02/2026 journal articles
ASSOCIATIONS OF MODIFIABLE AND NON-MODIFIABLE RISK FACTORS WITH LONGITUDINAL WHITE MATTER HYPERINTENSITIES, AMYLOID-Β AND TAU - A PROSPECTIVE COHORT STUDY
Isabelle Glans, Niklas Mattsson-Carlgren, Olof Strandberg, Erik Stomrud, Rik Ossenkoppele, Danielle van Westen, Nicola Spotorno, Oskar Hansson, Sebastian Palmqvist
J Prev Alz Dis 2026;2(13)
Show summaryHide summaryBACKGROUND: The global prevalence of dementia is rapidly expanding and is expected to triple by 2050. Approximately 45 % of dementia cases are estimated to be attributable to potentially modifiable risk factors. Identifying how these factors contribute to specific brain pathologies may improve strategies to reduce dementia incidence.
OBJECTIVES, DESIGN, SETTING: The aim of this study was to identify both non-modifiable and modifiable risk factors associated with longitudinal changes in white matter hyperintensities (WMH), amyloid-beta (Aβ) and tau. Data were acquired in the prospective observational Swedish BioFINDER-2 study between May 2017-January 2025. All participants underwent clinical assessments, questionnaires and at least two magnetic resonance imaging (MRI), Aβ Positron Emission Tomography (PET) and tau PET scans, respectively. Mixed-effects models were used to assess the associations between non-modifiable and modifiable risk factors and WMH (MRI), Aβ (PET) and tau (PET).
PARTICIPANTS: A total of 494 cognitively unimpaired participants were included, of whom 365 were amyloid-negative (CU Aβ−) and 129 were amyloid-positive (CU Aβ+).
MEASUREMENTS AND MAIN OUTCOMES: Non-modifiable (age, apolipoprotein E (APOE) ɛ4 genotype and sex) and modifiable risk factors (co-morbidities at baseline, such as hypertension and cardiovascular disease, BMI, and sleep duration) were analyzed with mixed-effects models, adjusted for age and sex, to predict longitudinal measurements of WMH, Aβ and tau.
RESULTS: Mean age was 64.8 (SD 13.3) years and mean follow-up was 3.9 (SD 1.5) years. Predictors represent baseline data, both predictors and outcomes are on standardized scales. Linear mixed-effects models, adjusted for age and sex, showed that higher blood pressure (β = 0.02, 95 % CI :0.01–0.02), presence of hyperlipidemia (β = 0.03, 0.01–0.05), ischemic heart disease (β = 0.06, 0.03–0.09), smoking (β = 0.02, 0.00–0.03) and lower education (β = -0.01, -0.02– -0.01) were associated with a longitudinal increase in WMH. Presence of the APOE ε4 allele was linked to faster Aβ accumulation (β = 0.03, 0.02–0.04) and tau (β = 0.01, 0.00–0.03), but only to Aβ among Aβ+ positive participants. Higher depression score (β = 0.01, 0.00–0.01) and diabetes (β = 0.02, 0.00–0.04) were associated with faster Aβ accumulation. Lower BMI was associated with faster accumulation of tau (β = -0.01, -0.02– -0.01).
CONCLUSIONS: Modifiable risk factors of future dementia primarily affect accumulation of cerebral vascular pathology, although lower BMI was associated with tau accumulation and diabetes with Aβ accumulation.
CITATION:
Isabelle Glans ; Niklas Mattsson-Carlgren ; Olof Strandberg ; Erik Stomrud ; Rik Ossenkoppele ; Danielle van Westen ; Nicola Spotorno ; Oskar Hansson ; Sebastian Palmqvist (2025): Associations of modifiable and non-modifiable risk factors with longitudinal white matter hyperintensities, amyloid-β and tau - a prospective cohort study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100448
ASSOCIATION OF NEIGHBORHOOD DISADVANTAGE WITH ALZHEIMER\'S DISEASE PATHOLOGY AND THE STABILITY OF BLOOD-BASED BIOMARKER PERFORMANCE
Alison Myoraku, Isabella Hausle, Marta Mila-Aloma, Pamela Thropp, Laura A. Wang, P. Murali Doraiswamy, Duygu Tosun, Alzheimer’s Disease Neuroimaging Initiative
J Prev Alz Dis 2026;2(13)
Show summaryHide summaryBACKGROUND: Neighborhood-level factors, measured by the Area Deprivation Index (ADI), are linked to comorbidities of Alzheimer's disease and related dementias (ADRD). However, their direct association with AD neuropathology is unclear. The accessibility of blood-based biomarkers (BBMs) like p-tau217 and Aβ42/40 offers a scalable way to investigate these relationships.
OBJECTIVES: To examine the relationship between ADI and levels of key BBMs (p-tau217/Aβ42, p-tau217, and Aβ42/40). We also aimed to assess whether the performance of these BBMs in predicting amyloid PET positivity is consistent across different levels of neighborhood disadvantage.
DESIGN: A cross-sectional analysis using data from an observational cohort study of the Alzheimer’s Disease Neuroimaging Initiative (ADNI).
SETTING: Multicenter observational cohort conducted at 55 sites across the United States.
PARTICIPANTS: The study included 755 ADNI participants with ADI and amyloid PET data. A sub-cohort of 438 participants also had BBM data available.
MEASUREMENTS: National ADI scores were used to stratify participants into least, intermediately, and most disadvantaged groups. Amyloid PET positivity was determined using Centiloid values. Plasma levels of p-tau217, Aβ42, and Aβ40 were measured using Fujirebio assays.
RESULTS: ADI groups differed by sex, ethnoracial background, and MMSE scores. The intermediately disadvantaged group had 1.55 times higher odds of being amyloid PET positive compared to the least disadvantaged group. While this group also showed higher levels of plasma p-tau217/Aβ42 and p-tau217, these differences were no longer significant after accounting for the higher prevalence of amyloid positivity. Critically, the predictive accuracy of all three BBMs for amyloid PET status did not differ across the ADI groups. The p-tau217/Aβ42 ratio performed best, yielding the fewest indeterminate cases in a two-cut-point classification model.
CONCLUSIONS: The diagnostic performance of plasma AD biomarkers is robust and is not compromised by neighborhood-level disadvantage. These findings support the generalizability and equitable clinical utility of biomarkers like p-tau217/Aβ42 for AD diagnosis across diverse socioeconomic settings.
CITATION:
Alison Myoraku ; Isabella Hausle ; Marta Mila-Aloma ; Pamela Thropp ; Laura A. Wang ; P. Murali Doraiswamy ; Duygu Tosun ; Alzheimer’s Disease Neuroimaging Initiative (2025): Association of neighborhood disadvantage with Alzheimer's disease pathology and the stability of blood-based biomarker performance. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100445
ASSOCIATION OF LIFE’S SIMPLE 7 WITH COGNITIVE FUNCTION IN A MULTI-ETHNIC COHORT
Xiangyuan Huang, Muhammad Haiman Bin Samad, Gerald Choon Huat Koh, Andre Matthias Müller, Falk Müller-Riemenschneider, Xueling Sim, Saima Hilal
J Prev Alz Dis 2026;2(13)
Show summaryHide summaryBACKGROUND AND OBJECTIVES: Multiple lifestyle and health factors could contribute to cognitive health, while not many studies examined the factors in a combined way, especially in Asian population. This study aims to examine the association of Life’s Simple 7 (LS7) with cognitive function and its change in a multi-ethnic Asian population.
