIPANTS: 1,913 participants, 50 years or older and free of dementia diagnosis at enrollment, were analyzed.
INTERVENTION: (if any) Not applicable.
MEASUREMENTS: Ultra-deep small RNA sequencing was performed on whole blood samples using a refined blocking protocol to eliminate highly abundant erythroid small RNAs, and thereby to open sequencing bandwidth for the discovery of less abundant biomarker RNAs. Biomarker RNAs were deconvolved into plasma or blood cell origin and analyzed for functional relevance. We define high and low amyloid groups based on a cutoff on the p-tau181/Aβ1-42 ratio as determined from cerebrospinal fluid.
RESULTS: We identified a combination of small RNAs that predicted early cognitive decline (Clinical Dementia Rating of 0.5) with an area under the receiver-operator curve of ∼0.7. Notably, when focusing on individuals with cognitive decline and high amyloid burden (Aβ+), the predictive accuracy improved to an AUC of 0.77. This performance could be extended to the entire cohort when combining blood RNA and CSF amyloid markers (AUC 0.76). We conducted bioinformatic analyses to interrogate the likely functional relevance of these small RNAs, uncovering several links to dementia-relevant pathways, including neuronal, cardiovascular, and inflammatory activities. Our findings also suggest that small nucleolar RNAs warrant further investigation as potential disease-relevant markers, in addition to microRNAs.
CONCLUSIONS: Integrating small RNA biomarkers with protein-based assays offers preliminary evidence for stratifying MCI, particularly within the amyloid positive continuum. Small nucleolar RNAs and microRNAs warrant further exploration as complementary diagnostic tools, and their use may enable more precise and effective interventions.
CITATION:
Tobias Sikosek ; Marco Heuvelman ; Jagoda Mika ; Mustafa Kahraman ; Julia Jehn ; Maurice Frank ; Alberto Daniel-Moreno ; Jessika Ceiler ; Jasmin Skottke ; Marta Sanchez-Delgado ; Patrick Neubert ; Christina Rudolf ; Kaja Tikk ; Rastislav Horos ; Jeffrey L. Cummings ; Josie Butchart ; Craig Ritchie ; Jean Manson ; Bruno R. Steinkraus ; the EPAD consortium (2025): Early detection of Alzheimer’s disease using small RNAs. Results from the EPAD cohort. The Journal of Prevention of Alzheimer’s Disease (JPAD).https://doi.org/10.1016/j.tjpad.2025.100257
CAN NON-PHARMACOLOGICAL INTERVENTIONS CHANGE LEVELS OF NEUROFILAMENT LIGHT IN OLDER ADULTS AT RISK OF DEMENTIA? A SECONDARY ANALYSIS OF THE SCD-WELL RANDOMIZED CLINICAL TRIAL
Lehané Masebo, Tim Whitfield, Harriet Demnitz-King, Amanda Heslegrave, Géraldine Poisnel, Antoine Lutz, Eric Frison, Miranka Wirth, Abdul Hye, Frank Jessen, Nicholas J. Ashton, Henrik Zetterberg, Natalie L. Marchant
J Prev Alz Dis 2025;8(12)
Show summaryHide summaryBACKGROUND: Older adults with subjective cognitive decline (SCD) and/or elevated neurofilament light (NfL), a neurodegeneration biomarker, are at increased risk of dementia. Non-pharmacological interventions offer a promising strategy for reducing dementia risk, yet none have utilized NfL as a marker of response in dementia prevention trials.
OBJECTIVE: To investigate the effects of two non-pharmacological interventions on NfL in older adults with SCD.
DESIGN: SCD-Well was an 8-week observer-blinded, randomized, clinical trial with 6-month follow-up, and was a part of the Horizon 2020 European Union-funded "Medit-Ageing" project. Data were analyzed from June 2022 to August 2024.
SETTING: Memory clinics at four sites in France, Germany, Spain, and UK.
PARTICIPANTS: Participants were enrolled from March 2017 to January 2018 after fulfilling SCD research criteria and performing within the normal range on cognitive testing. Of the 147 participants enrolled, 140 were included in this secondary analysis (7 did not consent to venipuncture).
INTERVENTIONS: Participants were randomly allocated to the Caring Mindfulness-Based Approach for Seniors (CMBAS) intervention or a structurally matched Health Self-Management Program (HSMP).
MEASUREMENTS: Plasma NfL was measured at baseline (V1), post-intervention (V2), and 6-month follow-up (V3), using Single molecule array technology, and log-transformed for analyses.
RESULTS: 137 older adults with SCD provided NfL data (mean [SD] age: 72.7 [6.8] years; 62.0 % female; CMBAS, n = 70; HSMP, n = 67). NfL data were available at V1 (n = 136), V2 (n = 119) and V3 (n = 115). The visit-by-arm interaction was not statistically significant, and no significant changes in NfL were observed within the CMBAS or HSMP arms from V1 to V2. However, within the HSMP arm, NfL levels reduced from V1 to V3 (-0.10, 95 % confidence interval [-0.18 to -0.02]). Modified intention-to-treat analyses, which included 140 participants, supported these findings, and additionally recorded significant reductions in the HSMP arm from V1 to V2 (n = 140, -0.07 [-0.14 to -0.00]).
CONCLUSIONS: In this study, NfL levels were reduced at 6-month follow-up after a health self-management program. Future interventions with longer duration, extended follow-up and clinical endpoints will help clarify whether NfL reductions are sustained over extended timeframes and translate to lower dementia incidence.
CITATION:
Lehané Masebo ; Tim Whitfield ; Harriet Demnitz-King ; Amanda Heslegrave ; Géraldine Poisnel ; Antoine Lutz ; Eric Frison ; Miranka Wirth ; Abdul Hye ; Frank Jessen ; Nicholas J. Ashton ; Henrik Zetterberg ; Natalie L. Marchant (2025): Can non-pharmacological interventions change levels of neurofilament light in older adults at risk of dementia? A secondary analysis of the SCD-Well randomized clinical trial. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100299
THE DIFFERENTIAL EFFECT OF STRENGTH, COGNITIVE AND AEROBIC TRAINING COMBINATIONS ON COGNITIVE PERFORMANCE AND FUNCTIONAL ABILITIES IN ELDERLY WITH COGNITIVE DECLINE: THE FIT4ALZ PROJECT
Ana Filipa Silva, Gilmara Assis, Rui Miguel Silva, Eugenia Murawska-Cia?owicz, Grzegorz Zurek, José Carvalho, Mafalda Sofia Roriz, José Alberto Azevedo, António Sampaio, Telmo Bento, Olivera Jovanovic, Marko Adamovic, Spartaco Grieco, Roberta Germini, Filipe Manuel Clemente
J Prev Alz Dis 2025;8(12)
Show summaryHide summaryBACKGROUND: Despite the global impact of neurodegenerative diseases and ongoing research efforts, pharmacological therapies have shown limited benefits. In contrast, physical exercise, with no side effects, has emerged as a non-pharmacological alternative that can enhance brain structure and function, promoting a healthier neurological phenotype.
OBJECTIVES: This study aimed to explore the effects of aerobic and strength training methods, both with and without cognitive training, on mitigating or reversing cognitive decline in older adults.
DESIGN, SETTING, PARTICIPANTS: In a randomized controlled trial, a total of 350 participants (average age 72.9 ± 6.0 years, 79 % female), with signs of decline (MoCA score below 26), were assigned to one of five groups: i) strength plus cognitive training (STCT, n = 92); ii) strength training (ST, n = 41); iii) aerobic training (AT, n = 97); iv) aerobic plus cognitive training (ATCT, n = 91); v) control (CG, n = 29).
INERVENTION: For 12 weeks, all groups followed a 60 min training session three times a week, tailored to their specific group, with half of the sample adding 20 min of cognitive stimulation after the physical exercise.
MEASUREMENTS: Cognitive and physical assessments were conducted at the start and end of the intervention using the MoCA and the Senior Fitness test. A mixed ANCOVA analysis revealed significant interactions between time and group for all tests.
RESULTS: After the intervention, the CG showed significantly lower scores compared to all experimental groups. The CG also performed significantly worse than the ATCT group (p < 0.001). Additionally, the ATCT outperformed the STCT in the 6-min walk test (p < 0.05), while the STCT showed superior performance in the flexibility tests (sit and reach, back scratch) compared to the CG (p < 0.05).
CONCLUSIONS: Results showed that 12-weeks of aerobic and strength training, with or without cognitive components, improved cognitive performance in older adults with cognitive decline, highlighting the importance of maintaining functional abilities for preserving skills, autonomy, independence, and quality of life in aging.
