Ahead of print articles
BRAIN PATTERNS AND RISK FACTORS IN THE FINGER RCT MULTIMODAL LIFESTYLE INTERVENTION
Giulia Lorenzon, Anna Marseglia, Rosaleena Mohanty, Jenni Lehtisalo, Konstantinos Poulakis, Tiia Ngandu, Alina Solomon, Miia Kivipelto, Eric Westman
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IMPORTANCE: Despite the emergence of anti-amyloid therapies for Alzheimer's disease, targeting modifiable risk factors remains the most effective primary prevention strategy for dementia. While cognitive benefits of multimodal lifestyle interventions have been demonstrated, the underlying effects on brain structure remain unclear, likely due to heterogeneity in brain structure among at-risk individuals.
OBJECTIVE: To investigate how distinct subgroups of at-risk individuals, defined by cortical and subcortical grey matter (GM) patterns, differ in their response to the FINGER intervention, as well as in their demographic, vascular, and lifestyle profiles.
CITATION:
Giulia Lorenzon ; Anna Marseglia ; Rosaleena Mohanty ; Jenni Lehtisalo ; Konstantinos Poulakis ; Tiia Ngandu ; Alina Solomon ; Miia Kivipelto ; Eric Westman (2025): Brain patterns and risk factors in the FINGER RCT multimodal lifestyle intervention. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2025.8
DESIGN: Observational study employing unsupervised clustering of MRI-based cortical thickness and subcortical volume metrics, followed by longitudinal assessment of a lifestyle intervention.
SETTING: The FINGER randomized controlled trial (RCT), a population-based, multidomain lifestyle intervention targeting older adults (aged 60–77) with elevated cardiovascular risk (CAIDE score ≥ 6) and average to slightly below-average cognitive performance.
PARTICIPANTS: A total of 120 participants (61 intervention, 59 control) with available baseline MRI data.
INTERVENTION: Participants were randomly assigned (1:1, double-blind) to a 2-year multidomain lifestyle intervention group – targeting diet, physical activity, cognitive training, social engagement, and metabolic and vascular risk management – or to a control group receiving standard health advice.
MAIN OUTCOMES AND MEASURES: Sociodemographic, vascular, and lifestyle factors, medical comorbidities, and cognitive performance, were assessed at baseline (pre-intervention). Additionally, brain structural outcomes (mean cortical thickness, Alzheimer’s disease and resilience-related cortical signatures, hippocampal volume), and cognition (global, executive function, processing speed, memory) were analysed post-intervention using hierarchical linear models stratified by GM cluster.
RESULTS: Clusters with diffuse or frontal-predominant cortical thinning, but with more favourable vascular profiles, characterized by lower blood pressure and reduced obesity, showed significantly less cortical thinning (mean thickness, AD-signature, and resilience-signature regions; all p < 0.05) following the intervention.
CONCLUSIONS AND RELEVANCE: Stratifying at-risk individuals by GM patterns and vascular risk revealed differential brain responses to the FINGER intervention. These findings underscore the value of brain-based subtyping to optimize personalized dementia prevention strategies in heterogeneous at-risk populations.
CITATION:
Giulia Lorenzon ; Anna Marseglia ; Rosaleena Mohanty ; Jenni Lehtisalo ; Konstantinos Poulakis ; Tiia Ngandu ; Alina Solomon ; Miia Kivipelto ; Eric Westman (2025): Brain patterns and risk factors in the FINGER RCT multimodal lifestyle intervention. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100390
CORRIGENDUM TO 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 (2025) 100268]
Fen Liu, Xuesong Xia, Chengjie Zheng, Feng Liu, Min Jiang
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CITATION:
Fen Liu ; Xuesong Xia ; Chengjie Zheng ; Feng Liu ; Min Jiang (2025): Corrigendum to 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 (2025) 100268]. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100371
ASSOCIATIONS OF CIRCULATING C-REACTIVE PROTEIN LEVELS WITH CENTRAL ALZHEIMER’S DISEASE BIOMARKERS
Hye Ji Choi, Min Soo Byun, Dahyun Yi, Hyejin Ahn, Gijung Jung, Sangyong Park, Joon Hyung Jung, Musung Keum, Bo Kyung Sohn, Yu Kyeong Kim, Hongyoon Choi, Yun-Sang Lee, Jun-Young Lee, Koung Mi Kang, Chul-Ho Sohn, Yen-Ning Huang, Andrew J. Saykin, Kwangsik Nho, Dong Young Lee, KBASE Research Group
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BACKGROUND: C-reactive protein (CRP) is well-known marker of inflammation and immune response. Its potential role in Alzheimer’s disease (AD) pathophysiology remains unclear, particularly in relation to central AD biomarkers, including beta-amyloid (Aβ), tau, and neurodegeneration.