METHODS: Longitudinal data were drawn from the Singapore Multi-Ethnic Cohort, involving 2601 participants (45–86 years). LS7 at baseline was calculated by summing seven metrics, and a higher LS7 (range: 0–7) score indicates a healthier lifestyle. Cognitive function was measured at two revisits with Mini-Mental State Examination (MMSE). Association of baseline LS7 with MMSE percentiles (10th, 30th and 50th) and its change over time were examined using linear quantile mixed model. Interactions between LS7 and age group, sex, ethnicity, education level and marital status were also explored.
RESULTS: Higher LS7 was significantly associated with higher MMSE scores at 10th (β = 0.11, 95% CI 0.01, 0.20), 30th (β = 0.12, 95% CI 0.05, 0.19), and 50th (β = 0.07, 95% CI 0.03, 0.11) percentiles. These associations were particularly pronounced among currently unmarried individuals, participants aged 60 and above, those with education above primary school and Chinese ethnicity. No significant association was found between LS7 and MMSE change over time.
DISCUSSION: Higher LS7 was significantly associated with better cognition particularly among older, unmarried individuals and participants with higher education or of Chinese ethnicity. These findings highlight the value of composite lifestyle scores for cognitive impairment risk modification in Asian populations.
CITATION:
Xiangyuan Huang ; Muhammad Haiman Bin Samad ; Gerald Choon Huat Koh ; Andre Matthias Müller ; Falk Müller-Riemenschneider ; Xueling Sim ; Saima Hilal (2025): Association of life’s simple 7 with cognitive function in a multi-ethnic cohort. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100453
A REVIEW OF EVIDENCE SUPPORTING AMYLOID BETA REDUCTION AS A SURROGATE ENDPOINT IN ALZHEIMER’S DISEASE
Tianle Chen, R. Matthew Hutchison, Carrie Rubel, Jennifer Murphy, Jing Xie, John O’Gorman, Gersham Dent, Geert Molenberghs, Maria Pia Sormani, Suzanne Hendrix, Oskar Hansson, Paul Aisen, Samantha Budd Haeberlein, Ying Tian
J Prev Alz Dis 2026;2(13)
Show summaryHide summaryAlzheimer’s disease (AD) is a heterogeneous neurodegenerative disease driven by pathological depositions of proteins that accumulate over decades. Compelling genetic and neurobiological evidence suggests that amyloid accumulation in the brain initiates and drives early-stage AD. Measurement of fibrillar amyloid has been pivotal to the development and approval of disease-slowing treatments. Various biomarkers of AD pathophysiology provide evidence of target engagement and downstream effects on disease progression, and their use as surrogate endpoints may help identify and expeditiously bring new treatments to patients. In clinical trials, a surrogate endpoint serves as a substitute for a direct measurement of a patient’s clinical status, and its use can provide ethical, logistical, and economic advantages. Establishing biomarkers as surrogate endpoints involves evaluating scientific evidence through diverse statistical approaches to demonstrate their predictivity of clinical benefit. This article evaluated evidence supporting amyloid β plaque reduction as a surrogate endpoint in symptomatic AD by exploring regulatory considerations and guidelines for surrogate endpoints, examining the amyloid hypothesis and the current therapeutic landscape in AD, and presenting supporting evidence of surrogate endpoints from a recent clinical development program of AD.
CITATION:
Tianle Chen ; R. Matthew Hutchison ; Carrie Rubel ; Jennifer Murphy ; Jing Xie ; John O’Gorman ; Gersham Dent ; Geert Molenberghs ; Maria Pia Sormani ; Suzanne Hendrix ; Oskar Hansson ; Paul Aisen ; Samantha Budd Haeberlein ; Ying Tian (2025): A review of evidence supporting amyloid beta reduction as a surrogate endpoint in Alzheimer’s disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100458
DONANEMAB IN EARLY SYMPTOMATIC ALZHEIMER’S DISEASE: RESULTS FROM THE TRAILBLAZER-ALZ 2 LONG-TERM EXTENSION
Jennifer A. Zimmer, John R. Sims, Cynthia D. Evans, Emel Serap Monkul Nery, Hong Wang, Alette M. Wessels, Giulia Tronchin, Shoichiro Sato, Lars Lau Raket, Lars Lau Raket, Christophe Sapin, Marie-Ange Paget, Ivelina Gueorguieva, Paul Ardayfio, Rashna Khanna, Dawn A. Brooks, Brandy R. Matthews, Mark A. Mintun, Alzheimer’s Disease Neuroimaging Initiative
J Prev Alz Dis 2026;2(13)
Show summaryHide summaryBACKGROUND: Donanemab significantly slowed clinical progression in participants with early symptomatic Alzheimer’s disease (AD) during the 76-week placebo-controlled period of TRAILBLAZER-ALZ 2.
METHODS: Participants who completed the placebo-controlled period were eligible for the 78-week, double-blind, long-term extension (LTE). Early-start participants were randomized to donanemab in the placebo-controlled period. Delayed-start participants (randomized to placebo) started donanemab in the LTE. Participants who met amyloid treatment course completion criteria were switched to placebo. An external control cohort comprised participants from the AD Neuroimaging Initiative (ADNI).
RESULTS: At 3 years, donanemab slowed disease progression on the Clinical Dementia Rating Scale (CDR)-Sum of Boxes (CDR-SB) in early-start participants versus a weighted ADNI control (-1.2 points; 95 % confidence interval [CI], -1.7, -0.7). Seventy-six weeks after initiating donanemab, delayed-start participants also demonstrated slower CDR-SB progression versus a weighted ADNI control (-0.8 points; 95 % CI, -1.3, -0.3). Participants who completed treatment by 52 weeks demonstrated similar slowing of CDR-SB progression at 3 years. Compared with delayed-start participants, early-start participants demonstrated a significantly lower risk of disease progression on the CDR-Global over 3 years (hazard ratio=0.73; p < 0.001). In both groups, >75 % of participants assessed by positron emission tomography 76 weeks after starting donanemab achieved amyloid clearance (<24.1 Centiloids). The addition of LTE data to prior modeling predicted a median reaccumulation rate of 2.4 Centiloids/year. No new safety signals were observed compared to the established donanemab safety profile.
CONCLUSIONS: Over 3 years, donanemab-treated participants with early symptomatic AD demonstrated increasing clinical benefits and a consistent safety profile, with limited-duration dosing.