CITATION:
Ana Filipa Silva ; Gilmara Assis ; Rui Miguel Silva ; Eugenia Murawska-Ciałowicz ; Grzegorz Zurek ; José Carvalho ; Mafalda Sofia Roriz ; José Alberto Azevedo ; António Sampaio ; Telmo Bento ; Olivera Jovanovic ; Marko Adamovic ; Spartaco Grieco ; Roberta Germini ; Filipe Manuel Clemente ; (2025): The differential effect of strength, cognitive and aerobic training combinations on cognitive performance and functional abilities in elderly with cognitive decline: The Fit4Alz project. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100267
ADHERENCE TO AN ANTI-INFLAMMATORY DIET IS ASSOCIATED WITH LOWER ALZHEIMER’S DISEASE MORTALITY: A MODIFIABLE RISK FACTOR IN A NATIONAL COHORT
Ching-Chi Hsu, Shiow-Ing Wang, Sebastian Yu, Eric S. Lin, James Cheng-Chung Wei
J Prev Alz Dis 2025;8(12)
Show summaryHide summaryBACKGROUND: Chronic neuroinflammation contributes to Alzheimer’s disease (AD) pathogenesis, and diet is a modifiable factor influencing inflammation. The impact of an anti-inflammatory diet on AD-specific mortality remains unclear.
OBJECTIVES: To examine the association between adherence to an anti-inflammatory diet (measured as the percentage of dietary energy from anti-inflammatory foods) and AD-specific mortality, as well as all-cause mortality, in a large national cohort, and to determine whether associations differ by sex or race/ethnicity.
METHODS: We analyzed 18,795 U.S. adults (≥18 years) from the 2007–2014 National Health and Nutrition Examination Survey. Anti-inflammatory diet adherence was defined as the percentage of total energy intake from anti-inflammatory foods, categorized as 0 %, <5 %, 5–9.99 %, or ≥10 %. Outcomes were AD-specific mortality and all-cause mortality ascertained via the National Death Index. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95 % confidence intervals (CIs) for mortality across intake categories, adjusting for demographic, lifestyle, and health factors. Analyses were stratified by sex, race/ethnicity, and age (≥45 years for AD mortality).
RESULTS: Participants with 0 % anti-inflammatory intake had a higher all-cause mortality risk (HR 3.82, 95 % CI 1.18–12.33) compared to those with ≥10 % intake. In the overall analysis, 0 % anti-inflammatory intake showed a trend of reduced AD-specific mortality although its did not reach statistical significance after full adjustment (HR 3.04, 95 % CI 0.74–12.46 vs. ≥10 % intake; p>0.05). Notably, the inverse association between anti-inflammatory diet and AD mortality emerged in subgroup analyses. Male participants and non-Hispanic White participants with 0 % intake had the highest AD mortality hazards (HR 12.83 and 3.77, respectively, vs. ≥10 % intake), indicating significant risk reductions with anti-inflammatory diet in these groups. In contrast, no significant associations were observed in female or non-White subgroups. Even a modest intake of anti-inflammatory foods (≥10 % of calories) was associated with lower AD mortality risk in the above subgroups and with lower all-cause mortality overall.
CONCLUSION: Greater consumption of anti-inflammatory foods was associated with lower all-cause and a trend toward lower AD-specific mortality. The observed protective effects were confined to certain subpopulations (notably men and non-Hispanic Whites). Even a small portion of the diet (10 % of calories) being anti-inflammatory was linked to reduced mortality risk in these groups, suggesting that achievable dietary changes could have an impact. These findings support modifying dietary content is a practical, low-cost intervention that could mitigate neuroinflammation to reduce AD mortality risk.
CITATION:
Ching-Chi Hsu ; Shiow-Ing Wang ; Sebastian Yu ; Eric S. Lin ; James Cheng-Chung Wei (2025): Adherence to an anti-inflammatory diet is associated with lower Alzheimer’s disease mortality: A modifiable risk factor in a national cohort. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100221
TAILORING MULTIDOMAIN INTERVENTION PROGRAMS TO REDUCE COGNITIVE AND PHYSICAL DECLINE IN OLDER ADULTS: EXAMINING RURAL-URBAN DIFFERENCES IN A NATIONWIDE CLUSTER-RANDOMIZED CONTROLLED TRIAL
Min-Yin Ho, Wei-Ju Lee, Ko-Han Yen, Chih-Kuang Liang, Li-Ning Peng, Ming-Hsien Lin, Ching-Hui Loh, Fei-Yuan Hsiao, Liang-Kung Chen
J Prev Alz Dis 2025;8(12)
Show summaryHide summaryBACKGROUND: Frailty and cognitive impairment are major challenges in aging populations. Multidomain interventions targeting physical, cognitive, and nutritional health show promise; however, evidence on rural-urban differences in efficacy remains limited.
OBJECTIVES: To evaluate the impact of rural-urban disparities on the clinical efficacy of a 12-month multidomain intervention for cognitive and physical outcomes in older adults.
DESIGN: Cluster-randomized controlled trial.
SETTING: Community clusters in five cities/counties across Taiwan.
PARTICIPANTS: A total of 1082 adults aged ≥65 years from 40 community clusters were randomized to intervention or control groups.
INTERVENTION: The intervention group received a 12-month program including physical exercise (45 min/session), cognitive training (1 hour/session), and nutritional guidance (15 min/session). The control group received telephone-based health education. This trial was registered at ClinicalTrials.gov (NCT03056768)
MEASUREMENTS: Outcomes included walking speed, grip strength, physical activity (METs), frailty (CHS score), and cognitive function (MoCA), assessed at baseline, 6, and 12 months.
RESULTS: Urban participants showed significantly greater gains in visuospatial/executive function at the 12 month (rural-urban difference 0.63, 95 % CI: 0.26 -1.03), and walking speed at the 12 month (rural-urban difference 0.12 m/s, 95 % CI: 0.05 – 0.19). Rural participants demonstrated better improvements in grip strength at the 12 month (rural-urban difference -2.59 kg, 95 % CI: -3.91 - -1.27) and language function (rural-urban difference -0.38, 95 % CI: -0.68 - -0.09). Frailty reduction was more pronounced in urban areas at the 12 month (−0.21, 95 % CI: -0.38 - -0.03, p = 0.025), but showed minimal change in the rural participants.
CONCLUSION: Rural-urban disparities influence the effectiveness of multidomain interventions. Tailored strategies are needed to optimize health outcomes across diverse settings.
CITATION:
Min-Yin Ho ; Wei-Ju Lee ; Ko-Han Yen ; Chih-Kuang Liang ; Li-Ning Peng ; Ming-Hsien Lin ; Ching-Hui Loh ; Fei-Yuan Hsiao ; Liang-Kung Chen (2025): Tailoring multidomain intervention programs to reduce cognitive and physical decline in older adults: Examining rural-urban differences in a nationwide cluster-randomized controlled trial. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100231
TARGETING COGNITIVE AGING WITH CURCUMIN SUPPLEMENTATION: A SYSTEMATIC REVIEW AND META-ANALYSIS
Lirong Yu, Na Li, Bin Li, Kaisy Xinhong Ye, Jiuyu Guo, Jiatong Shan, Luwen Cao, Mei Song, Yanyu Wang, Tih-Shih Lee, Andrea B Maier, Lei Feng
J Prev Alz Dis 2025;8(12)
Show summaryHide summaryBACKGROUND: Cognitive aging is a growing public health concern, and curcumin, a bioactive compound derived from turmeric, has been proposed as a potential intervention to support cognitive function due to its anti-inflammatory and antioxidant properties.
OBJECTIVES: This systematic review and meta-analysis aimed to evaluate the effects of curcumin on cognitive outcomes related to aging.
METHODS: A comprehensive search of PubMed, Embase, Cochrane Library, Web of Science, and Scopus was conducted to identify studies published up to June 18, 2024, including both in vivo preclinical animal studies and randomized controlled trials (RCTs) assessing curcumin's effects on cognitive function. In vivo animal studies using Alzheimer’s disease (AD) models and RCTs in human participants were included. Data were extracted and analyzed using meta-analytic techniques.
RESULTS: In preclinical in vivo murine studies (n = 25; total animals = 572), curcumin consistently improved both acquisition memory (SMD = -1.78, 95 % CI: -2.12 to -1.43) and retention memory (SMD = 2.36, 95 % CI: 1.72 to 3.00) in rodent models of AD. Ten human studies include 531 participants. Overall, curcumin showed no significant effect on global cognitive outcomes compared to placebo (SMD = 0.14, 95 % CI: -0.78 to 1.07). Subgroup analyses revealed significant improvements in working memory (SMD = 1.01, 95 % CI: 0.15 to 1.87) and processing speed (SMD = 0.37, 95 % CI: 0.07 to 0.67). The incidence of adverse events was higher in the curcumin group than in the control group.
