09/2025 journal articles
PSYCHIATRY MEETS NEURODEGENERATION – A COLLABORATIVE APPROACH TO DEMENTIA PREVENTION
Carolin Kurz, Martin Haupt, Stefanie Auer, Nicola Lautenschlager, Alexander Kurz
J Prev Alz Dis 2025;9(12)
Show summaryHide summaryThe advent of amyloid-targeting therapies and biomarker-based risk stratification has transformed the understanding of Alzheimer’s disease and related disorders. These conditions are now recognized as chronic, detectable and modifiable, often presenting decades before clinical symptoms appear. While this paradigm shift enables earlier intervention, it also raises ethical and psychological challenges that necessitate a redefined role for psychiatry. Instead of merely supporting late-stage care, psychiatry is well-placed to facilitate risk communication, promote resilience, and encourage adaptive behavior in individuals navigating preclinical or prodromal neurodegeneration. This article outlines an ethical, stepwise communication framework, clarifies the distinction between diagnosis and probabilistic risk, and explores psychiatric contributions—from motivational models to lifestyle-based prevention—that bridge the gap between biological insight and subjective experience. By reinterpreting risk as a chance for intervention rather than resignation, psychiatry broadens the therapeutic scope and helps safeguard independence, dignity and quality of life—making it a pivotal participant in dementia prevention and individualized, person-centered care.
CITATION:
Carolin Kurz ; Martin Haupt ; Stefanie Auer ; Nicola Lautenschlager ; Alexander Kurz (2025): Psychiatry meets neurodegeneration – A collaborative approach to dementia prevention. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100317
DIFFERENTIAL EFFECTS OF SOLUBLE AND PLAQUE AMYLOID ON LATE-LIFE DEPRESSION: THE MODERATING ROLE OF TAU PATHOLOGY
Gihwan Byeon, Suhyung Kim, Sunghwan Kim, Yoo Hyun Um, Sheng-Min Wang, Seunggyun Ha, Sonya Youngju Park, Yeong Sim Choe, Donghyeon Kim, Hyun Kook Lim, Chang Uk Lee, Dong Woo Kang
J Prev Alz Dis 2025;9(12)
Show summaryHide summaryBACKGROUND: Late-life depression frequently co-occurs with Alzheimer’s disease (AD); however, the interactive effects of amyloid-beta (Aβ) species and tau pathology on depressive symptoms remain unclear. Soluble oligomeric Aβ (OAβ) and amyloid plaques may differentially influence depression depending on tau burden.
OBJECTIVES: To examine how plasma OAβ and PET-measured amyloid plaque burden are associated with depressive symptoms across varying levels of tau pathology.
DESIGN: Cross-sectional analysis using generalized linear models with interaction terms, supported by stratified subgroup analyses and Johnson–Neyman procedures.
SETTING: Memory disorder clinic at a university-affiliated hospital.
PARTICIPANTS: A total of 103 individuals, including cognitively normal controls (n = 24), patients with mild cognitive impairment (n = 54), and amyloid-positive dementia (n = 25), all of whom underwent plasma biomarker testing and tau and amyloid PET imaging.
MEASUREMENTS: Depression was evaluated using the Cornell Scale for Depression in Dementia (CSDD), Hamilton Depression Rating Scale (HAM-D), and Geriatric Depression Scale–Short Version (GDS-SV). Plasma OAβ was measured by Multimer Detection System (MDS), and PET quantified amyloid and tau burden.
RESULTS: MDS-OAβ showed a significant negative interaction with tau PET SUVR on depression scores (FDR-adjusted p < 0.05). Higher OAβ levels were linked to greater depression severity in low-tau individuals, but inversely related in high-tau individuals. Amyloid plaque burden was associated with depression only in those with advanced tau pathology.
CONCLUSIONS: The association between amyloid pathology and depression differs depending on tau burden. Soluble OAβ may be a key contributor to depressive symptoms in early AD stages, while plaque effects become prominent later. These findings underscore the potential utility of OAβ as an early neuropsychiatric biomarker in AD and highlight the need to consider tau pathology when evaluating amyloid-related mood disturbances.
CITATION:
Gihwan Byeon ; Suhyung Kim ; Sunghwan Kim ; Yoo Hyun Um ; Sheng-Min Wang ; Seunggyun Ha ; Sonya Youngju Park ; Yeong Sim Choe ; Donghyeon Kim ; Hyun Kook Lim ; Chang Uk Lee ; Dong Woo Kang (2025): Differential effects of soluble and plaque amyloid on late-life depression: The moderating role of tau pathology. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100318
PROPORTION OF LIFE SPENT IN THE UNITED STATES AND COGNITIVE FUNCTIONING IN SPANISH-SPEAKING MIGRANTS: FINDINGS FROM THE BOSTON LATINO AGING STUDY
Isabel Solis, Randy Medrano, Lusiana Martinez, Nadeshka J. Ramirez, Nikole A. Bonillas Felix, Jorge Alcina, Averi Giudicessi, Jairo E. Martinez, Clara Vila-Castelar, Liliana A. Ramirez-Gomez, Marta Gonzalez Catalan, Daniel G. Saldana, Yakeel T. Quiroz
J Prev Alz Dis 2025;9(12)
Show summaryHide summaryLatino migrants are at increased risk for cognitive decline, yet the influence of immigration-related factors, such as time lived in the United States (U.S.), remains poorly understood. In the Boston Latino Aging Study (BLAST), 130 older Latino migrants completed a comprehensive neuropsychological assessment. We examined whether the proportion of years lived in the U.S. was associated with cognitive performance, adjusting for age, education, and acculturation. Greater time in the U.S was significantly associated with lower phonemic fluency, while no associations were found for other domains. Notably, 16 % of phonemic fluency errors involved English intrusions during a Spanish-language task, suggesting cross-linguistic interference. These findings underscore the importance of considering language dynamics and sociocultural context in studies of Latino cognitive aging.