CITATION:
Jennifer A. Zimmer ; John R. Sims ; Cynthia D. Evans ; Emel Serap Monkul Nery ; Hong Wang ; Alette M. Wessels ; Giulia Tronchin ; Shoichiro Sato ; Lars Lau Raket ; Scott W. Andersen ; Christophe Sapin ; Marie-Ange Paget ; Ivelina Gueorguieva ; Paul Ardayfio ; Rashna Khanna ; Dawn A. Brooks ; Brandy R. Matthews ; Mark A. Mintun ; Alzheimer’s Disease Neuroimaging Initiative (2025): Donanemab in early symptomatic Alzheimer’s disease: results from the TRAILBLAZER-ALZ 2 long-term extension. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100446
TAU IN ALZHEIMER\'S DISEASE: SHAPING THE FUTURE PATIENT JOURNEY
Catherine J. Mummery, Christopher Chen Li-Hsian, Cristian A. Lasagna-Reeves, Rik Ossenkoppele, Christopher C. Rowe, Douglas W. Scharre, Huali Wang, Simon Kyaga, Jeffrey L. Cummings
J Prev Alz Dis 2026;2(13)
Show summaryHide summaryAlzheimer’s disease is a complex and multifactorial disease characterized by two key pathological hallmarks: amyloid-beta plaques and tau neurofibrillary tangles. Recent progress has led to the development and approval of disease-targeted therapies for Alzheimer’s disease in the form of anti-amyloid-beta monoclonal antibodies. However, findings suggest that amelioration of multiple pathological drivers may be required to maximize clinical effect. An increasing body of evidence suggests that tau is a critical player in Alzheimer’s disease pathophysiology, contributing significantly to neurodegeneration and cognitive decline. There are now several tau-targeting drugs in clinical development. In this review, we build on research and advancements in the field of tau to envision how an increasing focus on tau could shape the future Alzheimer’s disease patient journey. We highlight the potential of tau as both a promising therapeutic target and a valuable biomarker, with the potential to inform treatment decisions and provide insight into disease trajectories. We also consider what a greater focus on tau may bring to an already evolving patient care pathway characterized by an increased influx of patients presenting earlier in the disease continuum, changes in workflow and infrastructural requirements, and increased complexity in treatment decision-making, treatment administration, treatment monitoring, and patient tracking. This review underscores the critical changes that may be required and knowledge gaps to be elucidated to ensure healthcare system preparedness for additional classes of disease-targeted therapy to move toward a next-generation, individualized treatment approach to Alzheimer’s disease diagnosis and care.
CITATION:
Catherine J. Mummery ; Christopher Chen Li-Hsian ; Cristian A. Lasagna-Reeves ; Rik Ossenkoppele ; Christopher C. Rowe ; Douglas W. Scharre ; Huali Wang ; Simon Kyaga ; Jeffrey L. Cummings (2025): Tau in Alzheimer's disease: Shaping the future patient journey. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100447
SYSTEMATIC POST-TRANSLATIONAL MODIFICATION GENOME WIDE IDENTIFIES THERAPEUTIC TARGETS FOR ALZHEIMER’S DISEASE: EVIDENCE FROM MULTI-COHORT ANALYSIS
Xiaoming Wang, Yuancheng Liu, Juncai Fu, Yizhao Li, Mengying Zhao, Qing Tian
J Prev Alz Dis 2026;2(13)
Show summaryHide summaryBACKGROUND: The rapid increase in the incidence of Alzheimer’s disease (AD) has raised concerns, given its profound effects on both society and the economy. Despite extensive research efforts in this area, there are no existing treatments that have the ability to change the progression of the disease.
METHODS: To identify the distinct subtypes of AD, consensus clustering was employed. Following this, module genes were identified through the implementation of WGCNA. In addition, the investigation included the identification of hub genes through the application of machine learning. Ultimately, a thorough analysis was performed utilizing a methodical strategy to perform post-translational modification (PTM) genome wide.
RESULTS: GO and KEGG analyses were conducted by examining of 21 different types of PTMs, revealing that the majority of these genes play key roles in the PTM pathways, as well as AD-related pathways. Correlation analysis revealed that these PTM were significantly correlated with gamma secretase activity, beta secretase activity, amyloid-beta 42, clinical dementia rating, Braak stage, plaque, and neurofibrillary tangle. Then, two distinct subtypes of PTM were identified, each characterized by unique clinical characteristic. By utilizing machine learning, we developed an PTM.score, and has shown impressive predictive capabilities for AD when tested against various datasets (brain AUC: 0.859, blood AUC: 0.898), indicating its potential utility in clinical settings for risk stratification and therapeutic decision-making. Moreover, our investigation led to the identification of two genes (TRIM47 and LNX1) that may represent potential drug targets for AD (brain tissues or blood samples). Research further indicated a potential correlation between TRIM47 and concentrations of CSF Aβ (OR 1.068 (1.029–1.108)), CSF p-tau (OR 1.315 (1.136–1.524)), and total hippocampal (OR 1.176 (1.058–1.307)).
CONCLUSIONS: The findings from this study not only enhance our comprehension of the underlying mechanisms of AD but also serve to inform and direct future initiatives in drug discovery. By focusing on TRIM47, the work paves the way for identifying innovative therapeutic strategies.
CITATION:
Xiaoming Wang ; Yuancheng Liu ; Juncai Fu ; Yizhao Li ; Mengying Zhao ; Qing Tian (2025): Systematic post-translational modification genome wide identifies therapeutic targets for Alzheimer’s disease: evidence from multi-cohort analysis. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100422>
ASSOCIATIONS OF PLASMA BIOMARKERS WITH LONGITUDINAL CO-PATHOLOGIES IN ALZHEIMER’S DISEASE AND CEREBRAL SMALL VESSEL DISEASE COMORBIDITY
Jing Yang, Xinyuan Zhao, Yidan Liu, Yangwei Cai, Yuhua Fan, Alzheimer’s Disease Neuroimaging Initiative
J Prev Alz Dis 2026;2(13)
Show summaryHide summaryBACKGROUND: Plasma glial fibrillary acidic protein (GFAP), neurofilament light (NfL), phosphorylated tau217 (p-tau217), and the β-amyloid (Aβ) 42/40 ratio are emerging indicators of neuroinflammation, neurodegeneration, and AD-specific pathology, while their specific roles within Alzheimer’s disease (AD) and cerebral small vessel disease (CSVD) comorbidity are not fully understood.
METHODS: Participants with normal cognition or mild cognitive impairment were drawn from the Alzheimer’s Disease Neuroimaging Initiative database. Multivariable linear regression and linear mixed-effects models were employed to examine associations of baseline plasma biomarkers with neuropathological features and cognition. Furthermore, Cox proportional hazards models assessed the associations of plasma biomarkers with the risk of comorbid AD and CSVD.