CONCLUSIONS: Preclinical in vivo evidence suggests curcumin enhances cognitive function in AD models. However, human studies show inconsistent findings with benefits limited to specific cognitive domains. Larger, well-designed randomized controlled trials are needed to establish curcumin's efficacy and safety in cognitive aging.
CITATION:
Lirong Yu ; Na Li ; Bin Li ; Kaisy Xinhong Ye ; Jiuyu Guo ; Jiatong Shan ; Luwen Cao ; Mei Song ; Yanyu Wang ; Tih-Shih Lee ; Andrea B Maier ; Lei Feng (2025): Targeting cognitive aging with curcumin supplementation: A systematic review and meta-analysis. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100248
ASSOCIATION OF VITAMIN B12 DEFICIENCY IN A DEMENTIA COHORT WITH HIPPOCAMPAL ATROPHY ON MRI
Asako Ueno, Tadanori Hamano, Miwako Nagata, Tomohisa Yamaguchi, Yoshinori Endo, Soichi Enomoto, Hirohiko Kimura, Masamichi Ikawa, Osamu Yamamura, Daiki Yamanaka, Yohei Kimura, Yasunari Nakamoto, Yasuhiro Nishiyama
J Prev Alz Dis 2025;8(12)
Show summaryHide summaryBACKGROUND: Vitamin deficiencies have been reported to cause brain atrophy. Hippocampal atrophy has been well reported in patients with dementia including Alzheimer’s disease.
OBJECTIVES: To investigate the association between hippocampal atrophy and vitamin deficiency
DESIGN: Cross sectional study.
SETTING: Three sites in one country.
PARTICIPANTS: Overall, 567 patients who visited an outpatient dementia clinic and underwent MRI-VSRAD (Voxel-Based Specific RegionalAnalysis System for Alzheimer's Disease) were included in this study.
INTERVENTION: Patients with a hippocampal atrophy Z-score of < 2 were classified as normal (n = 323), and those with a Z-score of ≥ 2 were diagnosed with hippocampal atrophy (n = 244).
MEASUREMENTS: Vitamin B12, folic acid, vitamin B1, homocysteine, HbA1c, and creatinine levels were measured and their association with hippocampal atrophy was assessed. Age, MMSE (Mini Mental State Examination), and hippocampal atrophy were also evaluated.
RESULTS: In the hippocampal atrophy group, the frequency of vitamin B12 deficiency was higher (p < 0.022), MMSE score was lower (p < 0.0001), and age was higher (p < 0.0001) than that in the normal group (Mann-Whitney U test). Patients with vitamin B12 deficiency (odds ratio, 3.46) and low MMSE score (odds ratio, 2.24) had an increased risk of hippocampal atrophy.
CONCLUSION: Vitamin B12 deficiency was associated with hippocampal atrophy detected by VSRAD analysis. Therefore, early vitamin B12 supplementation should be considered in patients with deficiencies to reduce dementia risk.
CITATION:
Asako Ueno ; Tadanori Hamano ; Miwako Nagata ; Tomohisa Yamaguchi ; Yoshinori Endo ; Soichi Enomoto ; Hirohiko Kimura ; Masamichi Ikawa ; Osamu Yamamura ; Daiki Yamanaka ; Yohei Kimura ; Yasunari Nakamoto ; Yasuhiro Nishiyama (2025): Association of vitamin B12 deficiency in a dementia cohort with hippocampal atrophy on MRI. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100265
A MULTIMODAL LIFESTYLE INTERVENTION COMPLEMENTED WITH EPIGALLOCATECHIN GALLATE TO PREVENT COGNITIVE DECLINE IN APOE- Ɛ4 CARRIERS WITH SUBJECTIVE COGNITIVE DECLINE: A RANDOMIZED, DOUBLE-BLINDED CLINICAL TRIAL (PENSA STUDY)
Laura Forcano, Natalia Soldevila-Domenech, Anna Boronat, Gonzalo Sánchez-Benavides, Albert Puig-Pijoan, Thais Lorenzo, Ana Aldea-Perona, Marc Suárez-Calvet, Aida Cuenca-Royo, Juan Domingo Gispert, Maria Gomis-Gonzalez, Carolina Minguillón, Patrícia Diaz-Pellicer, Karine Fauria, Iris Piera, Klaus Langohr, Mara Dierssen, Nieves Pizarro, Esther Mur-Gimeno, Oriol Grau-Rivera, José Luis Molinuevo, Rafael de la Torre, the PENSA working group
J Prev Alz Dis 2025;8(12)
Show summaryHide summaryBACKGROUND: The potential of dietary compounds to enhance the effects of multimodal lifestyle interventions (MLIs) on cognition in individuals at high risk of cognitive impairment remains unclear.
OBJECTIVES: To assess whether the addition of a green tea extract enriched with epigallocatechin-3-gallate (EGCG) enhances the effects of an MLI.
DESIGN: Double-blind, randomized, two-arm, and placebo-controlled trial. Exploratory comparisons were made with a non-randomized group (NRG) receiving healthy lifestyle recommendations. Setting: Population-based study conducted in Barcelona, Spain
PARTICIPANTS: APOE-ɛ4 carriers aged 60-80 with subjective cognitive decline.
INTERVENTION: A 12-month intensive MLI including dietary counseling, guided physical activity, and cognitive stimulation, combined with EGCG (5-6 mg/kg) or placebo, followed by a 3-month washout.
MEASUREMENTS: Primary endpoint was change in the modified Preclinical Alzheimer Cognitive Composite (PACC-exe) score.
RESULTS: 129 participants (65.1% 84 women, aged 66.7±5.5 years) were enrolled (52 MLI+EGCG, 52 MLI+placebo and 25 NRG), with126 (97.7%) included in the modified intention-to-treat analysis. After 12 months, no statistically significant difference was observed between MLI+EGCG and MLI+placebo in the PACC-exe (adjusted mean difference [AMD]: 0.12; 95%CI: -0.01, 0.24; p=0.061). However, participants in the MLI+EGCG group were 2.6 times more likely to show a reliable cognitive improvement. In exploratory analyses following a 3-month washout, the MLI+EGCG group showed significant cognitive benefits compared to the MLI+placebo (AMD: 0.19; 95%CI: 0.06, 0.32; p=0.005). Exploratory comparisons with the NRG also suggested greater gains in cognition and dementia risk reduction in both MLI groups, particularly with EGCG.
CONCLUSIONS: While the primary outcome was not met, this proof-of-concept trial suggests that combining MLIs with EGCG warrants further investigation in larger, confirmatory studies.
CITATION:
Laura Forcano ; Natalia Soldevila-Domenech ; Anna Boronat ; Gonzalo Sánchez-Benavides ; Albert Puig-Pijoan ; Thais Lorenzo ; Ana Aldea-Perona ; Marc Suárez-Calvet ; Aida Cuenca-Royo ; Juan Domingo Gispert ; Maria Gomis-Gonzalez ; Carolina Minguillón ; Patrícia Diaz-Pellicer ; Karine Fauria ; Iris Piera ; Klaus Langohr ; Mara Dierssen ; Nieves Pizarro ; Esther Mur-Gimeno ; Oriol Grau-Rivera ; José Luis Molinuevo ; Rafael de la Torre ; the PENSA working group (2025): A multimodal lifestyle intervention complemented with epigallocatechin gallate to prevent cognitive decline in APOE- ɛ4 carriers with Subjective Cognitive Decline: a randomized, double-blinded clinical trial (PENSA study). The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100271
POLYUNSATURATED FATTY ACIDS, APOE GENOTYPES, AND DEMENTIA INCIDENCE AND MORTALITY AMONG HYPERTENSIVE ADULTS
Yubo Zhang, Jindi Li, Shaohui Liu, Quanhong Chen, Xuexiu Wang, Sisi He, Yadong Wei, Yunfeng Zou, Yunan Xu, Lijun Wang, Hao Chen
J Prev Alz Dis 2025;8(12)
Show summaryHide summaryBACKGROUND: Individuals with hypertension have an elevated risk of dementia. The potential protective effects of dietary polyunsaturated fatty acids (PUFAs) against dementia remain unclear. In this study, we investigate associations between blood PUFA levels and dementia outcomes, while considering the genetic predisposition among hypertensive adults.