CITATION:
Isabel Solis ; Randy Medrano ; Lusiana Martinez ; Nadeshka J. Ramirez ; Nikole A. Bonillas Felix ; Jorge Alcina ; Averi Giudicessi ; Jairo E. Martinez ; Clara Vila-Castelar ; Liliana A. Ramirez-Gomez ; Marta Gonzalez Catalan ; Daniel G. Saldana ; Yakeel T. Quiroz (2025): Proportion of life spent in the United States and cognitive functioning in Spanish-speaking migrants: Findings from the Boston Latino Aging Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100320
A CRITICAL REVIEW AND CLASSIFICATION OF DEMENTIA RISK ASSESSMENT TOOLS TO INFORM DEMENTIA RISK REDUCTION
Md Hamidul Huque, Ranmalee Eramudugolla, Meiwei Li, Kim M. Kiely, Ruth Peters, Kaarin J. Anstey
J Prev Alz Dis 2025;9(12)
Show summaryHide summaryAddressing modifiable dementia risk factors requires reliable risk assessment methods. We aimed to synthesise knowledge on risk scores for all cause dementia, Alzheimer’s disease (AD) and vascular dementia, classify them according to target population, evaluate their content, cost, appropriateness of validation studies, and suitability for implementing risk reduction guidelines. A systematic search was conducted of PubMed, Cochrane Collaboration, ProQuest, Scopus, Embase, and PsycINFO databases using a pre-registered protocol. Data on risk factors, target population, predictive validity, cost, and alignment with WHO guidelines were extracted. Random-effects meta-analysis was performed. Of 45 risk scores identified, 29 were for all-cause dementia, including 11 based on late-life cohorts, 6 on midlife, and 7 covering mid to late-life. The pooled C-statistic across development and validation studies of dementia risk scores was 0.69 (95 % CI: 0.67, 0.71). Development study AUCs were higher than validation study AUCs and dropped from 0.74 to 0.66 for risk scores developed for clinical samples and from 0.79 to 0.71 for AD specific scores (which include functional indicators non-independent of disease). There were no validated risk scores for vascular dementia. Dem-NCD, CogDrisk, ANU-ADRI and LIBRA risk scores incorporated most WHO-recommended risk factors and demonstrated accuracy comparable to the overall pooled C-statistic. We conclude that across the field, there are methodological limitations relating to validation, and inappropriate comparison of tools designed for different purposes or target populations. However, there are now several validated, risk scores for all-cause dementia and AD that assess modifiable factors and offer cost-effective dementia risk assessment and risk reduction advice.
CITATION:
Md Hamidul Huque ; Ranmalee Eramudugolla ; Meiwei Li ; Kim M. Kiely ; Ruth Peters ; Kaarin J. Anstey (2025): A critical review and classification of dementia risk assessment tools to inform dementia risk reduction. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100333
A PRELIMINARY ECONOMIC EVALUATION OF A POTENTIAL PROGRAM FOR THE PRIMARY PREVENTION OF ALZHEIMER’S DISEASE
Soeren Mattke, Jiahe Chen, Eric M Reiman
J Prev Alz Dis 2025;9(12)
Show summaryHide summaryINTRODUCTION: We evaluated the potential cost-effectiveness of a hypothetical primary prevention screening and treatment program to avert the biological and clinical onset of Alzheimer’s disease (AD) in cognitively unimpaired older adults.
METHODS: This hypothetical program would use an amyloid plaque-clearing antibody therapy monthly in the first six months and annually thereafter in cognitively unimpaired 55–79 year-old APOE4 carriers and 60–79 year-old non-carriers with a negative AD blood test (sensitivity and specificity of 0.9), averting the onset of moderately frequent neuritic amyloid plaques by 75 %. Lifetime hypothetical treatment outcomes were compared to natural history outcomes to estimate cost-effectiveness.
RESULTS: The program would be cost-effective up to a per-dose price of $1173 in APOE4 carriers and $307 in non-carriers or a lifetime cost of $20,167 and $5146, respectively.
DISCUSSION: Primary AD prevention could be cost-effective in older adults, especially in those at higher risk. Our findings and assumptions need to be confirmed with actual data.
CITATION:
Soeren Mattke ; Jiahe Chen ; Eric M Reiman (2025): A preliminary economic evaluation of a potential program for the primary prevention of Alzheimer’s disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100334
IDENTIFYING THE OPTIMAL COMBINATIONS OF MODIFIABLE DEMENTIA RISK FACTORS TO TARGET IN MULTIDOMAIN INTERVENTION – THREE-YEAR LONGITUDINAL FINDINGS FROM THE CANADIAN LONGITUDINAL STUDY ON AGING Æ
Surim Son, Mark Speechley, Guangyong Zou, Manuel Montero-Odasso
J Prev Alz Dis 2025;9(12)
Show summaryHide summaryBACKGROUND: Recent multidomain prevention trials for dementia have shifted toward more targeted approaches, focusing on specific combinations of risk factors and interventions at certain times. However, the optimal combinations of modifiable risk factors that can be targeted to maximize intervention effect remain unclear. Identifying risk factor combinations with the highest prevalence and largest effect sizes can enhance efficiency of trial design.
OBJECTIVES: To identify risk factor combinations that are both highly prevalent and have the most detrimental effect on cognition, and to assess their interaction effect and synergism.
DESIGN: Longitudinal analysis of Canadian Longitudinal Study on Aging (CLSA).
SETTING: Community. PARTICIPANTS: 30,097 adults aged 45 to 85 at baseline.
MEASUREMENTS: The five most prevalent dyad, triad, and tetrad combinations of 12 modifiable risk factors were identified. Cognition was assessed with a composite Z-score from a neuropsychological test battery. Linear mixed effect models were used to examine the association between the identified combinations and 3-year cognitive changes. Interaction was assessed on additive scale, and synergism was explored.
RESULTS: The combinations that were both highly prevalent and had the most detrimental effect on global cognition were: hearing loss and physical inactivity for the dyad (mean difference in change score = -0.07 SD; 95 % CI: -0.09 to -0.06; p < 0.001; effect size = -0.28), hearing loss, physical inactivity, and hypertension for the triad (mean difference in change score = -0.07; 95 % CI: -0.09 to -0.06; p < 0.001; effect size = -0.28), and hearing loss, physical inactivity, hypertension, and sleep disturbance for the tetrad (mean difference in change score = -0.05; 95 % CI: -0.07 to -0.03; p < 0.001; effect size = -0.20). Similar patterns were observed for memory and executive function. A significant synergistic interaction was observed between hearing loss and physical inactivity for global cognition (p = 0.005).