RESULTS: In total populations, elevated GFAP and p-tau217 were significantly associated with greater white matter hyperintensity (WMH) burden, hippocampal atrophy, cerebral Aβ burden, and cognitive decline at baseline and with progression over time (|β| = 0.007 to 1.670, p = 0.047 to <0.0001). Within disease-specific subgroups, GFAP, p-tau217, and Aβ42/40 ratio demonstrated associations with hippocampal atrophy or WMH progression in CSVD (|β| = 0.011 to 0.220, p = 0.046 to 0.010), whereas GFAP, NfL, p-tau217, and Aβ42/40 ratio were linked to hippocampal atrophy and/or WMH progression in typical AD (|β| = 0.013 to 0.191, p = 0.044 to 0.0002). For Cox proportional hazards models, p-tau217 demonstrated greater precision in predicting progression to the CSVD phenotype within the AD subgroup (Hazard ratios = 1.267 to 3.811, p = 0.046 to 0.034).
CONCLUSION: These findings underscore the potential role of plasma biomarkers in elucidating the synergistic mechanisms underlying AD and CSVD comorbidity.
CITATION:
Jing Yang ; Xinyuan Zhao ; Yidan Liu ; Yangwei Cai ; Yuhua Fan ; Alzheimer’s Disease Neuroimaging Initiative (2025): Associations of plasma biomarkers with longitudinal co-pathologies in Alzheimer’s disease and cerebral small vessel disease comorbidity. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100449
TRAJECTORY OF COGNITIVE DECLINE BEFORE AND AFTER INCIDENT HEART FAILURE AMONG OLDER ADULTS: A 20-YEAR, POPULATION-BASED, PROSPECTIVE COHORT STUDY
Haibin Li, Frank Qian, Wuxiang Xie, Man Wang, Jianian Hua, Jiao Wang, Xinye Zou, Zhiyuan Wu, Xia Li, Deqiang Zheng, Xiuhua Guo, Hongjia Zhang
J Prev Alz Dis 2026;2(13)
Show summaryHide summaryBACKGROUND: The magnitude of cognitive change before and after incident heart failure (HF) is unclear. We investigated whether incident HF is associated with changes in cognitive function at the time of diagnosis and accelerated trajectory in cognitive decline in the subsequent years.
METHODS: We used data from the Health and Retirement Study, a nationally representative survey of US adults aged 50 years or older. Participants underwent a cognitive assessment at baseline (wave 5, 2000), and at least 1 other time point (from wave 6 [2002] to wave 15 [2020]). The outcomes were change in global cognition, memory, and executive function. Outcomes were standardized into Z-scores, with higher scores indicating better cognitive performance. Linear mixed-effects models estimated changes in cognition at the time of HF (change in the intercept) and the rate of cognitive change over the years after HF (change in the slope), after adjusting for pre-HF cognitive trajectories and potential confounders.
RESULTS: We included 12 850 adults (mean [SD] age, 66.1 [9.4] years; 61.8 % women). Over a median follow-up of 16 years (interquartile range: 8 to 20 years), 1457 participants had incident HF. The annual rate of cognitive decline before HF diagnosis among individuals with incident HF was similar to that of participants who remained HF-free throughout follow-up. However, incident HF was associated with subsequent decreases in global cognition (−0.073 SD [95 % CI −0.109 to −0.038]), memory (−0.070 SD [95 % CI −0.108 to −0.032]), and executive function (−0.054 SD [95 % CI −0.092 to −0.016]) around the time of the HF diagnosis. Moreover, individuals with incident HF vs those without HF demonstrated faster and long-term declines in global cognition (−0.011 SD/year [95 % CI −0.018 to −0.004]) and executive function (−0.008 SD/year [95 % CI −0.015 to −0.001]), but not in memory (−0.006 SD/year [95 % CI −0.013 to 0.001]) over the years after HF compared with pre-HF slopes.
CONCLUSIONS: Incident HF was associated with subsequent decreases in cognitive function at the time of diagnosis and accelerated cognitive decline over the following years.
CITATION:
Haibin Li ; Frank Qian ; Wuxiang Xie ; Man Wang ; Jianian Hua ; Jiao Wang ; Xinye Zou ; Zhiyuan Wu ; Xia Li ; Deqiang Zheng ; Xiuhua Guo ; Hongjia Zhang (2025): Trajectory of cognitive decline before and after incident heart failure among older adults: A 20-Year, population-based, prospective cohort study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100450
IRON DYSREGULATION IN CEREBRAL SMALL VESSEL DISEASE: A QUANTITATIVE SUSCEPTIBILITY MAPPING STUDY REVEALING SPATIAL PATTERNS AND COGNITIVE PREDICTIVE VALUE
Pengcheng Liang, Meng Li, Qihao Zhang, Nan Zhang, Yena Che, Yian Gao, Chaofan Sui, Xinyue Zhang, Na Wang, Yuanyuan Wang, Yiwen Chen, Zhenyu Cheng, Changhu Liang, Lingfei Guo, Jing Li
J Prev Alz Dis 2026;2(13)
Show summaryHide summaryBACKGROUND: White matter hyperintensities (WMHs) represent a cardinal feature of cerebral small vessel disease (CSVD), yet iron dysregulation alterations within these lesions and their relationship to cognitive decline remains poorly understood.
OBJECTIVES: To characterize iron dysregulation in WMH using quantitative susceptibility mapping (QSM) and examine their relationship with CSVD severity and cognitive function.
DESIGN: Cross-sectional study with longitudinal follow-up component.
SETTING: Single-center study at Shandong Provincial Hospital Affiliated with Shandong First Medical University, China.
PARTICIPANTS: 299 participants recruited from January 2021 to September 2023, with 71 participants completing longitudinal follow-up (mean interval 20.6 months). Participants were categorized into early CSVD (0 points, n = 171), mild CSVD (1 point, n = 70), and severe CSVD (≥2 points, n = 58) groups based on total burden scoring.
INTERVENTION: None (observational study).
MEASUREMENTS: 3.0T MRI with quantitative susceptibility mapping and diffusion tensor imaging. Spatial analysis examined susceptibility values in WMH cores and perilesional zones (0–2 mm, 2–4 mm, 4–6 mm). Cognitive assessments included Montreal Cognitive Assessment (MoCA), Symbol Digit Modalities Test (SDMT), and other neuropsychological tests.
RESULTS: WMH susceptibility values were significantly lower than normal-appearing white matter (-14.55 vs -7.77 ppb, P < 0.001) with progressive increases correlating with CSVD severity (P < 0.001). Cross-sectionally, higher WMH susceptibility values correlated with lower MoCA scores (r = -0.155, P = 0.045). Longitudinally, WMH susceptibility values predicted decline in information processing speed (SDMT: β = -0.247, P = 0.042). Spatial analysis revealed distinct patterns with perilesional regions showing intermediate susceptibility values.
CONCLUSIONS: Iron dysregulation alterations within WMH provide independent information about cognitive risk in CSVD. QSM emerges as a promising biomarker for monitoring cognitive trajectory and may facilitate early identification of patients at risk for cognitive decline.