METHODS: We employed data from UK Biobank and a prospective cohort of 123,235 hypertensive participants aged 40–69 years were included for the analysis (2006–2022). Cox proportional hazards models adjusting for covariates were applied to assess the associations of blood levels of docosahexaenoic acid (DHA), N3FA, N6FA, linoleic acid (LA), total PUFA, and the N6FA/N3FA ratio with incident dementia, dementia mortality, and all-cause mortality. The analyses were also stratified by polygenic risk scores (PRS) or APOE genotypes.
RESULTS: Higher levels of DHA (HR 0.41, 95 % CI 0.27–0.62), N3FA, LA, N6FA, and total PUFA were associated with significantly reduced dementia incidence (P < 0.001). In contrast, a higher N6FA/N3FA ratio was linked to increased dementia risk. Similar trends were observed for mortality. APOE genotypes, rather than PRS, modified PUFA–dementia associations: individuals with low-to-moderate APOE risk showed greater protective effects of high PUFA levels compared to those with high-risk genotypes.
CONCLUSIONS: Among hypertensive adults, higher PUFA levels are associated with reduced risks of dementia and mortality. An imbalanced N6FA/N3FA ratio increases risk, while APOE genotypes significantly modify PUFA-related dementia outcomes.
CITATION:
Yubo Zhang ; Jindi Li ; Shaohui Liu ; Quanhong Chen ; Xuexiu Wang ; Sisi He ; Yadong Wei ; Yunfeng Zou ; Yunan Xu ; Lijun Wang ; Hao Chen (2025): Polyunsaturated fatty acids, APOE genotypes, and dementia incidence and mortality among hypertensive adults. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100297
CAUSAL RELATIONSHIP AND MEDIATING ROLE BETWEEN DEPRESSION AND COGNITIVE PERFORMANCE
Xinyu Hao, Fuyang Cao, Ziyao Xu, Shaohua You, Tianyue Mi, Lei Wang, Yongxin Guo, Zhuoning Zhang, Jiangbei Cao, Jingsheng Lou, Yanhong Liu, Xianyang Chen, Zhikang Zhou, Weidong Mi, Li Tong
J Prev Alz Dis 2025;8(12)
Show summaryHide summaryBACKGROUND: Recent studies have increasingly emphasized the robust correlation between depression and cognitive function. However, it remains unclear whether this relationship is causal or merely coincidental. To address this uncertainty, we conducted two-sample bidirectional Mendelian randomization (MR) analyses to investigate the connection between depression and cognitive performance.
METHODS: We sourced genome-wide association study (GWAS) data for depression (NSNPs=21,306,230) from the FinnGen (R10) and for cognitive performance (NSNPs=10,049,954) from the IEU GWAS database. Causal effects employed methodologies such as Inverse variance weighted (IVW), weighted median, MR Egger, simple mode and weighted mode. Two-step analysis determined the contribution of the mediator variable to the outcomes. To determine stability and reliability, sensitivity analyses were performed that included an assessment of heterogeneity, horizontal pleiotropy, and the leave-one-out techniques.
RESULTS: This MR analysis identified 8 independent significant SNPs associated with depression and 81 SNPs linked to cognitive performance. Our findings revealed that depression increases the risk of developing deteriorating cognitive performance (IVW β, -0.11; 95 % confidence interval (CI), -0.18 – -0.05; PIVW value= 5.97E-04). Conversely, cognitive performance decline could also predispose individuals to depression [odds ratio (OR)IVW, 0.85; 95 % CI, 0.76 – 0.95; PIVW value=0.004]. Multivariate MR analysis confirmed the robustness of this bidirectional association. A two-step MR mediation analysis indicated that the pathway from depression to cognitive performance is mediated by pain, with a mediation effect size of -0.022 and a mediation ratio of 28.95 %. The pathway from cognitive performance to depression is mediated by frailty, with a mediation effect value of -0.028, representing 22.40 % of the mediation proportion.
CONCLUSION: A two-way causal relationship between depression and cognitive performance, with pain and frailty being mediating factors, respectively. Future research should prioritize mechanistic studies, targeted interventions, and personalized approaches to disentangle and mitigate the bidirectional effects of depression and cognitive performance.
CITATION:
Xinyu Hao ; Fuyang Cao ; Ziyao Xu ; Shaohua You ; Tianyue Mi ; Lei Wang ; Yongxin Guo ; Zhuoning Zhang ; Jiangbei Cao ; Jingsheng Lou ; Yanhong Liu ; Xianyang Chen ; Zhikang Zhou ; Weidong Mi ; Li Tong (2025): Causal relationship and mediating role between depression and cognitive performance. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100196
TRAJECTORIES OF CARDIORESPIRATORY FITNESS MEASURED BY METABOLIC EQUIVALENTS AND THE RISK OF ALZHEIMER\'S AND RELATED DEMENTIAS
Edward Zamrini, Yan Cheng, Peter Kokkinos, Charity J Morgan, Charles Faselis, Helen M Sheriff, Yijun Shao, Xuemei Sui, Ali Ahmed, Qing Zeng
J Prev Alz Dis 2025;8(12)
Show summaryHide summaryBACKGROUND: Higher fitness levels have been reported to protect against Alzheimer's Disease and Related Dementias (ADRD). However, the association between changes in fitness over time and ADRD risk remains unknown. This study aims to identify clusters of metabolic equivalents (METs) trajectories and examine their correlation with incident ADRD.
METHODS: A retrospective cohort study was conducted among Veterans with ≥3 standardized exercise treadmill tests (ETT) between 2000 and 2017. The exposure was change in fitness expressed in metabolic equivalents (METs). METs are based on treadmill speed, grade, and time. One MET is equivalent to 3.5 ml per kg of body weight per minute. The outcome was incident ADRD after the final ETT test, identified by diagnosis codes. Standardized METs scores were generated using mean and standard deviation for each age and sex stratum. Latent class growth analysis (LCGA) identified trajectory clusters. We assessed the association between clusters and ADRD using unadjusted Kaplan-Meier curves (overall and by age groups) and a multivariate Cox regression model adjusted for baseline characteristics at the first ETT.
RESULTS: A total of 75,851 veterans were included. The average number of ETTs was 4.0 ± 1.8, with the average time gap of 6.5 ± 3.8 years between first and last test. We identified five trajectory clusters: Group 1 (n = 22,485), Group 2 (n = 22,694), Group 3 (n = 6691), Group 4 (n = 19,386), and Group 5 (n = 4595). All groups, except for Group 3, showed a stable and slight improvement or decline over time, differing only in their initial standardized METs scores: Group 5 had the highest initial score, Group 1 had the lowest initial score, while Group 3 started out with a score almost as high as Group 4 and dropped to as low as Group 1. Compared to Group 1, Group 3 had a 12 % reduced risk of developing ADRD (HR = 0.88; 95 % CI: 0.77 – 1.01; p = 0.0660), with a greater reduction than Group 2 (10 %) but less than Group 4 (17 %) or Group 5 (24 %).
DISCUSSION: Our findings underscore the potential benefits of maintaining fitness to reduce the risk of ADRD with age. Although declining fitness levels are associated with an increased risk, the initial higher baseline fitness provides a degree of ongoing protection against ADRD.
CITATION:
Edward Zamrini ; Yan Cheng ; Peter Kokkinos ; Charity J Morgan ; Charles Faselis ; Helen M Sheriff ; Yijun Shao ; Xuemei Sui ; Ali Ahmed ; Qing Zeng (2025): Trajectories of Cardiorespiratory Fitness Measured by Metabolic Equivalents and the Risk of Alzheimer's and Related Dementias. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100222
HOUSEHOLD FUEL USE AND MOTORIC COGNITIVE RISK SYNDROME AMONG OLDER ADULTS: EVIDENCE FROM COHORT STUDY AND LIFE COURSE ANALYSIS
Guanghui Cui, Shaojie Li, Weiwei Li, Xuezhi Zhang
J Prev Alz Dis 2025;8(12)
Show summaryHide summaryBACKGROUND: Motoric cognitive risk syndrome (MCRS) is a predementia syndrome, and its prevention is valuable for reducing the incidence of dementia. However, few studies have focused on the association between indoor air pollution caused by household cooking fuel use and MCRS. This study aimed to investigate whether clean cooking fuel use is associated with reduced MCRS risk and whether the timing of clean fuel adoption across the life span is associated with MCRS prevalence.
METHODS: We used data from the China Health and Retirement Longitudinal Study. A prospective cohort analysis (n = 4251) examined baseline fuel use (2011) and incident MCRS over four years. A cross-sectional life course analysis (n = 6964) linked retrospective fuel use histories (2014 life history survey) to MCRS status in 2015. Modified Poisson regression was used to estimate relative risks (RRs) and 95 % confidence intervals (CIs), adjusting for covariates.