CONCLUSIONS: The combined effect of multiple risk factors varied by its combinations. The combination of hearing loss and physical inactivity offers a greater potential benefit than other dyad combinations. Hypertension and sleep disturbance can be further included for triad and tetrad combinations. Auditory health and exercise should be prioritized for multidomain interventions.
CITATION:
Surim Son ; Mark Speechley ; Guangyong Zou ; Manuel Montero-Odasso (2025): Identifying the optimal combinations of modifiable dementia risk factors to target in multidomain intervention – Three-year longitudinal findings from the Canadian longitudinal study on aging. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100321
A PHASE 2 RANDOMIZED, PLACEBO-CONTROLLED STUDY ON THE EFFICACY AND SAFETY OF AR1001, A PHOSPHODIESTERASE-5 INHIBITOR, IN PATIENTS WITH MILD-TO-MODERATE ALZHEIMER’S DISEASE
David Greeley, Marshall Nash, Brad Herskowitz, Fred Kim, James Rock, Neils Prins, SangYun Kim, Tianyang Xi, Jonathan A. Busam, Benoit Tete, Jai Jun Choung, Sharon J. Sha
J Prev Alz Dis 2025;9(12)
Show summaryHide summaryBACKGROUND: AR1001 is a phosphodiesterase-5 inhibitor that produces improved cognitive performance and reduces amyloid-β and phosphorylated tau burdens in preclinical models of Alzheimer’s disease (AD).
OBJECTIVES: To evaluate the safety and efficacy of AR1001 in participants with mild-to-moderate Alzheimer’s disease (AD).
DESIGN: Randomized, double-blind, placebo-controlled phase 2 trial conducted at 21 sites in the United States.
PARTICIPANTS: Adults aged 55–80 years with mild-to-moderate dementia as determined by National Institutes of Aging-Alzheimer’s Association (NIA-AA) stage 4 or 5 and Mini-mental State Exam (MMSE) score 16-26.
INTERVENTION: Once daily oral administration of placebo, 10 mg AR1001, or 30 mg AR1001 for 26 weeks followed by 26 weeks optional extension.
MEASUREMENTS: Co-primary efficacy endpoints were changes from baseline at Week 26 in Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-Cog 13) and Alzheimer’s Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC). Secondary endpoints included measures of cognition, daily living, and depression. Levels of plasma biomarkers pTau-181, pTau-217, Aβ42/40 ratio, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) were also examined.
RESULTS: A total of 210 participants were enrolled and 82% completed 26 weeks of treatment. AR1001 10 mg and 30 mg were well-tolerated with a similar safety profile compared to placebo. After 26 weeks, there were no differences in ADAS-Cog13, ADCS-CGIC, or in secondary efficacy endpoints between groups. Levels of plasma biomarkers pTau-181, pTau-217, and GFAP were improved in the 30 mg AR1001 group compared to placebo.
CONCLUSION: AR1001 was safe and well tolerated. Although primary efficacy endpoints were not met after 26 weeks of treatment, participants receiving 30 mg AR1001 showed favorable changes in AD-related plasma biomarkers compared to placebo.
CITATION:
David Greeley ; Marshall Nash ; Brad Herskowitz ; Fred Kim ; James Rock ; Neils Prins ; SangYun Kim ; Tianyang Xi ; Jonathan A. Busam ; Benoit Tete ; Jai Jun Choung ; Sharon J. Sha (2025): A phase 2 randomized, placebo-controlled study on the efficacy and safety of AR1001, a phosphodiesterase-5 inhibitor, in patients with mild-to-moderate Alzheimer’s disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100337
DISCLOSURE OF ALZHEIMER’S DISEASE BLOOD-BASED BIOMARKER RESULTS IN A PRIMARY CARE SETTING: OPPORTUNITIES AND CHALLENGES
Corey J. Bolton, Ayda Rostamzadeh, Nathaniel Chin, Nicole R. Fowler, Judith Heidebrink, Annalise Rahman-Fillipiak, Raymond R. Romano III, Lindsay R. Clark, Advisory Group on Risk Evidence Education in Dementia (AGREEDementia)
J Prev Alz Dis 2025;9(12)
Show summaryHide summaryBlood-based biomarkers (BBMs) for Alzheimer’s disease (AD) have advanced rapidly and may be a critical tool for broad community-based screening for AD and detection of AD pathology in individuals with cognitive impairment. To meet the impending demand for AD diagnosis, BBMs could be implemented in a primary care setting to maximize accessibility and efficiency. However, this primary care implementation would be associated with numerous challenges, including issues related to disclosure of test results to patients. In this perspective article, we highlight the need for and potential challenges of AD BBM results disclosure in a primary care setting. Drawing from existing studies of AD risk disclosure, we highlight key areas of consideration to maximize patient safety and comprehension of results. Resources are suggested to aid health systems in implementing BBM testing in primary care settings. Finally, we emphasize the need for further research on the accuracy of BBMs and the practice of disclosure in primary care settings.
CITATION:
Corey J. Bolton ; Ayda Rostamzadeh ; Nathaniel Chin ; Nicole R. Fowler ; Judith Heidebrink ; Annalise Rahman-Fillipiak ; Raymond R. Romano III ; Lindsay R. Clark ; Advisory Group on Risk Evidence Education in Dementia (AGREEDementia) (2025): Disclosure of Alzheimer’s disease blood-based biomarker results in a primary care setting: Opportunities and challenges. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100310
ASSOCIATION OF SUGAR INTAKE WITH INCIDENT DEMENTIA IN THE UK BIOBANK: A PROSPECTIVE COHORT STUDY
Yue Che, Wenming Wei, Tingting Mao, Lina Qin, Hanchi Wang, Yijia Li, Weixuan Da, Jin Feng, Li Liu, Bolun Cheng, Huan Liu, Yan Wen, Yumeng Jia, Feng Zhang
J Prev Alz Dis 2025;9(12)
Show summaryHide summaryBACKGROUND: Excessive sugar intake has been implicated in increased dementia risk; however, existing studies are constrained by small sample sizes and a primary focus on total sugar, with limited investigation into specific sugar subtypes. This study explores the relationship between sugar intake, its subtypes, and the incidence of dementia.