CITATION:
Pengcheng Liang ; Meng Li ; Qihao Zhang ; Nan Zhang ; Yena Che ; Yian Gao ; Chaofan Sui ; Xinyue Zhang ; Na Wang ; Yuanyuan Wang ; Yiwen Chen ; Zhenyu Cheng ; Changhu Liang ; Lingfei Guo ; Jing Li (2025): Iron dysregulation in cerebral small vessel disease: A quantitative susceptibility mapping study revealing spatial patterns and cognitive predictive value. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100451
MULTI-OMICS INTEGRATION REVEALS SHARED GENETIC ARCHITECTURE BETWEEN METABOLIC MARKERS AND GRAY MATTER ATROPHY IN ALZHEIMER’S DISEASE
Piaoran Wang, Xiangzheng Wu, Fengyu Sun, Hongchuan Zhang, Yurong Jiang, Qiuhui Wang, Hao Ding, Yujing Zhou, Feng Liu, Huaigui Liu
J Prev Alz Dis 2026;2(13)
Show summaryHide summaryBACKGROUND: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by widespread gray matter volume (GMV) reductions. Emerging evidence links glucose and lipid metabolic dysregulation to AD pathophysiology. However, the extent to which AD-related GMV alterations and metabolic traits share a common genetic basis remains poorly understood.
OBJECTIVES: To explore the shared genetic architecture between GMV alterations in AD and metabolites related to glucose and lipid metabolism, aiming to provide biological insights into the prevention and treatment of AD.
DESING: This is a multimodal, cross-disciplinary study combining neuroimaging meta-analysis, transcriptome-neuroimaging association analysis, conjunctional false discovery rate (conjFDR) analysis, and functional enrichment analysis to identify the shared genetic architecture between AD-related brain structural alterations and metabolic traits.
SETTING: Public databases and European populations.
PARTICIPANTS: The meta-analysis included 49 studies (1945 CE patients and 2598 controls). The largest genome-wide association study (GWAS) summary statistics were used for AD (Ncase = 39,918; Ncontrol =358,140), two glycemic traits—glucose (GLU, N = 459,772) and glycated hemoglobin (HbA1c, N = 146,864), and three lipid traits (N = 1320,016)—high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG).
MEASUREMENTS: We conducted a voxel-based morphometric meta-analysis of GMV in AD by systematically reviewing 49 neuroimaging studies, identified through a literature search in PubMed and Web of Science using a predefined search strategy. Building upon these neuroanatomical findings, we performed a transcriptome-neuroimaging association analysis using data from the Allen Human Brain Atlas to identify genes spatially correlated with GMV alterations. To further explore the shared genetic architecture, we integrated GWAS summary statistics for AD and five metabolic markers using conjFDR analysis. Finally, functional enrichment analyses were performed to elucidate the biological relevance of the identified genes through this integrative framework.
RESULTS: Consistent GMV reductions in AD were observed in the bilateral middle temporal gyrus, right superior temporal gyrus, and other key subcortical regions. The conjFDR analysis identified 20, 17, 78, 87, and 82 genes shared between AD-related GMV reductions and GLU, HbA1c, HDL-C, LDL-C, and TG, respectively. Notably, 6 genes were shared across all five metabolic markers. Enrichment analysis implicated these genes in biological processes related to Aβ aggregation and phosphatidylinositol metabolism.
CONCLUSIONS: This study reveals a convergent genetic architecture underlying AD-related GMV atrophy and metabolic dysfunction. These findings may offer novel insights into the molecular interplay between systemic metabolism and neurodegeneration in AD and highlight potential targets for therapeutic strategies.
CITATION:
Piaoran Wang ; Xiangzheng Wu ; Fengyu Sun ; Hongchuan Zhang ; Yurong Jiang ; Qiuhui Wang ; Hao Ding ; Yujing Zhou ; Feng Liu ; Huaigui Liu (2025): Multi-omics integration reveals shared genetic architecture between metabolic markers and gray matter atrophy in Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100452
HIPPOCAMPAL MICROSTRUCTURE AS A MEASURE OF COGNITIVE RESILIENCE TO TAU PET BURDEN IN OLDER ADULTS
Daniel D. Callow, Nisha Rani, Kylie H. Alm, Corinne Pettigrew, Michael Miller, Marilyn Albert, Arnold Bakker, Anja Soldan, the BIOCARD Research Team
J Prev Alz Dis 2026;2(13)
Show summaryHide summaryBACKGROUND: Cognitive resilience, the ability to maintain better than expected cognitive function despite neuropathological burden, is a key contributor to clinical outcomes in Alzheimer’s disease (AD), though the underlying neurobiological mechanisms remain poorly understood.
OBJECTIVES: To determine whether hippocampal volume and microstructure moderate the relationship between early tau pathology and cognitive performance, thereby serving as potential markers of cognitive resilience.
DESIGN: Cross-sectional observational study.
SETTING: Participant data was obtained from the longitudinal BIOCARD Study, a volunteer-based research cohort.
PARTICIPANTS: The sample included 190 dementia-free adults (mean age = 68 years), comprising 176 cognitively unimpaired individuals and 14 with mild cognitive impairment (MCI).
MEASUREMENTS: Hippocampal volume and microstructure (mean diffusivity (MD)) were measured using structural magnetic resonance imaging (MRI) and diffusion-weighted imaging (DWI), respectively. Tau pathology was measured using FMK-6240 tau PET imaging across Braak stages I–III. Cognitive performance was indexed using global and domain-specific composite scores. Regression models tested the interactions between hippocampal volume or MD and tau burden, adjusting for demographics, APOE genotype, amyloid status, and diagnostic status.
RESULTS: Lower hippocampal MD (indicative of better microstructural integrity) attenuated the negative association between tau burden in Braak stages II–III and both global cognition and episodic memory (ps < 0.010). Logistic regression models indicated that lower hippocampal MD was associated with a weaker relationship between tau burden in Braak stages II–III and the likelihood of MCI diagnosis (ps < 0.050). In contrast, hippocampal volume did not moderate the relationship between tau and any cognitive outcome (ps > 0.250).
CONCLUSIONS: Hippocampal MD may serve as a promising imaging marker of cognitive resilience to early tau pathology, with potential utility for risk stratification and as a target for preventive interventions in AD.
CITATION:
Daniel D. Callow ; Nisha Rani ; Kylie H. Alm ; Corinne Pettigrew ; Michael Miller ; Marilyn Albert ; Arnold Bakker ; Anja Soldan ; the BIOCARD Research Team (2025): Hippocampal microstructure as a measure of cognitive resilience to tau PET burden in older adults. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100454
PLASMA AΒ42/40 PREDICTS PROGRESSION FROM AΒ-AMYLOID NEGATIVE TO POSITIVE PET SCANS
Azadeh Feizpour, Vincent Doré, Pierrick Bourgeat, James D. Doecke, Rodrigo Canovas, Simon M. Laws, Tenielle Porter, Kun Huang, Christopher Fowler, Ralph N. Martins, Paul Maruff, Hamid R. Sohrabi, Michael W. Weiner, John C. Morris, Tammie L.S. Benzinger, Suzanne E. Schindler, Randall J. Bateman, Yan Li, Ovod Vitaliy, Larry Ward, Jurgen Mejan-Fripp, Colin L. Masters, Victor L. Villemagne, Christopher C. Rowe, ADOPIC Consortium (AIBL, ADNI, OASIS)
J Prev Alz Dis 2026;2(13)
Show summaryHide summaryBACKGROUND: The agreement between plasma Aβ42/40 and Aβ positron emission tomography (PET) is approximately 75 %, with ∼85 % of discrepancies due to positive plasma but negative PET results. It is unclear whether this reflects Aβ changes in plasma before PET-detectable.
