Ahead of print articles
EFFECT OF OBICETRAPIB, A POTENT CHOLESTERYL ESTER TRANSFER PROTEIN INHIBITOR, ON P-TAU217 LEVELS IN PATIENTS WITH CARDIOVASCULAR DISEASE
Michael H Davidson, Michael Szarek, Philip Scheltens, Everard Vijverberg, Andrew Hsieh, Marc Ditmarsch, Douglas Kling, Danielle Curcio, Stephen J Nicholls, Kausik K Ray, Jeffrey L. Cummings, John JP Kastelein
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BACKGROUND: Cholesteryl ester transfer protein (CETP) inhibition reduces low density lipoprotein-cholesterol (LDL-C) while simultaneously increasing high density lipoprotein-cholesterol (HDL-C) levels and improving HDL-particle functionality. These lipoprotein modifications may provide a novel pathway for Alzheimer disease (AD) prevention through effects on lipid modulation, antioxidant activity, and neuro-inflammation. This approach could prove particularly beneficial for APOE4 carriers, who face elevated risks for both AD and atherosclerotic cardiovascular disease (ASCVD).
OBJECTIVES: To examine the effects of obicetrapib, an oral CETP inhibitor, on biomarker changes indicative of AD pathology among patients with ASCVD
DESIGN: This was a pre-specified substudy of the BROADWAY trial, a phase 3, double-blind, placebo-controlled pivotal registration trial to evaluate the LDL-C lowering efficacy of obicetrapib in adult patients with established ASCVD and/or heterozygous familial hypercholesterolemia (HeFH), whose LDL-C was not adequately controlled, despite being on maximally tolerated lipid-lowering therapy.
SETTING: The trial was conducted across 188 sites in China, Europe, Japan, and the United States. Participants were recruited from cardiology clinics and lipid specialty centers from 2021 to 2024.
PARTICIPANTS: Participants with ASCVD in BROADWAY who had known ApoE status and phosphorylated tau-217 (p-tau217) measured at baseline and 12 months.
INTERVENTION: Participants in BROADWAY were randomized 2:1 to receive oral obicetrapib 10 mg daily or placebo for 12 months.
MEASUREMENTS: AD plasma biomarkers were measured at baseline and 12 months using standardized SIMOA assays. The key outcome measure of interest was change in plasma p-tau217 from baseline to 12 months. Other outcome measures included changes in p-tau217/(Aβ42:40), p-tau181, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL).
RESULTS: The analysis population consisted of 1535 (61 %) of the 2530 BROADWAY participants. Median age was 67 years and 67.0 % were male. Baseline p-tau217 levels varied significantly by ApoE subgroups, with ApoE4 carriers generally having higher concentrations and ApoE4/E4 participants exhibiting the highest median concentration (0.56 pg/mL). Obicetrapib significantly attenuated p-tau217 increases compared to placebo (adjusted mean 2.09 % vs 4.94 %; P = 0.025). Treatment differences were most pronounced in ApoE4 carriers, where adjusted mean increases were 1.92 % and 6.91 %, for obicetrapib and placebo, respectively (P = 0.041). Furthermore, among ApoE4/E4 participants, there was a 7.81 % adjusted mean decrease in p-tau217 with obicetrapib compared to a 12.67 % increase with placebo, representing a 20.48 % treatment difference (P = 0.010). Positive trends were observed across secondary biomarkers, with obicetrapib also significantly limiting increases in the p-tau217/Aβ42:40 ratio compared to placebo (2.51 % vs 6.55 %; P = 0.004). In addition, among ApoE4/E4 participants, obicetrapib demonstrated significant effects on GFAP (-6.39 % vs +8.85 %; P = 0.006) and NfL (-10.49 % vs +6.82 %; P = 0.020). Strong correlations were observed between end-of-study obicetrapib plasma concentrations and biomarker improvements (r=-0.64), suggesting CETP inhibition as a potential mechanism, although other drug effects may also contribute to these changes.
CONCLUSIONS: Obicetrapib significantly slowed AD biomarker progression over 12 months in participants with ASCVD, with the greatest effects in ApoE4 carriers. Among ApoE4/E4 participants, obicetrapib reduced p-tau217 levels by a placebo-adjusted 20.48 % and demonstrated consistent effects across multiple AD biomarkers. These findings represent the first demonstration of an oral intervention capable of reducing both beta-amyloid and tau pathology biomarkers in ApoE4 carriers, offering a potential preventive strategy for this high-risk population who currently have no effective prevention options. Future research will need to establish whether these biomarker changes translate to clinical benefits in dedicated AD prevention trials.