METHODS: We analyzed 172,516 participants from the UK Biobank who completed at least one 24-hour dietary recall (Oxford WebQ). Cox proportional hazards models estimated the hazard ratios (HRs) and 95 % confidence intervals (95 % CIs) for total sugar and its subtypes (free sugar, fructose, glucose, sucrose, maltose, lactose, and other sugars) about the risk of dementia. Sex-stratified analyses were also performed.
RESULTS: Higher intakes of total sugar (HR = 1.292, 95 % CI = 1.148–-1.453) and free sugar intake (HR = 1.254, 95 % CI = 1.117–-1.408) were significantly associated with increased dementia risk. Positive associations were also observed for non-milk extrinsic sugars (HR = 1.321, 95 % CI = 1.175–-1.486) and sucrose (HR = 1.291, 95 % CI = 1.147–-1.452). These associations were evident in women, with higher intakes of total sugars, free sugars, glucose, sucrose, and non-milk extrinsic sugars independently linked to increased dementia risk, whereas no significant associations were found in men.
CONCLUSION: Higher consumption of total sugars, free sugars, sucrose, and non-milk extrinsic sugars confers increased dementia risk, particularly among women.
CITATION:
Yue Che ; Wenming Wei ; Tingting Mao ; Lina Qin ; Hanchi Wang ; Yijia Li ; Weixuan Da ; Jin Feng ; Li Liu ; Bolun Cheng ; Huan Liu ; Yan Wen ; Yumeng Jia ; Feng Zhang (2025): Association of sugar intake with incident dementia in the UK Biobank: a prospective cohort study. The Journal of Prevention of Alzheimer’s Disease (JPAD).https://doi.org/10.1016/j.tjpad.2025.100311
DIETARY SUGAR INTAKE, GENETIC SUSCEPTIBILITY, AND RISK OF DEMENTIA: A PROSPECTIVE COHORT STUDY
Yu An, Limin Cao, Gang Zheng, Yashu Liu, Honghao Yang, Liangkai Chen, Yuhong Zhao, Xiaopeng Zhang, Yang Xia
J Prev Alz Dis 2025;9(12)
Show summaryHide summaryBACKGROUND: Sugar intake has been identified as a risk factor for incident dementia; however, the role of genetic susceptibility in such association remains unclear.
METHODS: This cohort study involved 158,408 participants from the UK Biobank to explore the effect of genetic susceptibility on the association between dietary sugar intake and dementia risk. Data on sugar intake were evaluated using repeated web-based 24-hour dietary recalls. Polygenic risk scores (PRS) for sugar metabolism (Triglyceride Glucose, TyG), gut microbiota, and disease susceptibility (Alzheimer's disease) were generated based on genome-wide association studies.
RESULTS: Over a median follow-up period of 9.94 years, 1,219 dementia cases (0.7%) were documented. There were significant positive dose-response relationships between sugar intake and dementia risk (non-free sugar: HR, 95% CI, Quartile 4 vs. Quartile 1 = 1.26, 1.04–1.52; free sugar: 1.43, 1.20–1.70). Genetic susceptibility, including TyG-PRS, gut microbiota, and disease susceptibility, showed a combined effect on the association between sugar intake and dementia risk. Notably, significant interactions were observed between sugar intake, PRS for Ruminococcaceae UCG-014 and dementia, as well as between free sugar, PRS for Oscillospira and dementia. Participants with lower PRS of Ruminococcaceae UCG-014, or higher PRS of Oscillospira, posed a higher risk of dementia due to sugar intake.
CONCLUSION: Both free and non-free sugar intake are independent risk factors for dementia incidence. The role of genetic susceptibility among such association cannot be ignored. These results underscore the importance of personalized nutritional interventions targeting both dietary habits and genetic risk profiles in dementia prevention strategies.
CITATION:
Yu An ; Limin Cao ; Gang Zheng ; Yashu Liu ; Honghao Yang ; Liangkai Chen ; Yuhong Zhao ; Xiaopeng Zhang ; Yang Xia (2025): Dietary sugar intake, genetic susceptibility, and risk of dementia: A prospective cohort study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100312
PREGNANCY HYPERTENSION IS ASSOCIATED WITH HIGHER P-TAU217 IN HEALTHY MIDLIFE WOMEN
Eu-Leong Yong, Beverly Wen Xin Wong, Darren Yuen Zhang Tan, Liang Shen, Benecia Wan Qing Thia, Joyce Ruifen Chong, Christopher Li-Hsian Chen
J Prev Alz Dis 2025;9(12)
Show summaryHide summaryINTRODUCTION: There is very limited knowledge on the relationship between pregnancy hypertension and the occurrence of pre-clinical Alzheimer's disease (AD).
METHODS: Community-dwelling midlife women without dementia were enrolled from well-woman clinics of the National University Hospital, Singapore. Sociodemographic parameters and history of pregnancy hypertension were obtained. Cognition was assessed using the Montreal Cognitive Assessment-Basic tool. Fasted blood samples were stored for batched analysis of renal function, APOE genotyping and p-tau217 levels using Simoa® ALZpath p-tau217 Advantage PLUS (Quanterix, MA, USA). General linear modelling was used to examine the association between pregnancy hypertension and p-tau217.
RESULTS: Among 743 women (mean age 62.9 ± 6.0; range: 50.7 to 76.6 years) enrolled, 68 (9.2%) reported pregnancy hypertension. General linear modelling showed that an older age [mean difference: 0.002 (95% CI: 0.001, 0.003)], mild cognitive impairment [0.016 (0.001, 0.032)], lower BMI [0.068 (0.027, 0.109)], eGFR<60 mL/min/1.73 m2 [0.132 (0.072, 0.193)] and the APOE4 carrier genotype [0.038 (0.018, 0.058)] were independently associated with higher serum p-tau217 levels. History of pregnancy hypertension remained significantly associated with subsequent higher serum p-tau217 [0.040 (0.013, 0.067)], after adjustment for age, mild cognitive impairment, hypertension, BMI, renal function, and APOE4 genotype status.