OBJECTIVES: To assess the influence of Aβ42/40 positivity on risk of progression to Aβ PET positivity, and feasibility of using plasma Aβ42/40 tests to enrich a primary prevention trial.
DESIGN: A prospective longitudinal cohort study.
SETTING: Participants of Australian Imaging, Biomarkers and Lifestyle study (AIBL), Alzheimer’s Disease Neuroimaging Initiative (ADNI), and Open Access Series of Imaging Studies 3 (OASIS3).
PARTICIPANTS: 507 cognitively unimpaired adults at baseline, with a baseline Aβ PET < 20 Centiloid (CL) and available longitudinal Aβ PET data.
MEASUREMENTS: Baseline Aβ PET and plasma Aβ42/40 measurement by mass-spectrometry, followed by 1–6 additional Aβ PET scans every 1.5–3 years. Those < 5 CL were classified as PET- and 5–20 CL as PETLow. Plasma -/+ was defined using the Aβ42/40 Youden’s Index threshold (0.119), corresponding to Aβ PET status.
RESULTS: At baseline, 283 were Plasma-/PET-, 97 Plasma+/PET-, 76 Plasma-/PETLow, and 51 Plasma+/PETLow. Among Plasma+/PET- individuals, 19 % progressed to PET+ (>20 CL), indicating a higher risk of progression, compared to Plasma-/PET- (HR: 3.90 [90 % CI: 2.00–7.61], p < 0.001). This elevated risk remained significant after matching the groups’ baseline CL (3.43 [1.43–8.26], p = 0.010), or adjustment for age, sex, APOE ε4 and baseline CL (2.48 [1.22 - 5.07], p = 0.013). Plasma+/PET- individuals accumulated Aβ ∼8 times faster (1.14 CL/year) than Plasma-/PET- (0.15 CL/year, p < 0.001). Plasma+/PET- progressors became PET+ two years earlier than Plasma-/PET- progressors. Among the Plasma+/PETLow individuals, 67 % progressed to PET+. Their progression was faster and earlier than in the Plasma-/PETLow group (HR: 20.82 [11.28 - 38.42], p < 0.001 vs. 6.67 [3.51 - 12.65], p < 0.001; reference: Plasma-/PET-), largely driven by higher baseline CL in the Plasma+ group. In a primary prevention paradigm targeting high-risk PETLow individuals, pre-screening with Aβ42/40 blood test reduced the number of PET scans by 49 %, compared to a PET-only strategy.
Conclusions
Cognitively unimpaired individuals with abnormal Aβ42/40 are at increased risk for future Aβ PET positivity. In the 5–20 CL subgroup, baseline CL is the main driver of this risk. Combining blood-based pre-screening with PET imaging may help efficiently enrich primary prevention trials.
CITATION:
Azadeh Feizpour ; Vincent Doré ; Pierrick Bourgeat ; James D. Doecke ; Rodrigo Canovas ; Simon M. Laws ; Tenielle Porter ; Kun Huang ; Christopher Fowler ; Ralph N. Martins ; Paul Maruff ; Hamid R. Sohrabi ; Michael W. Weiner ; John C. Morris ; Tammie L.S. Benzinger ; Suzanne E. Schindler ; Randall J. Bateman ; Yan Li ; Ovod Vitaliy ; Larry Ward ; Jurgen Mejan-Fripp ; Colin L. Masters ; Victor L. Villemagne ; Christopher C. Rowe ; ADOPIC Consortium (AIBL, ADNI, OASIS) (2025): Plasma Aβ42/40 predicts progression from Aβ-amyloid negative to positive PET scans. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100455
SYNAPTIC TOXICITY OF OGA INHIBITORS AND THE FAILURE OF CEPEROGNASTAT
Jonathan Meade, Haylee Mesa, Shahriar Alamgir, Isabell Bieniecka, Lei Liu, Qi Zhang
J Prev Alz Dis 2026;2(13)
Show summaryHide summaryO-GlcNAcase inhibitors (OGAi) have emerged as a promising therapeutic strategy in Alzheimer’s disease (AD) by enhancing O-GlcNAcylation, which competes with tau phosphorylation and reduces tau aggregation. However, the Phase II clinical trial failure of ceperognastat, marked by accelerated cognitive decline in the treatment group, has raised significant safety concerns. Here, we examined the acute synaptic effects of three structurally distinct OGAi compounds—ceperognastat, ASN90, and MK8719—in mouse hippocampal slices. Electrophysiological recordings revealed suppression of both short- and long-term synaptic plasticity, including paired-pulse facilitation/depression and long-term potentiation. Immunohistochemical analysis confirmed disrupted synaptic protein levels (increased PSD-95, reduced Synaptophysin 1) and a biphasic shift in tau phosphorylation. These convergent findings suggest a class-wide synaptotoxic mechanism and call for a great caution in the development of disease-modifying therapies in AD. We argue that preclinical drug screening for synaptic functionality is essential in CNS-targeted therapeutic pipelines.
CITATION:
Jonathan Meade ; Haylee Mesa ; Shahriar Alamgir ; Isabell Bieniecka ; Lei Liu ; Qi Zhang (2025): Synaptic toxicity of OGA inhibitors and the failure of ceperognastat. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100456
SOLUBLE AND PLAQUE AMYLOID ASSOCIATIONS WITH PERIPHERAL GLUCOSE DYSREGULATION MODULATED BY TAU PATHOLOGY IN ALZHEIMER’S DISEASE
Dong Woo Kang, Suhyung Kim, Sunghwan Kim, Yoo Hyun Um, Sheng-Min Wang, Seunggyun Ha, Sonya Youngju Park, Seung-Hwan Lee, Yeong Sim Choe, Donghyeon Kim, Chang Uk Lee, Hyun Kook Lim
J Prev Alz Dis 2026;2(13)
Show summaryHide summaryBACKGROUND: Glucose metabolic dysfunction in Alzheimer’s disease (AD) has been reported to be associated with soluble amyloid-β oligomers (OAβ) and plaque amyloid. However, the potential modulatory role of tau pathology in these associations remains to be fully elucidated.
OBJECTIVES: To investigate whether tau pathology modifies the relationship between plasma OAβ burden, plaque amyloid, and systemic glucose metabolism in individuals across the AD spectrum.
DESIGN: Cross-sectional observational study.
SETTING: Memory clinic-based cohort from a single tertiary academic medical center in Republic of Korea.