CITATION:
Michael H Davidson ; Michael Szarek ; Philip Scheltens ; Everard Vijverberg ; Andrew Hsieh ; Marc Ditmarsch ; Douglas Kling ; Danielle Curcio ; Stephen J Nicholls ; Kausik K Ray ; Jeffrey L. Cummings ; John JP Kastelein (2025): Effect of obicetrapib, a potent cholesteryl ester transfer protein inhibitor, on p-tau217 levels in patients with cardiovascular disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100394
LETTER TO THE EDITOR : COGNITIVE DECLINE AMONG CHINESE OLDER ADULTS: FINDINGS FROM THE CHINESE LONGITUDINAL HEALTHY LONGEVITY SURVEY (CLHLS)
Kaisy Xinhong Ye, Lei Feng, Tih-Shih Lee, Yi Zeng, Zhengliang Wang
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CITATION:
Kaisy Xinhong Ye ; Lei Feng ; Tih-Shih Lee ; Yi Zeng ; Zhengliang Wang (2025): Letter to the Editor: Cognitive decline among Chinese older adults: Findings from the Chinese Longitudinal Healthy Longevity Survey (CLHLS). The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100393
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
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
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
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
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
JPAD Volume 12, N°10 - 2025
EDITORIAL: HARNESSING COMBINATION THERAPY: CURRENT TREATMENTS, RECENT ADVANCEMENTS, AND FUTURE DIRECTIONS IN ALZHEIMER\'S DISEASE
Howard M Fillit, Jacques Touchon, Bruno Vellas, Laura K Nisenbaum, Aaron H Burstein
J Prev Alz Dis 2025;10(12)
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CITATION:
Howard M Fillit ; Jacques Touchon ; Bruno Vellas ; Laura K Nisenbaum ; Aaron H Burstein (2025): Editorial: Harnessing combination therapy: Current treatments, recent advancements, and future directions in Alzheimer's disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100327
ALZHEIMER COMBINATION THERAPIES: OVERVIEW AND SCENARIOS
Jeffrey L Cummings, Aaron H Burstein, Howard Fillit
J Prev Alz Dis 2025;10(12)
Show summaryHide summaryProgress in understanding the complexity of Alzheimer's disease informs the search for combination therapies that can successfully prevent or substantially slow the progression of the disease. Anti-amyloid monoclonal antibodies are the first approved disease targeted therapies; they slow disease progression by approximately 30 %. Building on these agents in add-on therapies is one avenue to designing combination treatments. Development of combination drugs consisting of two or more novel interventions is an alternate pathway for combination treatment development. Combination therapies can involve small molecule drugs, biological agents, devices, stem cells, gene therapies, lifestyle interventions, or cognitive training. Nonclinical assessment of drug combinations may involve animal models or new approach methodologies such as induced pluripotent stem cells or organoids. Phase 1 trials are required to characterize each member of a novel combination. Phase 2 trials may use a 2-by-2 factorial design comparing each drug to placebo and the drug combination. In Phase 3, comparison of the novel combination to standard of care may be sufficient or more complex designs may be required. Targets for combination therapies beyond amyloid-related processes include tau abnormalities, inflammation, neurodegeneration, and co-pathologies such as alpha-synuclein and TDP-43. The choice of combination therapies will depend on the strength of the information regarding the target, biomarkers to guide clinical trials, and a candidate agent with the appropriate mechanism of action. Computational strategies based on network analysis of disease and drugs, validation in non-clinical models, and use of real-world data may facilitate prioritization of candidates for combination treatments.