DISCUSSION: Pregnancy hypertension was associated with AD pathology with mean differences similar to high risk APOE4 carrier genotypes. Information on pregnancy hypertension could help physicians to identify women who might benefit from early p-tau217 screening for Alzheimer’s disease, allowing for early clinical intervention.
CITATION:
Eu-Leong Yong ; Beverly Wen Xin Wong ; Darren Yuen Zhang Tan ; Liang Shen ; Benecia Wan Qing Thia ; Joyce Ruifen Chong ; Christopher Li-Hsian Chen (2025): Pregnancy hypertension is associated with higher p-tau217 in healthy midlife women. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100316
MEDICAL RISK FACTORS, APOE HAPLOTYPE, AND ALZHEIMER’S DISEASE: A LARGE-SCALE ANALYSIS
Uri Elias, Lidor Gazit, Roei Zucker, Amos Stern, Michal Linial, Gilles Allali, Tamir Ben-Hur, Gad A. Marshall, Shahar Arzy
J Prev Alz Dis 2025;9(12)
Show summaryHide summaryBACKGROUND: The multifactorial nature of Alzheimer’s disease (AD) has become increasingly evident. In addition to well-established features like neurodegeneration, amyloid-beta and tau deposition, or glial changes, other processes—such as metabolic, circulatory, and inflammatory factors—may also play a key role in driving or accelerating AD-related pathology and cognitive decline. These factors represent important targets for slowing disease progression.
OBJECTIVES: Although many studies have examined individual risk factors and meta-analyses have been performed, a large-scale, comprehensive comparison using formal medical data from a single, unified cohort is needed.
DESIGN: A retrospective case-control study leveraging comprehensive health database.
SETTING: Data were obtained from the UK-Biobank, a large (∼500 K people) population-based biomedical database in the United Kingdom.
PARTICIPANTS: The study included participants aged 40-69 at enrollment between 2006 and 2010, comprising 3,843 individuals who were clinically diagnosed with AD by August 2022 and 387,275 individuals without dementia or cognitive-impairment diagnoses.
MEASUREMENTS: ICD-10-coded diagnoses, recorded at least 10 years prior to AD diagnosis, were analyzed. Logistic regression was used to estimate the impact and significance of various medical conditions and their interactions with genetic risk factors, while accounting for demographic determinants.
RESULTS: The analysis identified 45 medical factors (96 ICD-10 entities) across multiple systems—particularly metabolic, circulatory, gastrointestinal, and sensorimotor—that significantly differentiated individuals with clinical AD from cognitively unimpaired individuals. Interaction analyses revealed that circulatory and metabolic factors had a weaker influence on AD risk in Apolipoprotein E ε4 carriers, suggesting a gene-environment interaction in disease susceptibility.
CONCLUSIONS: These findings enhance the understanding of system-level risk factors for clinical AD, highlight the relevance of less frequently reported factors in the AD prevention literature—such as gastrointestinal and sensorimotor disorders—and underscore the complex interplay between genetic susceptibility and vascular risk factors.
CITATION:
Uri Elias ; Lidor Gazit ; Roei Zucker ; Amos Stern ; Michal Linial ; Gilles Allali ; Tamir Ben-Hur ; Gad A. Marshall ; Shahar Arzy (2025): MEDICAL RISK FACTORS, APOE HAPLOTYPE, AND ALZHEIMER’S DISEASE: A LARGE-SCALE ANALYSIS. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100301
SYSTEMATIC REVIEW AND META-ANALYSIS OF RURAL-URBAN DISPARITIES IN ALZHEIMER’S DISEASE DEMENTIA PREVALENCE
Abe Mollalo, Mackenzie Kramer, Maxwell Cutty, Benyamin Hoseini
J Prev Alz Dis 2025;9(12)
Show summaryHide summaryBACKGROUND: The prevalence of Alzheimer’s disease (AD) dementia varies between rural and urban areas worldwide, with studies reporting mixed patterns. In this study, we conducted a systematic review and meta-analysis to pool the odds ratio (OR) of rural-to-urban prevalence and explored contributing regional and socioeconomic factors.
METHODS: We performed comprehensive searches in PubMed, MEDLINE, CINAHL, Web of Science, and Scopus (January 2000-August 2024) for peer-reviewed studies reporting individual-level AD dementia prevalence comparisons between rural and urban settings. A random-effects model was used to calculate pooled OR at a 95 % confidence interval (CI). Prespecified subgroup analyses examined variations by WHO-defined regions, healthcare expenditure, income level, and educational attainment.
RESULTS: The meta-analysis incorporated 19 studies (22 datasets, N = 584,863) and found significantly higher AD dementia prevalence in rural areas (pooled OR = 1.247, 95 % CI: 1.059–1.468), with considerable between-study heterogeneity (I2=95.5 %). Regional subgroup analyses revealed marked disparities in the Western Pacific (OR = 1.416, 95 % CI: 1.083–1.851) and Southeast Asia (OR = 1.382, 95 % CI: 1.058–1.805), contrasting with nonsignificant findings in the Americas (OR = 0.989, 95 % CI: 0.785–1.247). Socioeconomic stratification showed pronounced rural disadvantages in: (1) lower healthcare expenditure regions (≤7.5 % GDP: OR = 1.268, 95 % CI: 1.043–1.542) and (2) among lower-middle to upper-middle income countries (OR = 1.260, 95 % CI: 1.030–1.542). This disparity attenuated in high-income settings (OR = 1.206, 95 % CI: 0.979–1.486) and in regions with healthcare expenditure >7.5 % GDP (OR = 1.16, 95 % CI: 0.87–1.53). Educational stratification revealed significant rural-urban disparities in regions with lower educational attainment (≤8.1 mean schooling years: OR=1.43, 95 % CI: 1.15–1.79). In contrast, regions with higher educational attainment (>8.1 years) showed no significant difference (OR=1.05, 95 % CI: 0.89–1.25).
CONCLUSION: This review provides useful evidence that AD dementia prevalence is higher in rural areas than in urban areas, particularly in resource-limited settings. Our findings call for targeted rural interventions in vulnerable regions and further research into how healthcare infrastructure and education jointly influence AD dementia disparities.