PARTICIPANTS: A total of 113 older adults, including cognitively normal individuals, patients with mild cognitive impairment, and Aβ-PET–positive dementia patients.
MEASUREMENTS: Plasma oligomeric Aβ (OAβ) levels were measured in blood samples using the Multimer Detection System, which quantifies oligomeric forms of Aβ in plasma. Aβ plaque deposition was assessed using [18F]-flutemetamol PET, and tau pathology was assessed using [18F]-flortaucipir PET, from which Braak staging was determined. Glucose metabolism was evaluated using fasting plasma glucose and hemoglobin A1c (HbA1c). Generalized linear models were used to examine the associations and potential interactions between plasma OAβ burden and plaque Aβ with tau pathology, adjusting for clinical covariates.
RESULTS: A significant interaction was identified between plasma OAβ levels and Braak stage III/IV, but not Braak I or V/VI, when referenced to Braak 0. Only at Braak 0, higher plasma OAβ levels were associated with higher HbA1c compared with Braak stage III/IV (β = −4.191, 95 % CI −7.714 to −0.669, p = 0.020). No significant interactions were observed for fasting glucose or for Aβ-PET SUVR. Sensitivity analyses adjusting for diabetes diagnosis and excluding dementia participants confirmed the robustness of these findings.
CONCLUSION: Soluble Aβ oligomers, rather than plaque amyloid, are selectively associated with systemic glucose dysregulation in the absence of overt tau pathology. Tau staging may be crucial for identifying AD subgroups vulnerable to metabolic dysfunction potentially associated with early Aβ toxicity.
CITATION:
Dong Woo Kang ; Suhyung Kim ; Sunghwan Kim ; Yoo Hyun Um ; Sheng-Min Wang ; Seunggyun Ha ; Sonya Youngju Park ; Seung-Hwan Lee ; Yeong Sim Choe ; Donghyeon Kim ; Chang Uk Lee ; Hyun Kook Lim (2025): Soluble and plaque amyloid associations with peripheral glucose dysregulation modulated by tau pathology in Alzheimer’s disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100459
COST-EFFECTIVENESS OF MULTIMODAL INTERVENTION FOR THE PREVENTION OF DEMENTIA IN JAPAN
Naoki Takashi, Shosuke Ohtera, Yujiro Kuroda, Hidenori Arai, Takashi Sakurai, J-MINT investigators
J Prev Alz Dis 2026;2(13)
Show summaryHide summaryBACKGROUND: This analysis evaluated the potential cost-effectiveness of the Japan-Multimodal Intervention Trial for the prevention of dementia (J-MINT), targeting older adults with mild cognitive impairment (MCI) from a societal perspective.
METHODS: Using a time-dependent cohort state-transition model, we estimated the long-term economic impact of J-MINT. Costs included medical, long-term, and informal care. Incremental cost-effectiveness ratios (ICERs) were calculated based on simulated costs and quality-adjusted life years (QALYs).
RESULTS: The base-case analysis indicated that the J-MINT was dominant, demonstrating cost saving and more effective compared to usual care. Over 35 years, J-MINT was projected to achieve cost savings of JPY 452,826 per person and a gain of 0.08 QALYs. Deterministic and probabilistic sensitivity analyses confirmed the robustness of these findings. Scenario analysis suggested that targeting APOE ε4 carriers or individuals with high adherence to exercise yielded even greater benefits.
CONCLUSION: J-MINT demonstrates cost-effectiveness by reducing overall care costs while improving QALYs in individuals with MCI.
CITATION:
Naoki Takashi ; Shosuke Ohtera ; Yujiro Kuroda ; Hidenori Arai ; Takashi Sakurai ; J-MINT investigators (2025): Cost-effectiveness of multimodal intervention for the prevention of dementia in Japan. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100460
INDIVIDUALIZED PREDICTION OF TRANSITION FROM SUBJECTIVE COGNITIVE DECLINE TO MILD COGNITIVE IMPAIRMENT BASED ON MULTIMODAL MRI: A 10-YEAR FOLLOW-UP STUDY
Xingyan Le, Junbang Feng, Xiaoli Yu, Yuyin Wang, Qingbiao Zhang, Yuwei Xia, Feng Shi, Chuanming Li
J Prev Alz Dis 2026;2(13)
Show summaryHide summaryBACKGROUND: Predicting the transition from subjective cognitive decline (SCD) to mild cognitive impairment (MCI) is critical for dementia prevention.
OBJECTIVE: Comprehensive assessment of MRI-based macro-/micro-structural and functional brain changes in SCD to develop an individualized model predicting transition to MCI.
DESIGN, SETTING, AND PARTICIPANTS: Patients with SCD were screened from the ADNI, NACC, and OASIS-3 databases. 89 patients met the inclusion criteria and underwent structural magnetic resonance imaging (sMRI) and resting-state functional MRI (rs-fMRI). Over a 10-year follow-up, 49 patients progressed to MCI, while 40 remained stable.
MEASUREMENTS: The VB-net automated brain segmentation, extracting hippocampal radiomics and whole brain subregion volume features. Brain functional features were extracted based on rs-fMRI. Cox regression was used to develop predictive models, which were independently validated with the testing set. The nomogram was constructed to estimate the probability of transition to MCI at 5-/7-/10-year. The nomogram’s accuracy was assessed using calibration curves and concordance index (C-index), and clinical utility was evaluated through decision curve analysis.
RESULTS: The model incorporating age, brain volume, functional, and radiomics features demonstrated the highest predictive performance for SCD progression in training (C-index: 0.962; 95 % CI: 0.95–0.98) and testing (C-index: 0.911; 95 % CI: 0.861–0.968) sets. A nomogram comprising 10 predictors was constructed to estimate individualized risk of progression to MCI at 5-/7-/10-year. The calibration curve showed good agreement between predicted and observed values. Decision curve analysis demonstrated the nomogram had substantial clinical value.
CONCLUSIONS: This multivariate model and nomogram could accurately predict the individual progression from SCD to MCI.
CITATION:
Xingyan Le ; Junbang Feng ; Xiaoli Yu ; Yuyin Wang ; Qingbiao Zhang ; Yuwei Xia ; Feng Shi ; Chuanming Li (2025): Individualized prediction of transition from subjective cognitive decline to mild cognitive impairment based on multimodal MRI: a 10-year follow-up study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100462
LONGITUDINAL CHANGES IN SUBCORTICAL FUNCTIONAL CONNECTIVITY DURING ALZHEIMER’S DISEASE PROGRESSION
Sunghun Kim, Sewook Oh, Hyunjin Park, Bo-yong Park
J Prev Alz Dis 2026;2(13)
Show summaryHide summaryHuman cognition and behavior rely on the integration of large-scale neural networks that connect the cerebral cortex and subcortical structures. Emerging evidence suggests that alterations in the functional connectivity (FC) between the cortical and subcortical regions in Alzheimer’s disease (AD) may influence the onset and progression of both cognitive and noncognitive symptoms at the group level. However, an individualized and longitudinal framework to capture deviations in subcortico-cortical FC from normative brain aging remains underexplored. We addressed this gap by leveraging large-scale longitudinal neuroimaging datasets and applying a normative modeling approach to characterize subcortical FC trajectories across the adult lifespan. First, we quantified individual deviations in the subcortical FC in individuals with cognitive impairment (CI) relative to a normative aging group using centile scores and tracked longitudinal changes across multiple follow-ups. We examined the relationship between changes in subcortical FC and clinical measures of cognitive function, including episodic memory, executive function, and language. Our findings revealed widespread decreases in the subcortical FC in individuals with CI, except in the limbic network, which diverged from the patterns observed in normal aging. These alterations are significantly associated with a decline in memory and executive functions. Collectively, our results may advance our understanding of AD-related connectopathy and provide a direction for profiling individualized longitudinal FC changes in individuals with CI. Furthermore, our results could inform individualized prognosis and targeted interventions.