RESULTS: In the cohort study, clean fuel use at baseline was associated with a reduced risk of MCRS (RR = 0.76; 95 % CI: 0.61–0.96). Lower risks were also observed among participants who transitioned from solid to clean fuels and those who consistently used clean fuels. In the life course analysis, clean fuel adoption in early or middle adulthood was linked to lower MCRS prevalence.
CONCLUSION: Clean fuel use for cooking and transitioning from solid to clean fuels decreases MCRS risk among older adults. Moreover, earlier adoption of clean cooking fuels is associated with a lower prevalence of MCRS in later life.
CITATION:
Guanghui Cui ; Shaojie Li ; Weiwei Li ; Xuezhi Zhang (2025): Household fuel use and motoric cognitive risk syndrome among older adults: Evidence from cohort study and life course analysis. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100227
THE COUPLING OF GLOBAL BRAIN ACTIVITY AND CEREBROSPINAL FLUID FLOW AS A POTENTIAL PREDICTIVE MARKER OF BRAIN AMYLOID-Β ACCUMULATION
Yuya Tanaka, Koji Kamagata, Yuya Saito, Kaito Takabayashi, Rinako Iseki, Wataru Uchida, Christina Andica, Akifumi Hagiwara, Akihiko Wada, Toshiaki Akashi, Osamu Abe, Shigeki Aoki, Alzheimer’s Disease Neuroimaging Initiative
J Prev Alz Dis 2025;8(12)
Show summaryHide summaryBACKGROUND: Impaired cerebrospinal fluid (CSF) clearance is thought to contribute to amyloid-β (Aβ) accumulation in Alzheimer’s disease (AD). Global brain activity–CSF flow coupling (gBOLD–CSF coupling), measured through resting-state functional MRI, reflects CSF clearance capacity. A higher coupling value indicates weaker coupling. Its potential as a predictive marker for Aβ accumulation remains unclear.
OBJECTIVES: This study aims to determine whether weaker gBOLD–CSF coupling precedes Aβ accumulation in cognitively normal, Aβ-negative individuals and to explore its predictive potential for amyloid conversion.
DESIGN: A longitudinal observational study using Alzheimer’s Disease Neuroimaging Initiative (ADNI) data.
SETTING: Data from ADNI-participating sites.
PARTICIPANTS: 16 cognitively normal participants, initially Aβ-negative: seven fast-converters (transitioned to Aβ-positive within two years) and nine slow-converters (remained Aβ-negative for at least two years).
MEASUREMENTS: gBOLD–CSF coupling was calculated as the Pearson correlation coefficient between global Blood-Oxygen-Level-Dependent (BOLD) and CSF inflow signals. Group differences in gBOLD–CSF coupling were analyzed, along with partial correlation analyses between gBOLD–CSF coupling and annual changes in Aβ biomarkers and cognitive scores.
RESULTS: Fast-converters showed significantly higher gBOLD–CSF coupling values, indicating weaker coupling (Cohen’s d = 1.76, p = 0.012). Coupling values positively correlated with annual changes in Aβ-PET SUVR (r = 0.594, p = 0.054) and negatively with MoCA scores (r = −0.654, p = 0.021).
CONCLUSION: Weaker gBOLD–CSF coupling precedes brain Aβ accumulation, indicating its potential as a predictive marker for amyloid conversion. Future studies should refine clinical thresholds for early intervention strategies in AD prevention.
CITATION:
Yuya Tanaka ; Koji Kamagata ; Yuya Saito ; Kaito Takabayashi ; Rinako Iseki ; Wataru Uchida ; Christina Andica ; Akifumi Hagiwara ; Akihiko Wada ; Toshiaki Akashi ; Osamu Abe ; Shigeki Aoki ; Alzheimer’s Disease Neuroimaging Initiative (2025): The coupling of global brain activity and cerebrospinal fluid flow as a potential predictive marker of brain amyloid-β accumulation. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100228
PSYCHOSOCIAL STRESSORS AND COGNITIVE FUNCTION: AN ANALYSIS USING DATA FROM THE ENGLISH LONGITUDINAL STUDY OF AGEING
Jiahao Li, Natalia Ortí-Casañ, Irem Bayraktaroglu, Giulia Mozzanica, Feng Zhang, Jocelien D.A. Olivier, Ulrich L.M. Eisel
J Prev Alz Dis 2025;8(12)
Show summaryHide summaryBACKGROUND: Growing evidence suggests that psychosocial stressors—such as financial strain, caregiving responsibilities, disability, and limiting long-term illnesses—may contribute to accelerated cognitive decline in older adults. However, the heterogeneity of stressor profiles and their distinct impact on specific cognitive domains remain poorly understood.
OBJECTIVE: To examine the associations between varying burdens of psychosocial stressors and cognitive function over a 10-year period using data from the English Longitudinal Study of Ageing (ELSA).
METHODS: We used longitudinal data from wave 4 (2008–2009) to wave 9 (2018–2019) of ELSA, comprising 10,893 participants aged ≥50 years at baseline who had valid measurements of psychosocial stressors and cognitive outcomes. Psychosocial stressors—financial strain, caregiving, disability, and limiting long-term illness—were assessed as binary indicators and summed into three categories (No Stressors, One Stressor, Multiple Stressors). Cognitive function was assessed using an overall global cognition score and scores of three specific domains: memory, executive function, and orientation. Baseline associations were examined via multiple linear regression, while linear mixed-effects models evaluated longitudinal trajectories of cognitive change. All models were progressively adjusted for demographic, lifestyle, and clinical covariates.
RESULTS: At baseline, participants reporting multiple stressors (18.2 % of the sample) had significantly lower global cognitive and executive function scores compared to those with no stressors (43.3 %). Over the 10-year follow-up, a higher stress burden predicted faster declines in global cognition, memory, and executive function. These associations remained robust after adjusting for sociodemographic characteristics, health behaviors, and chronic conditions. Random intercept and random slope models yielded consistent findings, indicating a dose–response relationship between stress burden and cognitive deterioration.
CONCLUSION: Older adults experiencing multiple psychosocial stressors face an elevated risk of both lower initial cognitive function and accelerated decline over time. These findings underscore the importance of identifying and mitigating modifiable stressors—such as financial strain and caregiving demands—to potentially preserve cognitive health in later life. Interventions tailored to individuals with higher stress burdens may be especially beneficial in slowing cognitive deterioration.
CITATION:
Jiahao Li ; Natalia Ortí-Casañ ; Irem Bayraktaroglu ; Giulia Mozzanica ; Feng Zhang ; Jocelien D.A. Olivier ; Ulrich L.M. Eisel (2025): Psychosocial stressors and cognitive function: An analysis using data from the English longitudinal study of ageing. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100232
SYNERGISTIC EFFECTS OF MULTIPLE PATHOLOGICAL PROCESSES ON ALZHEIMER\'S DISEASE RISK: EVIDENCE FOR AGE-DEPENDENT STROKE INTERACTIONS
Fen Liu, Xuesong Xia, Chengjie Zheng, Feng Liu, Min Jiang
J Prev Alz Dis 2025;8(12)
Show summaryHide summaryBACKGROUND: Alzheimer's disease (AD) pathogenesis involves complex interactions between multiple neuropathological processes, yet traditional approaches focus on individual markers. The cumulative effects of multiple pathologies and their interactions with cerebrovascular compromise and age remain poorly understood. This study aimed to develop a comprehensive Pathological Burden Score (PBS) and examine its relationship with AD risk, including interactions with stroke history and age.
METHODS: We analyzed 11,308 participants from the National Alzheimer's Coordinating Center database. A PBS was constructed integrating six neuropathological domains: Braak neurofibrillary tangle staging, CERAD neuritic plaque density, Thal amyloid-β phasing, stroke history, white matter rarefaction severity, and cerebral atrophy severity (range 0–16 points). PBS was categorized into four burden levels: low (0–4), moderate (5–8), high (9–12), and very high (13–16). Multivariable logistic regression examined associations between PBS categories and AD risk, with formal interaction testing for stroke × PBS effects. Age-stratified analyses were conducted using a 75-year cutpoint.
RESULTS: A clear dose-response relationship was observed between PBS and AD risk, with very high burden conferring over 5-fold increased odds compared to low burden. Significant stroke × PBS interaction was detected (interaction OR 1.23, p < 0.001), with stroke amplifying pathological burden effects. Among participants with very high burden, AD risk was 92.5 % in stroke patients versus 24.1 % in non-stroke patients. Age-dependent effects were profound: younger participants (<75 years) with high burden plus stroke showed 18.67-fold increased odds, while older participants (≥75 years) with equivalent burden showed 7.89-fold increased odds.