CITATION:
Abe Mollalo ; Mackenzie Kramer ; Maxwell Cutty ; Benyamin Hoseini (2025): Systematic review and meta-analysis of rural-urban disparities in Alzheimer’s disease dementia prevalence. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100305
APOE ε4-RELATED DIFFERENCES IN BRAIN STRUCTURE, FUNCTION, AND CONNECTIVITY AT MIDLIFE: A SCOPING REVIEW
Rikki Lissaman, Sidra Anjum, Andrea Quaiattini, M. Natasha Rajah
J Prev Alz Dis 2025;9(12)
Show summaryHide summaryBACKGROUND: The apolipoprotein E (APOE) ε4 allele is a major genetic risk factor for late-onset Alzheimer’s disease (AD), yet there is little consensus about how and when the allele exerts its influence on the brain.
METHODS: In this scoping review, we synthesized research examining APOE ε4-related differences on MRI-derived measures of brain structure, function, and connectivity in cognitively unimpaired, middle-aged adults (aged 40–65 years). Four online databases (Ovid MEDLINE, Ovid Embase, Ovid PsycINFO, Scopus) were searched on July 11, 2024, and forward/backward reference searching was conducted on identified studies. We extracted data on sample characteristics, methods, and key APOE ε4-related results.
RESULTS: Our pre-registered search strategy identified 30 relevant studies. Overall, we found little evidence of robust, consistent differences between APOE ε4 carriers and non-carriers at midlife, especially in relation to brain structure. However, among the studies identified, small samples were common, and limited consideration was afforded to factors such as sex and ethnocultural diversity.
CONCLUSIONS: Overall, the existing literature indicates that APOE ε4 exerts little, if any, influence on brain structure at midlife, while differences in brain function and connectivity remain poorly characterized.
CITATION:
Rikki Lissaman ; Sidra Anjum ; Andrea Quaiattini ; M. Natasha Rajah (2025): APOE ε4-related differences in brain structure, function, and connectivity at midlife: A scoping review. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100364
PREVALENCE AND CO-OCCURRENCE OF DEMENTIA RISK FACTORS IN DENMARK: A NATIONWIDE STUDY
Janet Janbek, Thomas Munk Laursen, Kasper Jørgensen, Martin Mejlby Jensen, Marie Holm Eliasen, Anne Illemann Christensen, Sebastian Walsh, Andrew Sommerlad, Carol Brayne, Gunhild Waldemar
J Prev Alz Dis 2025;9(12)
Show summaryHide summaryBACKGROUND: The clustering of dementia risk factors is common and has implications for policies targeting risk reduction.
OBJECTIVES: To estimate the prevalence of 16 dementia risk factors and their co-occurrence.
DESIGN: Cross-sectional based on a closed cohort on 1 January 2022 with nationwide data on risk factors from 1969/1977.
SETTING: Denmark.
PARTICIPANTS: Whole population; closed cohort of individuals ≥65 years on 1 January 2022, and a subpopulation of responders in the 2010/2013 Danish National Health Survey.
INERTVENTION (EXPOSURES): Sixteen dementia risk factors: hypertension, cardiovascular disease, diabetes, hypercholesterolemia, obesity, smoking, alcohol, physical inactivity, depression, hearing loss, vision impairment, traumatic brain injury, sleep disorders, hospital-diagnosed infections, social isolation, and low education.
MEASUREMENTS: Period and point prevalence proportions of the dementia risk factors and of all possible combinations of factors (those occurring in ≥10 % of individuals). The prevalence estimates reflect a population-level view of persons who have experienced, were diagnosed, or were treated for the risk factors assessed.
RESULTS: In the whole population (N = 1,214,286) and the subpopulation (N = 88,565), 5 % had no risk factors, 12 % had only one, and 82 % had multiple. Hypertension was the most prevalent (57 %), and vision impairment the least (2 %). Men, individuals ≥85 years, and those with low education had the highest prevalence of risk factors (with exceptions).
CONCLUSIONS: Clustering of risk factors is very common, and findings emphasize the need to focus on multidomain interventions for dementia risk reduction that account for the clustering of risk.
CITATION:
Janet Janbek ; Thomas Munk Laursen ; Kasper Jørgensen ; Martin Mejlby Jensen ; Marie Holm Eliasen ; Anne Illemann Christensen ; Sebastian Walsh ; Andrew Sommerlad ; Carol Brayne ; Gunhild Waldemar (2025): Prevalence and co-occurrence of dementia risk factors in Denmark: A nationwide study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100365
EARLY ALZHEIMER’S DISEASE (MILD COGNITIVE IMPAIRMENT OR MILD DEMENTIA): PREVALENCE, DIAGNOS-TICS, TREATMENT OPTIONS, AND GUIDELINES IN ASIA, AUSTRALASIA, AND PACIFIC NATIONS COUNTRIES
Jung-Lung Hsu, Kee Hyung Park, Peter K. Panegyres, Yao Hsien Huang, Young In Eom, Vinay Prusty, Lolita Stephanie Tan, Yat Fung Shea
J Prev Alz Dis 2025;9(12)
Show summaryHide summaryEarly diagnosis of mild cognitive impairment (MCI) and Alzheimer’s disease (AD) with mild dementia is becoming increasingly important to enable patients to receive appropriate treatment with available amyloid-targeting therapies. Reviews of AD prevalence and diagnostic and treatment patterns typically focus on global or western populations, but the situation in Asia, Australasia, and Pacific Nations (AAPN) countries is less clear. We performed a narrative review of literature for AD in several AAPN countries, focusing on patients with MCI or mild dementia who may benefit from early treatment. Published information regarding AD incidence and prevalence and current practice in AAPN countries is limited and the nature of available information differs between countries. However, AAPN countries include some of the most rapidly aging populations and show the associated increasing trend of all-cause dementia prevalence observed globally. Although lecanemab and donanemab are now approved for AD with MCI and mild dementia in several AAPN countries, the most appropriate diagnostic pathway for patients with MCI and early AD is not established. Even though the AAPN region includes countries with routine access to advanced technologies, concerns have already been raised about the ability of healthcare systems in Australia, New Zealand, and Korea to respond to approvals of new AD therapies, including the need to ensure availability of biomarker testing and dementia specialists to allow patients to receive the early diagnosis required to enable appropriate treatment. Guidelines and national policies also need updating to differentiate between dementia subtypes and include amyloid-targeting therapies for eligible patients with early AD.