CITATION:
Sunghun Kim ; Sewook Oh ; Hyunjin Park ; Bo-yong Park (2025): Longitudinal changes in subcortical functional connectivity during Alzheimer’s disease progression. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100463
THE ASSOCIATION OF ESTIMATED GLUCOSE DISPOSAL RATE WITH WHITE MATTER HYPERINTENSITIES: A LARGE PROSPECTIVE COHORT STUDY
Han Wang, Zhi-Ming Li, Ben-Bo Xiong, Zi-Jie Wang, Yi Qian, Xiao Hu, Shan-Yu Zhang, Chu Chen, Tian-Nan Yang, Qi Li
J Prev Alz Dis 2026;2(13)
Show summaryHide summaryBACKGROUND AND OBJECTIVES: Estimated glucose disposal rate (eGDR) is a novel and reliable marker of insulin resistance (IR), yet its association with white matter hyperintensities (WMH) remains unclear. This study investigates the relationship between eGDR and WMH in a cohort from the UK Biobank.
METHODS: We included 34,789 participants without a history of stroke or dementia at baseline. WMH volume was estimated from T2-FLAIR brain magnetic resonance imaging (MRI) scans acquired in 2014, normalized to intracranial volume, and log-transformed. Multiple linear regression models were used to examine the association between eGDR and WMH volume. Additionally, restricted cubic spline (RCS) analysis was employed to explore the dose-response relationship between eGDR and WMH volume.
RESULTS: Each 1-SD increase in eGDR was significantly associated with a reduction in WMH volume (β = -0.057; 95% CI: -0.062 to -0.051; p < 0.001). Compared to participants in the lowest eGDR quartile (Q1), those in quartiles Q2, Q3, and Q4 exhibited progressively lower WMH volumes, with β coefficients of -0.068 (95% CI: -0.097 to -0.039), -0.199 (95% CI: -0.228 to -0.169), and -0.295 (95% CI: -0.330 to -0.259), respectively (p for trend < 0.001). RCS analysis demonstrated a significant linear inverse relationship between eGDR and WMH volume (p for nonlinearity > 0.05). Subgroup analyses indicated consistent associations across most predefined groups.
CONCLUSION: Lower eGDR levels are associated with a greater burden of WMH, suggesting that eGDR may serve as a potential marker for predicting WMH burden in future clinical practice.
CITATION:
Han Wang ; Zhi-Ming Li ; Ben-Bo Xiong ; Zi-Jie Wang ; Yi Qian ; Xiao Hu ; Shan-Yu Zhang ; Chu Chen ; Tian-Nan Yang ; Qi Li (2025): The association of estimated glucose disposal rate with white matter hyperintensities: A large prospective cohort study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100464
ASSOCIATION BETWEEN PLANT-BASED DIETS AND INCIDENT DEMENTIA: RESULTS FROM PROSPECTIVE COHORT STUDIES AND A META-ANALYSIS
Jie Shen, Hui Chen, Yiying Gong, Yuhui Huang, Minyu Wu, Yuxuan Gu, Tian Wang, Luigi Fontana, Shuang Rong, Shujiao Qian, Maurizio Tonetti, Xiaoran Liu, Changzheng Yuan
J Prev Alz Dis 2026;2(13)
Show summaryHide summaryBACKGROUND: Plant-based diets are increasingly advocated for their health benefits, yet their associations with dementia risk remains inconclusive. We evaluated the associations between plant-based dietary patterns and dementia risk across three prospective cohorts and a meta-analysis.
METHODS: Cohort analyses included the Health and Retirement Study (HRS; N = 6642), Framingham Heart Study Offspring cohort (FOS; N = 3045), and Whitehall II study (WHII; N = 8219). Participants were aged ≥45 years and free of dementia at baseline. The overall plant-based diet index (PDI), healthful plant-based diet index (hPDI) and unhealthful plant-based diet index (uPDI) were calculated from validated food frequency questionnaires. Further, a meta-analysis was conducted incorporating data from 5 cohort studies (N = 207,981).
RESULTS: In the cohort analyses, 891 incident dementia cases were identified over 166,762 person-years. In multivariable-adjusted Cox proportional hazard models, higher scores in PDI and hPDI were associated with lower risk of dementia (highest vs. lowest tertile: pooled HR for PDI = 0.70, 95% CI, 0.53–0.92, p for trend <0.001; pooled HR for hPDI = 0.71, 0.48–1.06, p for trend = 0.03). Main contributors to lower risk were higher intake of vegetables, nuts, tea or coffee, and legumes. Conversely, higher uPDI was associated with higher dementia risk (highest vs. lowest tertile: pooled HR = 1.42, 1.19–1.70, p for trend <0.001). In the meta-analysis, individuals in the highest hPDI tertile had 21% lower dementia risk, and those in the highest uPDI tertile had 24% higher risk.
CONCLUSIONS: The healthful plant-based diet was associated with lower risk of dementia, whereas the unhealthful plant-based diet was linked to higher risk. These findings support recommendations to adopt diets rich in healthy plant foods for dementia prevention.
CITATION:
Jie Shen ; Hui Chen ; Yiying Gong ; Yuhui Huang ; Minyu Wu ; Yuxuan Gu ; Tian Wang ; Luigi Fontana ; Shuang Rong ; Shujiao Qian ; Maurizio Tonetti ; Xiaoran Liu ; Changzheng Yuan (2025): Association between plant-based diets and incident dementia: results from prospective cohort studies and a meta-analysis. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100457
LETTER TO THE EDITOR : ADVANCING NUTRITIONAL STRATEGIES FOR BRAIN HEALTH: RECONCILING EPIDEMIOLOGIC FINDINGS WITH CLINICAL APPLICABILITY
Hui Guo, Xiongfei Zhao
J Prev Alz Dis 2026;2(13)
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CITATION:
Hui Guo ; Xiongfei Zhao (2025): Letter to the Editor: Advancing nutritional strategies for brain health: Reconciling epidemiologic findings with clinical applicability. The Journal of Prevention of Alzheimer’s Disease (JPAD).https://doi.org/10.1016/j.tjpad.2025.100466