CONCLUSIONS: Cumulative pathological burden demonstrates a strong dose-response relationship with AD risk, significantly amplified by stroke history. The pronounced age-dependent effects highlight the need for age-specific prevention strategies, with particular emphasis on aggressive vascular risk management in younger populations. These findings support comprehensive pathological burden assessment for enhanced risk stratification and personalized dementia care approaches.
CITATION:
Fen Liu ; Xuesong Xia ; Chengjie Zheng ; Feng Liu ; Min Jiang (2025): Synergistic effects of multiple pathological processes on Alzheimer's disease risk: Evidence for age-dependent stroke interactions. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100268
STRESS INTERNALIZATION IS A TOP RISK FOR AGE-ASSOCIATED COGNITIVE DECLINE AMONG OLDER CHINESE IN THE U.S
Michelle H Chen, Yiming Ma, Charu Verma, Stephanie Bergren, William T Hu
J Prev Alz Dis 2025;8(12)
Show summaryHide summaryBACKGROUND: Behavioral and sociocultural factors are often examined in population-based studies as independent variables, yet latent factors often influence multiple behaviors all at once. This may be especially true in immigrant populations living in or near ethnic enclaves. Better characterization of internal or external factors underlying multiple behaviors is critical to modify the root causes of health-related behaviors.
OBJECTIVES: To identify inter-relatedness of multiple internal (acculturation, behavior, well-being) and external (neighborhood & community) characteristics, as well as their influence on age-associated cognitive decline in a large group of non-demented older Chinese Americans living in the Chicago metropolitan area.
SETTING: Secondary data analysis of the Population Study of ChINese Elderly (PINE).
PARTICIPANTS: 1528 non-demented older Chinese Americans (aged 60+) who attended three waves of PINE.
DESIGN: Longitudinal cohort study.
INTERVENTION(S): Not applicable.
MEASUREMENTS: Three psychobehavioral and 3 sociocultural factors were included in factor analysis for independent variables; Chinese versions of the Mini-Mental State Examination, East Boston Memory Test, Digit Span Backward, and oral Symbol Digit Modalities Test were included in principal component analysis to derive dependent variables.
RESULTS: Factor analysis identified three main behavioral/sociocultural constructs: stress internalization, neighborhood/community cohesion, and external stress alleviation. Among these, only stress internalization – consisting of greater perceived stress, greater hopelessness, and lower conscientiousness – was associated with longitudinal decline in memory, while none with decline in executive functioning. Neither acculturation nor activity engagement was related to longitudinal decline in memory or executive functioning, even though participants with greater acculturation or activity engagement had better baseline cognitive performance.
CONCLUSIONS: Only the factor underlying stress processing, hopelessness, and conscientiousness was associated with rates of longitudinal memory decline in this older non-demented Chinese American cohort. These maladaptive traits have been linked to the Asian model minority stereotype but all the same potentially modifiable. Limitations include potential selection bias, potential cultural inappropriateness of the measures, and limited cognitive test battery and clinical information.
CITATION:
Michelle H Chen ; Yiming Ma ; Charu Verma ; Stephanie Bergren ; William T Hu (2025): Stress internalization is a top risk for age-associated cognitive decline among older Chinese in the U.S. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100270
ASSOCIATIONS OF CARDIOVASCULAR HEALTH ASSESSED BY LIFE’S CRUCIAL 9 WITH INCIDENT CARDIOVASCULAR DISEASE AND DEMENTIA: A PROSPECTIVE COHORT STUDY
Yiwen Dai, Yuling Liu, Yang Pan, Jingya Ma, Jie Liang, Wenya Zhang, Xuyang Diao, Menghan Zhu, Xinqing Yang, Darui Gao, Yanyu Zhang, Mengmeng Ji, Yichi Zhang, Wuxiang Xie, Fanfan Zheng
J Prev Alz Dis 2025;8(12)
Show summaryHide summaryBACKGROUND: The associations of the renewed cardiovascular health (CVH) assessed by Life’s Crucial 9 (LC9), which consisted of Life’s Essential 8 (LE8) and psychological health, with incident cardiovascular disease (CVD) and dementia remained unexplored.
OBJECTIVES: This study aims to investigate the associations and determine whether LC9 has a higher discrimination ability than LE8 in predicting incident CVD and dementia.
DESIGN, SETTING, AND PARTICIPANTS: This study was a prospective population-based cohort study using data from the UK Biobank.
MEASUREMENTS: LC9 was assessed as American Heart Association recommended. Incident CVD and dementia were based on self-reported data, hospital inpatient records, and death register records.
RESULTS: Of 289,649 included participants, 137,480 (47.5 %) were male, and the mean age was 56.6 ± 8.1 years. Compared with participants having low LC9, those having moderate or high LC9 had lower risks of incident CVD (moderate: 0.46 [0.43–0.48]; high: 0.25 [0.23–0.27]; p for trend <0.001) and dementia (moderate: 0.57 [0.50–0.64]; high: 0.45 [0.39–0.52]; p for trend <0.001) after multivariate adjustment. Both the LE8 and LC9 achieved good discriminative performance for incident CVD (LE8 Harrell C-statistic= 0.7138 vs. LC9 Harrell C-statistic=0.7144, p = 0.136); the net reclassification improvement was estimated at 0.07 % (p = 0.749), and integrated discrimination improvement was estimated at 0.009 (p < 0.001). The results for dementia showed similar patterns.
CONCLUSIONS AND RELEVANCE: Optimal LC9 was associated with lower risks of incident CVD and dementia. Although psychological health is essential for preventing CVD and dementia, including it into CVH's evaluation criteria did not significantly improve CVH's predictive performance.
CITATION:
Yiwen Dai ; Yuling Liu ; Yang Pan ; Jingya Ma ; Jie Liang ; Wenya Zhang ; Xuyang Diao ; Menghan Zhu ; Xinqing Yang ; Darui Gao ; Yanyu Zhang ; Mengmeng Ji ; Yichi Zhang ; Wuxiang Xie ; Fanfan Zheng (2025): Associations of cardiovascular health assessed by life’s crucial 9 with incident cardiovascular disease and dementia: A prospective cohort study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100273
UNDERDETECTION OF NEUROCOGNITIVE DISORDERS IN SOUTHERN ITALY: EVIDENCE FROM THE SALENTO REGION
Davide Vilella, Daniele Urso, Agnese Valguarnera, Giuseppe Volpe, Valentina Gnoni, Eleonora Rollo, Alessia Giugno, Marcella Caggiula, Brigida Coluccia, Annamaria Mauro, Roberta Barone, Miriam Accogli, Marzia Leopizzi, Alessandro Introna, Marco Musio, Stefano Giannoni-Luza, Giancarlo Logroscino
J Prev Alz Dis 2025;8(12)
Show summaryHide summaryBACKGROUND: Neurocognitive disorders, including dementia and mild cognitive impairment, are increasingly prevalent, demanding efficient detection and management strategies.
OBJECTIVES: This study is part of the Puglia Region’s initiative under the Italian Dementia National Plan (DNP) and aimed to assess the capacity of the Lecce province healthcare system to identify new neurocognitive disorders cases by comparing observed cases with expected rates derived from meta-analyses and Global Burden of Disease estimates.
DESIGN: Using complete case ascertainment across 10 hospital-based and community centers, a total of 857 incident cases were identified in one year, including 441 Minor neurocognitive disorders (51.46 %) and 416 major neurocognitive disorders cases (48.54 %).
SETTING: Public Centers for Cognitive Disorders and Dementia (CCDDs) across hospital and community services in the Lecce province, Southern Italy.
PARTICIPANTS: Eligible participants included all individuals aged between 65 and 89 residing in the Lecce province who received a diagnosis of neurocognitive disorder. 857 participants were enrolled (519 females – 338 males).
MEASUREMENTS: Incident cases of neurocognitive disorder, both minor and major, accordingly to DSM-5 criteria.
RESULTS: Only 10.65 % of expected major neurocognitive disorders and 7.24 % of expected minor neurocognitive disorders cases were detected, with significant age and sex disparities, with higher underdetection rates in females. Detection rates declined with advancing age, with the observed-to-expected ratio for major neurocognitive disorders falling from 18.23 % in individuals aged 65–69 years to just 5.24 % in those aged 85–89 years. These findings were validated against Global Burden of Disease estimates.
CONCLUSIONS: This study highlights the critical gaps in detecting neurocognitive disorders, particularly in older adults and prodromal stages such as minor neurocognitive disorders, where early intervention could yield the greatest benefits. The findings underscore the urgent need for targeted reforms to improve e diagnostic pathways and better align healthcare systems with emerging disease-modifying therapies and preventive strategies.