CITATION:
Jung-Lung Hsu ; Kee Hyung Park ; Peter K. Panegyres ; Yao Hsien Huang ; Young In Eom ; Vinay Prusty ; Lolita Stephanie Tan ; Yat Fung Shea (2025): Early Alzheimer’s disease (mild cognitive impairment or mild dementia): Prevalence, diagnostics, treatment options, and guidelines in Asia, Australasia, and Pacific nations countries. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100362
PRECLINICAL DETECTION OF AL-ZHEIMER’S DISEASE PATHOLOGY USING CONCEPTUAL DISCRIMINATION ABILITIES
Lara Huyghe, Yasmine Salman, Lise Colmant, Thomas Gérard, Vincent Malotaux, Gabriel Besson, Emma Delhaye, Christine Bastin, Quentin Dessain, Laurence Dricot, Renaud Lhommel, Adrian Ivanoiu, Lisa Quenon, Bernard Hanseeuw
J Prev Alz Dis 2025;9(12)
Show summaryHide summaryBACKGROUND: Performance on the Conceptual Matching Task (CMT), a measure of discrimination between conceptually confusable items, has been suggested as a cognitive marker of rhinal cortex atrophy, one of the first brain regions affected by Alzheimer’s disease (AD) pathology.
OBJECTIVES: We aimed to determine whether CMT can detect preclinical AD, and whether CMT performance is related to regional deposition of tau protein or other AD-associated lesions including amyloid (Aβ) accumulation and white matter hyperintensities (WMH).
DESIGN, SETTING AND PARTICIPANTS: This cross-sectional study include 101 participants from the UCL2016–121 cohorts in Brussels, Belgium, classified as 56 Aβ-negative cognitively unimpaired (Aβ-CU), 25 Aβ-positive CU (Aβ+CU, preclinical AD), and 20 Aβ-positive mildly cognitively impaired (Aβ+MCI, prodromal AD) individuals.
MEASUREMENTS: Participants underwent CMT and a standard neuropsychological assessment that included the Preclinical Alzheimer Cognitive Composite (PACC5), an Aβ status examination, a 3D-T1 MRI and a [18F]MK-6240 tau-PET scan.
RESULTS: CMT performance was lower among Aβ+MCI and Aβ+CU than Aβ-CU individuals. The effect of Aβ on CMT performance was stronger in the presence of WMH, but rhinal tau burden did not explain CMT performance beyond the effects of Aβ and WMH. CMT performance correlated with executive, memory, and language performance. Finally, CMT was more sensitive than PACC5 to detect CU individuals with Aβ or tau pathology.
CONCLUSION: Given that impaired performance is observed earlier in the CMT than in standard neuropsychological tests, this test shows promise as an early diagnostic tool for AD and may offer significant utility in the context of clinical trials.
CITATION:
Lara Huyghe ; Yasmine Salman ; Lise Colmant ; Thomas Gérard ; Vincent Malotaux ; Gabriel Besson ; Emma Delhaye ; Christine Bastin ; Quentin Dessain ; Laurence Dricot ; Renaud Lhommel ; Adrian Ivanoiu ; Lisa Quenon ; Bernard Hanseeuw (2025): Preclinical detection of Alzheimer’s disease pathology using conceptual discrimination abilities. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100332
DEMENTIA RISK PREDICTION: A COMPARATIVE ANALYSIS OF THE ANU-ADRI, CAIDE, COGDRISK, LIBRA, AND LIBRA2 INDICES IN THE HUNT STUDY
Josephine Stubs, Ellen Melbye Langballe, Gill Livingston, Kaarin J. Anstey, Kay Deckers, Fiona E. Mathews, Mika Kivimäki, Bjørn Heine Strand, Anne-Marie Rokstad, Steinar Krokstad, Geir Selbæk
J Prev Alz Dis 2025;9(12)
Show summaryHide summaryBACKGROUND/OBJECTIVE:Dementia is a major global health concern, necessitating effective risk assessment tools and early intervention. This study compared the performance of five modifiable dementia risk indices – ANU-ADRI, CAIDE, CogDrisk, LIBRA, and LIBRA2 and a “demographics-only” (age, education) model.
METHODS: We analyzed data from 5247 Norwegian participants in the Trøndelag Health Study (HUNT4 70+, 2017–2019) and dementia risk indices from baseline data in HUNT3 (2006–2008). Logistic regression models assessed associations between standardized index scores and all-cause dementia and Alzheimer’s disease (AD) across age group (<65 vs. ≥65 years), sex, and APOE4 status.
RESULTS: During the mean follow-up of 10.6 (9.3–12.3) years (SD=0.74), all indices significantly predicted dementia and AD, though none outperformed the demographics-only model. CogDrisk showed significantly better discriminative ability than all other indices (0.76, 95 % CI:0.74–0.78; DeLong p < 0.05), followed by LIBRA (0.75, 95 % CI:0.72–0.77) and ANU-ADRI (0.74, 95 % CI:0.72–0.76). LIBRA2 (0.69, 95 % CI:0.66–0.71) and CAIDE (0.59, 95 % CI:0.56–0.61) had significantly lower accuracy (DeLong p < 0.001). Removing demographics maintained rank order but reduced accuracy across all indices. Stratified analyses showed stronger performance in those ≥65 years and females at HUNT3, while APOE4 status did not affect performance.
CONCLUSION: All indices were associated with dementia risk, with CogDrisk performing best across all conditions, and LIBRA2 and CAIDE performing weakest. No index outperformed a model including age and education only. Future research should refine risk indices for age- and sex-specific applications and assess whether simpler demographic models may suffice in some contexts.