CITATION:
Jeffrey L Cummings ; Aaron H Burstein ; Howard Fillit (2025): Alzheimer Combination Therapies: Overview and Scenarios. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100328
ADD-ON COMBINATION THERAPY WITH MONOCLONAL ANTIBODIES: IMPLICATIONS FOR DRUG DEVELOPMENT
Jeffrey Cummings, Aaron H Burstein, Howard Fillit
J Prev Alz Dis 2025;10(12)
Show summaryHide summaryThree anti-amyloid monoclonal antibodies (MABs) including aducanumab, lecanemab, and donanemab have been approved by the FDA and lecanemab and donanemab are available in the US market and a variety of other national markets. The increasing use of anti-amyloid MABs to treat early AD will require that development of novel agents occur as add-on treatment to MABs. There is limited experience with add-on therapy to anti-amyloid agents. In most cases, it is prudent to initiate novel agents after at least six-months exposure to the MAB at the highest dose. Agents with extensive data on pharmacokinetics and pharmacodynamics and well-known safety may employ alternative approaches. Anti-amyloid MABs have different mechanisms of action, titration, and side effect profiles suggesting that add-on trials include only one type of MAB if possible. Demonstration of clinical benefit with add-on therapy will require showing additional slowing beyond that provided by the anti-amyloid MAB. Anti-amyloid therapies have profound effects on biomarkers including amyloid positron emission tomography and plasma p-tau and plasma GFAP measures. Definition of the biomarker profile of a novel agent prior to initiation of add-on therapies, inclusion of target engagement biomarkers specific to the novel intervention, assessment of biomarkers not known to be affected by anti-amyloid MABs, and interrogation of the magnitude, timing, and trajectory of biomarker change in the add-on context compared to monotherapy with MABs will provide insight into the biological impact of the novel therapy on AD. Patient convenience in terms of formulation and timing of add-on therapies will be important to successful clinical implementation. Add-on therapies are an important step in addressing the complexity of AD and optimizing patient outcomes.
CITATION:
Jeffrey Cummings ; Aaron H Burstein ; Howard Fillit (2025): Add-on combination therapy with monoclonal antibodies: Implications for drug development. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100359
THE ROLE FOR ARTIFICIAL INTELLIGENCE IN IDENTIFYING COMBINATION THERAPIES FOR ALZHEIMER’S DISEASE
Feixiong Cheng, Zhendong Sha, Yadi Zhou, Yuan Hou, Pengyue Zhang, Andrew A. Pieper, Jeffrey Cummings
J Prev Alz Dis 2025;10(12)
Show summaryHide summaryDespite substantial investment in biomedical and pharmaceutical research over the past two decades, the global prevalence of Alzheimer’s disease (AD) and AD-related dementias (AD/ADRD) is still rising. This underscores the significant unmet need for identifying effective disease-modifying therapies. Here, we provide a critical perspective on the application of data science and artificial intelligence (AI) to the rational design of drug combinations in AD and ADRD, addressing their potential to transform therapeutic development. We examine AI’s current and prospective capabilities in therapeutic discovery, identify areas where AI-driven strategies can enhance drug combination development, and outline how multidisciplinary professionals in the field, including clinical trialists, neuropsychiatrists, pharmacologists, medicinal chemists, and computational scientists, can leverage these tools to address therapeutic gaps. We also highlight AI’s role in synthesizing the rapidly growing amount of biomedical data in the field of AD/ADRD, especially clinical trials, biomarkers, multi-omics data (genomics, transcriptomics, proteomics, metabolomics, interactomics, and radiomics), and real-world patient data. We further explore AI’s utility in prioritizing potential drug combination regimens and estimating clinical effect size in combination therapy trials for AD/ADRD. Lastly, we emphasize AI-powered network medicine methodologies for prioritizing drug combinations targeting AD/ADRD co-pathologies and summarize the challenges of their translation to clinical practice.
CITATION:
Feixiong Cheng ; Zhendong Sha ; Yadi Zhou ; Yuan Hou ; Pengyue Zhang ; Andrew A. Pieper ; Jeffrey Cummings (2025): The role for artificial intelligence in identifying combination therapies for Alzheimer’s disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100366
THE IMPACT OF RECENT APPROVALS ON FUTURE ALZHEIMER’S DISEASE CLINICAL DEVELOPMENT: STATISTICAL CONSIDERATIONS FOR COMBINATION TRIALS
Samuel P Dickson, Craig Mallinckrodt, Aaron H Burstein, Laura Nisenbaum, Howard M Fillit, Chenge Zhang, Suzanne B Hendrix
J Prev Alz Dis 2025;10(12)
Show summaryHide summaryBACKGROUND: A new era of Alzheimer’s disease (AD) research is beginning with multiple approved anti-amyloid monoclonal antibodies (mABs). These drugs are currently not widely used, but may be soon, especially at clinical trial sites. Putative disease-modifying therapies (DMTs) may alter the progression rate, potentially reducing our ability to detect effects on top of mABs. Co-administration of amyloid-targeted agents may diminish benefit (antagonism, due to the overlapping mechanism of action); alternatively, complementary treatment mechanisms may increase benefit (synergy).