OBJECTIVES: To investigate the associations between circulating CRP levels and central AD biomarkers-including Aβ deposition, tau, and AD-signature neurodegeneration-in nondemented older adults.
DESIGN, SETTING, PARTICIPANTS: This cross-sectional observational study analyzed data from a Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer Disease conducted from 2014 to 2020. A total of 417 nondemented older adults underwent comprehensive evaluations, including blood sampling and multimodal neuroimaging for measuring of Aβ and AD-signature neurodegeneration. A subset of participants (N = 123) also underwent tau positron emission tomography (PET) scan.
MEASUREMENTS: The primary outcomes were A/T/N biomarkers of AD, including brain Aβ and tau deposition measured via amyloid and tau PET, as well as AD-signature neurodegeneration measured by fluorodeoxyglucose (FDG)-PET. Associations between CRP levels and these biomarkers were analyzed while adjusting for CRP-decreasing allele scores, as well as other confounders, including age, sex, vascular risk score, body mass index, nonsteroidal anti-inflammatory drug (NSAID) usage, smoking status, and APOE ε4 carrier status.
RESULTS: The mean (SD) age of participants was 70.57 (8.00) years, with 179 (42.9 %) females. Circulating CRP levels showed non-linear associations with A/T/N biomarkers of AD, showing a U-shaped relationship with Aβ and tau deposition and an inverted U-shaped association with neurodegeneration. Threshold effect analyses revealed that CRP was inversely associated with Aβ deposition (B = -0.081; 95 % CI, -0.153 to -0.007; p = 0.031) below 0.63 mg/L, after adjusting for all confounding variables. In contrast, higher CRP levels were associated with lower cerebral glucose metabolism in AD-signature regions, indicative of greater AD-related neurodegeneration, when above 2.15 mg/L (B = -0.056; 95 % CI, -0.112 to -0.001; p = 0.042).
CONCLUSIONS: Our study revealed differential associations between circulating CRP levels and central AD biomarkers that varied according to the CRP concentration. Further studies are necessary to elucidate the mechanisms underlying the inverse relationship between circulating CRP and brain Aβ within the clinically normal range, as well as potential aggravating effects of elevated CRP on Aβ-independent neurodegeneration.
CITATION:
Hye Ji Choi ; Min Soo Byun ; Dahyun Yi ; Hyejin Ahn ; Gijung Jung ; Sangyong Park ; Joon Hyung Jung ; Musung Keum ; Bo Kyung Sohn ; Yu Kyeong Kim ; Hongyoon Choi ; Yun-Sang Lee ; Jun-Young Lee ; Koung Mi Kang ; Chul-Ho Sohn ; Yen-Ning Huang ; Andrew J. Saykin ; Kwangsik Nho ; Dong Young Lee ; KBASE Research Group (2025): Associations of circulating c-reactive protein levels with central Alzheimer’s disease biomarkers. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100368
TRENDS IN COGNITIVE IMPAIRMENT AMONG OLDER ADULTS IN CHINA FROM 2002 TO 2022: EVALUATING THE IMPACT OF THE COVID-19 PANDEMIC
Lei Feng, Kaisy Xinhong Ye, Qiushi Feng, Yan Mo, Zuqi Cai, Chunbo Li, Jintai Yu, Bin Li, Andrea B. Maier, Yi Zeng, Zhenglian Wang
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BACKGROUND: Cognitive impairment is a growing public health concern, particularly in aging populations. While trends in CI prevalence in China were studied up to 2018, no previous research has explored how the COVID-19 pandemic has affected these trends.
OBJECTIVES: This study aims to extend the analysis to 2022, examining the impact of the pandemic on cognitive impairment prevalence.
PARTICIPANTS: The Chinese Longitudinal Healthy Longevity Survey (CLHLS) data across multiple waves (2002 to 2022) was used (n=64,872).
MEASUREMENTS: Cognitive impairment was assessed using a Chinese version of the Mini-Mental State Examination (MMSE). The rural/urban-sex-single age-specific prevalence of cognitive impairment across different waves were estimated using the DemoRates R package. Cognitive impairment trends before and after the onset of the COVID-19 pandemic were compared to identify any significant changes.