CITATION:
Davide Vilella ; Daniele Urso ; Agnese Valguarnera ; Giuseppe Volpe ; Valentina Gnoni ; Eleonora Rollo ; Alessia Giugno ; Marcella Caggiula ; Brigida Coluccia ; Annamaria Mauro ; Roberta Barone ; Miriam Accogli ; Marzia Leopizzi ; Alessandro Introna ; Marco Musio ; Stefano Giannoni-Luza ; Giancarlo Logroscino (2025): Underdetection of neurocognitive disorders in Southern Italy: Evidence from the Salento region. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100295
TRAJECTORIES OF MUSCLE STRENGTH AND PHYSICAL PERFORMANCE PRECEDING DEMENTIA IN OLDER US AND EUROPEAN POPULATIONS
Youjin Jiang, Yi Ding, Qiuyu Cao, Xianglin Wu, Xiaoran Li, Yu Xu, Zhiyun Zhao, Min Xu, Jieli Lu, Tiange Wang, Guang Ning, Weiqing Wang, Yufang Bi, Yuchen Xu, Mian Li
J Prev Alz Dis 2025;8(12)
Show summaryHide summaryBACKGROUND: The association between muscle function and dementia risk remains elusive, as studies suggest that impaired muscle function may act as both a risk factor for and a consequence of dementia, hindering causal inference.
OBJECTIVES: We aimed to clarify the temporal relationship between muscle function and incident dementia by investigating non-linear trajectories of muscle function in the years preceding dementia onset in older US and European populations.
DESIGN: Case-control study.
SETTING: Data were combined from the English Longitudinal Study of Ageing (ELSA, 2004–2018, waves 2–9), Health and Retirement Study (HRS, 2004–2018, waves 7–14), and Survey of Health, Ageing and Retirement in Europe (SHARE, 2004–2017, waves 1–7).
PARTICIPANTS: For handgrip strength analysis, 18,335 participants aged 60 and older were included from the ELSA, HRS, and SHARE cohorts. For gait speed analysis, 11,690 participants aged 60 and older were included from the ELSA and HRS cohorts.
MEASUREMENTS: Muscle strength was assessed by handgrip strength using a Smedley dynamometer, and physical performance was evaluated by gait speed using the Timed 8-Foot Walk test, with assessments conducted biennially or quadrennially. Dementia was diagnosed using self-reported physician diagnosis and cognitive-functional assessments. Trajectories of muscle strength and physical performance were analyzed on a backward timescale using latent-process mixed models within a nested case-control design.
RESULTS: Significant differences in muscle function trajectories were observed between cases and controls 12 and 13 years prior to dementia onset (handgrip strength: coefficient [SE], -0.23 [0.05], P < 0.001; gait speed: coefficient [SE], -0.24 [0.08], P = 0.003). The pathological trajectories of handgrip strength and gait speed revealed periods of acceleration beginning 6 and 8 years prior to diagnosis, respectively. After adjusting for pre-dementia acceleration, greater handgrip (per 1-kg increment) was associated with a modest reduction in dementia risk (hazard ratio, 0.98; 95 % CI, 0.97–0.99), while faster gait speed (per 1-m/s increment) markedly lowered risk (hazard ratio, 0.35; 95 % CI, 0.23–0.53).
CONCLUSIONS: These findings highlight muscle function as a cost-effective tool for early detection and dynamic monitoring of dementia risk and identify it as a modifiable target for prevention. Muscle function may also assist in identifying high-risk groups for preferential enrollment into clinical trials for dementia prevention and treatment.
CITATION:
Youjin Jiang ; Yi Ding ; Qiuyu Cao ; Xianglin Wu ; Xiaoran Li ; Yu Xu ; Zhiyun Zhao ; Min Xu ; Jieli Lu ; Tiange Wang ; Guang Ning ; Weiqing Wang ; Yufang Bi ; Yuchen Xu ; Mian Li (2025): Trajectories of muscle strength and physical performance preceding dementia in older US and European populations. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100296
MULTIMODAL NEUROIMAGING UNVEILS BASAL FOREBRAIN-LIMBIC SYSTEM CIRCUIT DYSREGULATION IN COGNITIVE IMPAIRMENT WITH DEPRESSION: A PATHWAY TO EARLY DIAGNOSIS AND INTERVENTION
Xiaowen Xu, Xiereniguli Anayiti, Peiying Chen, Zhongfeng Xie, Mengling Tao, Yongsheng Xiang, Mingyu Tan, Yingying Liu, Ling Yue, Shifu Xiao, Peijun Wang
J Prev Alz Dis 2025;8(12)
Show summaryHide summaryBACKGROUND: Alzheimer’s disease (AD) frequently co-occurs with depressive symptoms, exacerbating both cognitive decline and clinical complexity, yet the neural substrates linking this co-occurrence remain poorly understood. We aimed to investigate the role of basal forebrain-limbic system circuit dysregulation in the interaction between cognitive impairment and depressive symptoms, identifying potential biomarkers for early diagnosis and intervention.
METHODS: This cross-sectional study included participants stratified into normal controls (NC), cognitive impairment without depression (CI-nD), and cognitive impairment with depression (CI-D). Multimodal MRI (structural, diffusion, functional, perfusion, iron-sensitive imaging) and plasma biomarkers were analyzed. Machine learning models classified subgroups using neuroimaging features.
RESULTS: CI-D exhibited distinct basal forebrain-limbic circuit alterations versus CI-nD and NC: (1) Elevated free-water fraction (FW) in basal forebrain subregions (Ch123/Ch4, p < 0.04), indicating early neuroinflammation; (2) Increased iron deposition in the anterior cingulate cortex and entorhinal cortex (p < 0.05); (3) Hyperperfusion and functional hyperactivity in Ch123 and amygdala; (4) Plasma neurofilamentlightchain exhibited correlated with hippocampal inflammation in CI-nD (p = 0.03) but linked to basal forebrain dysfunction in CI-D (p < 0.05). Multimodal support vector machine achieved 85 % accuracy (AUC=0.96) in distinguishing CI-D from CI-nD, with Ch123 and Ch4 as key discriminators. Pathway analysis in the CI-D group further revealed that FW-related neuroinflammation in the basal forebrain (Ch123/Ch4) indirectly contributed to cognitive impairment via structural atrophy.
CONCLUSION: We identified a neuroinflammatory-cholinergic pathway in the basal forebrain as an early mechanism driving depression-associated cognitive decline. Multimodal imaging revealed distinct spatiotemporal patterns of circuit dysregulation, suggesting neuroinflammation and iron deposition precede structural degeneration. These findings position the basal forebrain-limbic system circuit as a therapeutic target and provide actionable biomarkers for early intervention in AD with depressive symptoms.
CITATION:
Xiaowen Xu ; Xiereniguli Anayiti ; Peiying Chen ; Zhongfeng Xie ; Mengling Tao ; Yongsheng Xiang ; Mingyu Tan ; Yingying Liu ; Ling Yue ; Shifu Xiao ; Peijun Wang (2025): Multimodal neuroimaging unveils basal forebrain-limbic system circuit dysregulation in cognitive impairment with depression: a pathway to early diagnosis and intervention. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100298
THE EFFICACY AND SAFETY OF ANTI-AMYLOID MONOCLONAL ANTIBODY VERSUS ACETYLCHOLINESTERASE INHIBITOR WITH AN IN-DEPTH ANALYSIS ACROSS GENOTYPES AND DISEASE STAGES: A SYSTEMATIC REVIEW AND META-ANALYSIS
Chih-Wei Hsu, Tien-Wei Hsu, Yu-Chen Kao, Yu-Hsuan Lin, Trevor Thompson, Andre F. Carvalho, Brendon Stubbs, Ping-Tao Tseng, Fu-Chi Yang, Chia-Kuang Tsai, Chia-Ling Yu, Yu-Kang Tu, Chih-Sung Liang
J Prev Alz Dis 2025;8(12)
Show summaryHide summaryBACKGROUND: To date, studies have not compared the efficacy and safety of monoclonal antibodies (mABs) with acetylcholinesterase inhibitors (AChEIs).
METHODS: Five electronic databases were systemic searched from inception to 10 November 2024 for double-blinded randomized controlled trial (RCT) of patients diagnosed with MCI or mild AD treated with mABs or AChEIs for at least 6 months. The primary outcome was change in cognitive function, measured by the Alzheimer's Disease Assessment Scale–cognitive subscale 14-item (ADAS-Cog) and Clinical Dementia Rating Scale–Sum of Boxes (CDR-SOB). The secondary outcomes were acceptability, tolerability, serious adverse events (SAE), and all -cause mortality. For mABs, amyloid-related imaging abnormalities-edema (ARIA-E), and amyloid-related imaging abnormalities-hemorrhage (ARIA-H) were also assessed. Subgroup analyses included (i) MCI versus mild AD; (ii) with versus without concomitant AD medications; and (iii) Apolipoprotein E (ApoE4) carriers versus non-carriers. Data were pooled using a random effects model within a Bayesian framework.