METHOD: We consider several clinical trial design scenarios: a 2-arm trial added-on to a mAB, a 2-arm combination compared to double placebo, and a 4-arm full factorial trial. We calculate the required sample sizes for the shortest practical study for secondary prevention (prevention of AD clinical diagnosis in biomarker positive individuals, 2-year study), early AD (18-months), and mild-to-moderate AD (1-year). We consider additivity, antagonism, and synergy.
RESULT: The expected interaction between investigational and mAB treatment can have a large effect on power and study design. Antagonistic treatment effects often require double the sample size of synergistic effects. The 4-arm scenario required ∼10-fold increase compared to a 2-arm combination study.
CONCLUSION: Studies evaluating investigational therapies as add-on to mABs are complex, and their cost will depend on the interaction between treatments. An inescapable fact in add-on trials is the slower progression of the control arm; and it is difficult to further slow already slow progression. Treatments that are likely to work better with amyloid removal will be easier to study due to their complementary MOA. Symptomatic treatments may require fewer additional subjects than disease-modifying treatments since they are less affected by the presence or absence of mABs.
CITATION:
Samuel P Dickson ; Craig Mallinckrodt ; Aaron H Burstein ; Laura Nisenbaum ; Howard M Fillit ; Chenge Zhang ; Suzanne B Hendrix (2025): The impact of recent approvals on future alzheimer’s disease clinical development: Statistical considerations for combination trials. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100391
STATISTICAL INNOVATIONS IN CLINICAL TRIAL DESIGN WITH A FOCUS ON DRUG COMBINATIONS, FACTORIALS, AND OTHER MULTIPLE THERAPY ISSUES
Donald A. Berry
J Prev Alz Dis 2025;10(12)
Show summaryHide summaryStatistical methods in clinical research tend to become entrenched. Innovations threaten the status quo. The “right way” becomes frozen in lore. This is so even when the “right way” is not best. “Statistical significance” and the associated requirement of “high power” is an example. This attitude is an impediment to efficient design. Willingness to address some design issues with moderate power enables building highly informative and highly efficient clinical trials. This article considers several types of clinical trials, including dose-finding, combinations, and factorial designs. Bayesian adaptive methods are used to show that trials can be made more efficient and more informative. Surprisingly, the approach is consistent with many attitudes of the widely regarded “Father of Modern Statistics,” R.A. Fisher. Fisher was anti-Bayesian in rejecting its subjective interpretations. But Fisher and Bayes come to the same conclusion in many applied matters. Fisher invented factorial design. Its principal attraction for him was enabling addressing two or more questions with a single experiment. He complained about attitudes that hindered progress: “No aphorism is more frequently repeated in connection with field trials [and clinical trials], than that we must ask Nature few questions, or, ideally, one question at a time… this view is wholly mistaken.” Fisher’s primary analysis required modeling and making assumptions. For example, his first analysis in a factorial setting assumed no interactions among the factors. He investigated possibilities of interactions but he did not see the need for doing so with high power.