RESULTS: In 2018 and previous waves, an average of 16,191 participants per wave were surveyed (four waves), with a cognitive impairment prevalence of 4.3%. In 2022, post–COVID-19, the survey included 14,022 participants and showed a significant increase in CI prevalence to 6.8%. The observed trends were independent of gender, age group, and residential environment (P-trend < 0.001). However, a significant decrease in mean calf circumference, increase in proportion of overweight participants, and increases in daily fruit and vegetable intake and regular physical activity were notable after the pandemic.
CONCLUSION: The study suggests that the COVID-19 pandemic may have contributed to the observed increase in cognitive impairment prevalence in China, underscoring the importance of further research into the long-term cognitive effects of global health crises. These findings highlight the need to strengthen healthcare systems to support cognitive health in an aging population, while considering both pandemic-related and ongoing factors in the management of cognitive impairment.
CITATION:
Lei Feng ; Kaisy Xinhong Ye ; Qiushi Feng ; Yan Mo ; Zuqi Cai ; Chunbo Li ; Jintai Yu ; Bin Li ; Andrea B. Maier ; Yi Zeng ; Zhenglian Wang (2025): Trends in cognitive impairment among older adults in China from 2002 to 2022: Evaluating the impact of the COVID-19 pandemic. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100370
LETTER TO THE EDITOR: CLARIFYING WHAT BP PREDICTS: COMMENTARY ON CSF AΒ42/40, P-TAU181, AND CENTILOID IN UNIM-PAIRED POPULATIONS
Shaoxiang Huang, Xueyu Wang, Peili Zhang
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CITATION:
Shaoxiang Huang ; Xueyu Wang ; Peili Zhang (2025): Letter to the Editor: Clarifying what BP Predicts: Commentary on CSF Aβ42/40, p-tau181, and centiloid in unimpaired populations. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100372
FOLIC ACID SUPPLEMENTATION IMPROVES COGNITION FUNCTION IN PARTICIPANTS WITH CEREBRAL SMALL VASCULAR DISEASE-RELATED COGNITIVE IMPAIRMENT: A RANDOMIZED CONTROLLED TRIAL
Yinyue Liu, Yinyue Liu, Zhengjun Cai, Li Zhao, Yu Wang, Yajie Guo, Xiaonan Su, Yuli Miao, Bin Yi, Yanhong Wang, Xumei Zhang
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BACKGROUND: The potential improvement of cognitive function through folic acid (FA) supplementation in patients with vascular cognitive impairment (VCI) remains unclear, and no randomized controlled trials (RCTs) have been conducted specifically in populations with cerebral small vessel disease-related cognitive impairment (CSVD-CI).
OBJECTIVE: This study aimed to explore the effects of FA supplementation on cognitive function and angiogenesis-related indicators in patients with CSVD-CI.
DESIGN: Double-blinded, parallel group, randomized controlled trial, with a six-month follow-up period.
SETTING: Department of neurology and neurosurgery in Shanxi, China.
PARTICIPANTS: 220 CSVD-CI patients.
INTERVENTIONS: The intervention consisted of FA tablets (0.4 mg/tablet) administered orally at a dose of two tablets daily for six months, while the placebo tablets were identical in appearance and administration but lacked FA.
MEASUREMENTS: The primary outcome was the Montreal Cognitive Assessment (MoCA) score at six months assessed in the intention-to-treat (ITT) population. Secondary outcomes included Mini-Mental State Examination (MMSE) score, Trail Making Test (TMT), Tinetti Performance Oriented Mobility Assessment (POMA), and five-level EuroQol five-dimensional questionnaire (EQ-5D-5 L).
RESULTS: MoCA and MMSE scores improved significantly in the FA group compared to placebo (both P < 0.05). Additionally, the FA group had statistically significant increases in serum folate and decreases in serum homocysteine (Hcy) (both P < 0.001). Matrix metalloproteinase-9 (MMP-9) expression decreased significantly in the FA group compared with placebo (P < 0.05).
CONCLUSIONS: FA improved cognitive outcomes in CSVD-CI, accompanied by a reduction in serum Hcy levels and MMP-9 expression. Early FA supplementation could help prevent vascular-related cognitive decline in CSVD-CI patients.