RESULTS: There were 8010 participants (mean age: 71.5 years) across seven mAB trials, and 4993 participants (mean age:70.7 years) in nine AChEI trials. When compared to placebo, only mABs, not AChEIs, were associated with a slower progression of cognitive decline on CDR-SOB (mean difference -0.41 (95 % credible interval -0.61 to -0.22); minimally important difference (MID) -1) and ADAS-Cog (-1.35 (-2.36 to -0.36), MID -2); however, these benefits of mABs did not reach MID across the two cognitive measurements. Besides, mABs were associated with a slower progression of cognitive decline on CDR-SOB (-0.30 (-0.60 to -0.001)) than AChEIs, although mABs and AChEIs did not differ across safety outcomes, including acceptability, tolerability, SAE, and all-cause mortality. Further analysis of mABs indicated that their efficacy did not differ by disease stage, concomitant AD medications, or APOE4 carrier status. However, APOE4 homozygotes carriers were associated with a 5.53-fold (2.48 to 13.07) increased odds of developing ARIA-E compared to non-carriers. Finally, lecanemab demonstrated relatively better efficacy and a more favorable profile on ARIA-E compared to aducanumab and donanemab.
CONCLUSIONS: mABs were associated with a slower progression of cognitive decline than AChEIs; however, this effect did not reach the MID. The incidence of ARIA-E with mABs was associated with APOE4 carrier status and was not indicative of treatment efficacy.
CITATION:
Chih-Wei Hsu ; Tien-Wei Hsu ; Yu-Chen Kao ; Yu-Hsuan Lin ; Trevor Thompson ; Andre F. Carvalho ; Brendon Stubbs ; Ping-Tao Tseng ; Fu-Chi Yang ; Chia-Kuang Tsai ; Chia-Ling Yu ; Yu-Kang Tu ; Chih-Sung Liang (2025): The efficacy and safety of anti-amyloid monoclonal antibody versus acetylcholinesterase inhibitor with an in-depth analysis across genotypes and disease stages: a systematic review and meta-analysis. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100195
COMMENTARY : TREATMENTS FOR ALZHEIMER’S AND THE DECLARATION OF HELSINKI
Timothy Daly, Andi Olluri, Markku Kurkinen
J Prev Alz Dis 2025;8(12)
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CITATION:
Timothy Daly ; Andi Olluri ; Markku Kurkinen (2025): Commentary: Treatments for Alzheimer’s and the declaration of Helsinki. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100260
LETTER TO THE EDITOR: BLOOD-BRAIN BARRIER WATER EXCHANGE AND PARAMAGNETIC SUSCEPTIBILITY ALTERATIONS DURING ANTI-AMYLOID THERAPY: PRELIMINARY MRI FINDINGS
Yuto Uchida, Yuya Kano, Hirohito Kan, Keita Sakurai, Hideyasu Morita, Yoshihiro Akagawa, Noriyuki Matsukawa, Kenichi Oishi
J Prev Alz Dis 2025;8(12)
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CITATION:
Yuto Uchida ; Yuya Kano ; Hirohito Kan ; Keita Sakurai ; Hideyasu Morita ; Yoshihiro Akagawa ; Noriyuki Matsukawa ; Kenichi Oishi (2025): Letter to the Editor: Blood-brain barrier water exchange and paramagnetic susceptibility alterations during anti-amyloid therapy: preliminary MRI findings. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100256
LETTER TO THE EDITOR: COMMENT BY EUROPEAN ALZHEIMER’S DISEASE CONSORTIUM (EADC) INVESTIGATORS ON THE NEGATIVE RECOMMENDATION OF THE CHMP ON THE MARKETING AUTHORIZATION OF DONANEMAB FOR EARLY ALZHEIMER’ S DISEASE
Frank Jessen, Javier Arbizu, Mercé Boada, Karim Bennys, Marina Boban, Katharina Bürger, Andrea Chincarini, Annachiara Cagnin, Peter Paul De Deyn, Emrah Düzel, Sebastiaan Engelborghs, Michael Ewers, Lieza G. Exalto, Wiesje M. van der Flier, Juan Fortea, Kristian Steen Frederiksen, Giovanni B Frisoni, Lutz Frölich, Alejandro J. Garza-Martinez, Timo Grimmer, Bernard Hanseeuw, Jakub Hort, Adrian Ivanoiu, Patrick G Kehoe, Sean P Kennelly, Silke Kern, Stefan Klöppel, Lenka Kraj?ovi?ová, Milica G. Kramberger, Bernadette McGuinness, Patrizia Mecocci, Timo Jan Oberstein, Pierre-Jean Ousset, Claire Paquet, Robert Perneczky, Fabrizio Piazza, Domenico Plantone, Innocenzo Rainero, Guillaume Sacco, Eric Salmon, Isabel Santana, Nikolaos Scarmeas, Anja Schneider, Jonathan M Schott, Eino Solje, Elka Stefanova, Elisabeth Stögmann, Mélanie Strauss, Stanislav Sutovsky, Gunhild Waldemar, Bengt Winblad
J Prev Alz Dis 2025;8(12)
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CITATION:
Frank Jessen ; Javier Arbizu ; Mercé Boada ; Mircea Balasa ; Karim Bennys ; Marina Boban ; Katharina Bürger ; Andrea Chincarini ; Annachiara Cagnin ; Peter Paul De Deyn ; Emrah Düzel ; Sebastiaan Engelborghs ; Michael Ewers ; Lieza G. Exalto ; Wiesje M. van der Flier ; Juan Fortea ; Kristian Steen Frederiksen ; Giovanni B Frisoni ab, Lutz Frölich ; Alejandro J. Garza-Martinez ; Timo Grimmer ; Bernard Hanseeuw ; Jakub Hort ag, Adrian Ivanoiu ; Patrick G Kehoe ; Sean P Kennelly ; Silke Kern ; Stefan Klöppel ; Lenka Krajčovičová ; Milica G. Kramberger ; Bernadette McGuinness ; Patrizia Mecocci ; Timo Jan Oberstein ; Pierre-Jean Ousset ; Claire Paquet ; Robert Perneczky ; Fabrizio Piazza ; Domenico Plantone ; Innocenzo Rainero ; Guillaume Sacco ; Eric Salmon ; Isabel Santana ; Nikolaos Scarmeas ; Anja Schneider ; Jonathan M Schott ; Eino Solje ; Elka Stefanova ; Elisabeth Stögmann ; Mélanie Strauss ; Stanislav Sutovsky ; Gunhild Waldemar ; Bengt Winblad (2025): Letter to the Editor: Comment by European Alzheimer’s Disease Consortium (EADC) investigators on the negative recommendation of the CHMP on the marketing authorization of donanemab for early Alzheimer’ s disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100259
LETTER TO THE EDITOR : REFINING THE EVIDENCE LINKING DIETARY DIVERSITY, GENETIC SUSCEPTIBILITY, AND DEMENTIA
Hongye Yao, Yangbo Lv
J Prev Alz Dis 2025;8(12)
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CITATION:
Hongye Yao ; Yangbo Lv (2025): Letter to the Editor : Refining the evidence linking dietary diversity, genetic susceptibility, and dementia. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100247
REPLY TO LETTER TO THE EDITOR: “REFINING THE EVIDENCE LINKING DIETARY DIVERSITY, GENETIC SUSCEPTIBILITY, AND DEMENTIA”
Boyue Zhao, Boyue Zhao
J Prev Alz Dis 2025;8(12)
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CITATION:
Boyue Zhao ; Feng Zhang (2025): Reply to Letter to the Editor: “Refining the evidence linking dietary diversity, genetic susceptibility, and dementia”. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100246
LETTER TO THE EDITOR : THE SINGAPORE DEMENTIA PREVENTION PROGRAMME: TEN YEARS ON AND LOOKING AHEAD
Lei Feng, Kaisy Xinhong Ye, Lee Gan Goh, Ee-Heok Kua
J Prev Alz Dis 2025;8(12)
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CITATION:
Lei Feng ; Kaisy Xinhong Ye ; Lee Gan Goh ; Ee-Heok Kua (2025): Letter to the Editor : The singapore demen-tia prevention programme: Ten years on and looking ahead. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100272