CITATION:
Donald A. Berry (2025): Statistical innovations in clinical trial design with a focus on drug combinations, factorials, and other multiple therapy issues. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100392
RISK REDUCTION AND PRECISION PREVENTION ACROSS THE ALZHEIMER’S DISEASE CONTINUUM: A SYSTEMATIC REVIEW OF CLINICAL TRIALS COMBINING MULTIDOMAIN LIFESTYLE INTERVENTIONS AND PHARMACOLOGICAL OR NUTRACEUTICAL APPROACHES
Erika Bereczki, Francesca Mangialasche, Mariagnese Barbera, Paola Padilla, Yuko Hara, Howard Fillit, Alina Solomon, Miia Kivipelto
J Prev Alz Dis 2025;10(12)
Show summaryHide summaryTo effectively combat dementia onset and progression, lifestyle-based interventions targeting multiple risk factors and disease mechanisms through a multidomain approach - tailored and implemented early in the disease process - have emerged as promising. Electronic databases and relevant websites (clinicaltrials.gov, euclinicaltrials.eu, PubMed and EMBASE) were systematically searched for randomized controlled trials (RCTs) testing the combination of multidomain lifestyle and pharmacological interventions. Studies were included if 1) lifestyle intervention was multimodal (≥2 domains); 2) it was combined with drugs, supplements, or medical food; 3) the study population was within the Alzheimer’s disease (AD) and related dementias continuum, including cognitively normal individuals at-risk for dementia, people with subjective cognitive decline (SCD), mild cognitive impairment (MCI), or prodromal AD; 4) outcomes included cognitive or dementia-related measure(s), and 5) intervention lasted at least 6 months. Twelve combination RCTs were identified, incorporating 2 to 7 lifestyle domains (physical exercise, cognitive training, dietary guidance, social activities, sleep hygiene, cardiovascular/metabolic risk management, psychoeducation or stress management), combined with pharmacological components (e.g., Omega-3, Tramiprosate, vitamin D, BBH-1001, epigallocatechin gallate, Souvenaid, and metformin). Seven RCTs targeted participants with prodromal AD, MCI or early dementia, five focused on at risk individuals or SCD. Additionally, 2 studies adopted a precision medicine approach by enriching populations with APOE-ε4 carriers. Findings suggest that well-designed interventions - tailored to the right individuals, implemented at the optimal time - may effectively improve cognition. However, further refinement of the RCT methodology is warranted, for better alignment with the multifaceted nature of dementia prevention and management.
CITATION:
Erika Bereczki ; Francesca Mangialasche ; Mariagnese Barbera ; Paola Padilla ; Yuko Hara ; Howard Fillit ; Alina Solomon ; Miia Kivipelto (2025): Risk reduction and precision prevention across the Alzheimer’s disease continuum: a systematic review of clinical trials combining multidomain lifestyle interventions and pharmacological or nutraceutical approaches. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100367
IDENTIFYING SYNERGISTIC COMBINATIONS OF REPURPOSED TREATMENTS FOR ALZHEIMER’S DISEASE
Clive Ballard, Janet Sultana, Pat Doherty, Gareth Williams, Anne Corbett
J Prev Alz Dis 2025;10(12)
Show summaryHide summaryThere is considerable opportunity to fast-track novel treatments for Alzheimer’s Disease (AD) through repurposing of existing licensed medications as a way of complementing ongoing drug discovery efforts. Given the complex interplay between AD neuropathological mechanisms, there is also a strong rationale that treatment benefits may be enhanced by examining combinations of treatments to identify potential synergies that would address multiple disease-modifying mechanisms. A Delphi consensus programme combined with a pragmatic analysis of primary care data has identified a series of individual and combined therapies that warrant further investigation in pre-clinical and clinical trials. These include treatments which target well-established neurodegeneration pathways and more explorative agents, including hormonal and anti-infective agents, which align to emerging hypotheses relating to endocrine and immune pathways in AD. Whilst caution is critical when considering combined therapy due to the risks of interaction and polypharmacy, this study provides valuable indications of potential synergistic drug pairs that warrant further investigation.
CITATION:
Clive Ballard ; Janet Sultana ; Pat Doherty ; Gareth Williams ; Anne Corbett (2025): Identifying synergistic combinations of repurposed treatments for Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD).https://doi.org/10.1016/j.tjpad.2025.100329
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
J Prev Alz Dis 2025;10(12)
Show summaryHide summaryBACKGROUND: 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
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
J Prev Alz Dis 2025;10(12)
Show summaryHide summaryIMPORTANCE: 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
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
J Prev Alz Dis 2025;10(12)
Show summaryHide summaryBACKGROUND: 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
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
J Prev Alz Dis 2025;10(12)
Show summaryHide summaryBACKGROUND: 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
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
J Prev Alz Dis 2025;10(12)
Show summaryHide summaryBACKGROUND: 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
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)
J Prev Alz Dis 2025;10(12)
Show summaryHide summaryBACKGROUND: 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
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
J Prev Alz Dis 2025;10(12)
Show summaryHide summaryBACKGROUND: 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
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
J Prev Alz Dis 2025;10(12)
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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
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
J Prev Alz Dis 2025;10(12)
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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