CITATION:
Yinyue Liu ; Zili Yu ; Zhengjun Cai ; Li Zhao ; Yu Wang ; Yajie Guo ; Xiaonan Su ; Yuli Miao ; Bin Yi ; Yanhong Wang ; Xumei Zhang (2025): Folic acid supplementation improves cognition function in participants with cerebral small vascular disease-related cognitive impairment: a randomized controlled trial. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100369
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
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
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
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
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
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
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
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
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
JPAD Volume 12, N°09 - 2025
PSYCHIATRY MEETS NEURODEGENERATION – A COLLABORATIVE APPROACH TO DEMENTIA PREVENTION
Carolin Kurz, Martin Haupt, Stefanie Auer, Nicola Lautenschlager, Alexander Kurz
J Prev Alz Dis 2025;9(12)
Show summaryHide summaryThe 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
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
J Prev Alz Dis 2025;9(12)
Show summaryHide summaryBACKGROUND: 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
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
J Prev Alz Dis 2025;9(12)
Show summaryHide summaryLatino 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
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
J Prev Alz Dis 2025;9(12)
Show summaryHide summaryAddressing 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 PRELIMINARY ECONOMIC EVALUATION OF A POTENTIAL PROGRAM FOR THE PRIMARY PREVENTION OF ALZHEIMER’S DISEASE
Soeren Mattke, Jiahe Chen, Eric M Reiman
J Prev Alz Dis 2025;9(12)
Show summaryHide summaryINTRODUCTION: 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
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
J Prev Alz Dis 2025;9(12)
Show summaryHide summaryBACKGROUND: 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
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
J Prev Alz Dis 2025;9(12)
Show summaryHide summaryBACKGROUND: 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
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)
J Prev Alz Dis 2025;9(12)
Show summaryHide summaryBlood-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
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
J Prev Alz Dis 2025;9(12)
Show summaryHide summaryBACKGROUND: 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
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
J Prev Alz Dis 2025;9(12)
Show summaryHide summaryBACKGROUND: 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
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
J Prev Alz Dis 2025;9(12)
Show summaryHide summaryINTRODUCTION: 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
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
J Prev Alz Dis 2025;9(12)
Show summaryHide summaryBACKGROUND: 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
SYSTEMATIC REVIEW AND META-ANALYSIS OF RURAL-URBAN DISPARITIES IN ALZHEIMER’S DISEASE DEMENTIA PREVALENCE
Abe Mollalo, Mackenzie Kramer, Maxwell Cutty, Benyamin Hoseini
J Prev Alz Dis 2025;9(12)
Show summaryHide summaryBACKGROUND: 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
APOE ε4-RELATED DIFFERENCES IN BRAIN STRUCTURE, FUNCTION, AND CONNECTIVITY AT MIDLIFE: A SCOPING REVIEW
Rikki Lissaman, Sidra Anjum, Andrea Quaiattini, M. Natasha Rajah
J Prev Alz Dis 2025;9(12)
Show summaryHide summaryBACKGROUND: 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
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
J Prev Alz Dis 2025;9(12)
Show summaryHide summaryBACKGROUND: 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
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
J Prev Alz Dis 2025;9(12)
Show summaryHide summaryEarly 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
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
J Prev Alz Dis 2025;9(12)
Show summaryHide summaryBACKGROUND: 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
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
J Prev Alz Dis 2025;9(12)
Show summaryHide summaryBACKGROUND/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
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
J Prev Alz Dis 2025;9(12)
Show summaryHide summaryBACKGROUND: 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
J Prev Alz Dis 2025;9(12)
Show summaryHide summaryBACKGROUND: 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
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
J Prev Alz Dis 2025;9(12)
Show summaryHide summaryBACKGROUND 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
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
J Prev Alz Dis 2025;9(12)
Show summaryHide summaryBACKGROUND: 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
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
J Prev Alz Dis 2025;9(12)
Show summaryHide summaryBACKGROUND: 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
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
J Prev Alz Dis 2025;9(12)
Show summaryHide summaryIMPORTANCE: 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
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
J Prev Alz Dis 2025;9(12)
Show summaryHide summaryBACKGROUND: 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
LETTER TO THE EDITOR: REEVALUATING THE NEUROPROTECTIVE PROMISE OF DIETARY NITRATE: COMMENTARY ON RAJENDRA ET AL. (2025)
Parth Aphale, Himanshu Shekhar, Shashank Dokania
J Prev Alz Dis 2025;9(12)
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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
J Prev Alz Dis 2025;9(12)
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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