CITATION:
Josephine Stubs ; Ellen Melbye Langballe ; Gill Livingston ; Kaarin J. Anstey ; Kay Deckers ; Fiona E. Mathews ; Mika Kivimäki ; Bjørn Heine Strand ; Anne-Marie Rokstad ; Steinar Krokstad ; Geir Selbæk (2025): Dementia risk prediction: A comparative analysis of the ANU-ADRI, CAIDE, CogDrisk, LIBRA, and LIBRA2 indices in the HUNT study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100326
ASSESSMENT OF DEMENTIA RISK SCORES IN PREDICTING MILD COGNITIVE IMPAIRMENT: A COMPARISON OF COGDRISK, CAIDE, LIBRA, AND ANU-ADRI
Md Hamidul Huque, Kaarin J. Anstey
J Prev Alz Dis 2025;9(12)
Show summaryHide summaryBACKGROUND: Given the lack of widely accessible dementia treatments, identifying individuals at high risk of dementia is vital for prevention. No prior study has compared multiple validated dementia risk tools for predicting mild cognitive impairment (MCI) across multiple datasets. We assess the performance of the CogDrisk, ANU-ADRI, CAIDE, and LIBRA in predicting MCI.
METHOD: Data were obtained from the ARIC, Whitehall II, and PATH Through Life cohorts. Participants without dementia or MCI at baseline were included. Risk scores were computed using available risk factors and analysed using logistic regression, with Area Under the Curve (AUC) estimates. Multiple imputation was used to evaluate the impact of missing data.
RESULTS: The ARIC (n = 5778), Whitehall II (n = 6387), and PATH (n = 2115) cohorts had mean baseline ages of 51.9, 55.8, and 62.5 years, with follow-ups of 28.2, 15.7, and 11.2 years, respectively. AUCs for MCI prediction were generally similar across tools and datasets. Dementia prevalence following MCI was highest in ARIC (23.6%), followed by Whitehall II (14.1%) and PATH (7.0%). In ARIC, CogDrisk showed slightly better AUCs for predicting MCI cases that progressed to dementia. Whitehall II and PATH showed mixed results, with wider confidence intervals for progressing MCI cases, and higher AUCs for non-progressing MCI cases using CogDrisk and ANU-ADRI. All tools performed consistently when predicting dementia without prior MCI.
DISCUSSION: Dementia risk scores demonstrated comparable performance of MCI prediction and are more sensitive for identifying cases that progress to dementia, supporting their greater utility for informing risk reduction strategies.
CITATION:
Md Hamidul Huque ; Kaarin J. Anstey (2025): Assessment of dementia risk scores in predicting mild cognitive impairment: A comparison of CogDrisk, CAIDE, LIBRA, and ANU-ADRI. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100324
A NOVEL EARLY IMAGING BIOMARKER FOR GLYMPHATIC FUNCTION: CEREBRAL CORTICAL ARTERIAL PULSATILITY INDEX FROM 2-MINUTE PHASE-CONTRAST MRI
Sung-Hye You, Byungjun Kim, Byungjun Kim, Kyung-Sook Yang, Hye-Won Park, InSeong Kim, SuGil Kim, Kyung Min Kim, Bo Kyu Kim, Jae Ho Shin
J Prev Alz Dis 2025;9(12)
Show summaryHide summaryBACKGROUND: Arterial pulsatility is one of the driving forces of glymphatic flow.
OBJECTIVES: To evaluate the feasibility of the pulsatility index (PI) of cortical arteries in the centrum semiovale (PICSO) as a novel non-invasive imaging biomarker for Alzheimer’s disease (AD) in the context of glymphatic function.
DESIGN: Retrospective cross-sectional study.
SETTING: Single tertiary academic center equipped with both 3.0 T MRI systems.
PARTICIPANTS: A total of 160 individuals were enrolled: 50 healthy volunteers, 46 cognitively normal controls, and 64 AD patients who underwent diffusion tensor imaging (DTI) and 2D phase-contrast MRI.
MEASUREMENTS: Diffusion Tensor Imaging Analysis along the Perivascular Space (DTI-ALPS) index and PICSO were assessed using 2D phase-contrast MRI. Correlations with age, DTI-ALPS index, and Mini-Mental State Examination (MMSE) scores were analyzed.
RESULTS: PICSO was significantly higher in the AD group than those in healthy volunteers (P<0.001) and cognitively normal aging (P=0.001) groups. PICSO correlated positively with age (rho=0.613, P<0.001) and negatively with both the DTI-ALPS index (rho=-0.439, P<0.001) and MMSE scores (rho=-0.486, P<0.001) in total group.
CONCLUSION: PICSO derived from 2D phase-contrast 3.0T MRI may serve as a novel imaging biomarker for Alzheimer’s disease in relation to glymphatic function.
CITATION:
Sung-Hye You ; Byungjun Kim ; Moonjung Hwang ; Kyung-Sook Yang ; Hye-Won Park ; InSeong Kim ; SuGil Kim ; Kyung Min Kim ; Bo Kyu Kim ; Jae Ho Shin (2025): A novel early imaging biomarker for glymphatic function: Cerebral cortical arterial pulsatility index from 2-Minute phase-contrast MRI. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100323
ORGAN-SPECIFIC PROTEOMIC AGING AND COGNITIVE PERFORMANCE: IMPLICATIONS FOR RISK PREDICTION OF ALZHEIMER’S DISEASE AND RELATED DEMENTIAS IN OLDER ADULTS
Sujin Kang, Susan Baker, Benedict Hayhoe, Geraint Price, Gerald Novak, Janice Wong, Lefkos Middleton, Oliver Robinson
J Prev Alz Dis 2025;9(12)
Show summaryHide summaryBACKGROUND AND OBJECTIVES: Biological aging, characterized by cellular and molecular changes, may play a key role in neurodegenerative diseases. While recent proteomic advancements have introduced new aging clocks, widespread validation remains necessary. This study evaluated organ-specific and cognition-enriched proteomic clocks in relation to chronological age and cognitive change.
METHODS: We analyzed plasma proteomic data from the CHARIOT PRO SubStudy (N = 409), measured using the SomaScan assay (version 4.1) at four time points over three years (months 0, 12, 24, and 36). Using published proteomic organ age weights, we calculated conventional, organ-specific, and cognition-enriched biological ages and compared them with chronological age. Adjusted multilevel regression analyses assessed associations between baseline proteomic AgeGaps (biological−chronological age differences) and cognitive performance over 54 months.
RESULTS: The cohort (mean age: 71.8 ± 5.5 years; 50.1 % female) showed moderate to strong correlations between proteomic ages and chronological age (r = 0.37–0.80; MAE = 4.2–2.7). Over three years, AgeGaps increased across the conventional, organismal, muscle, liver, artery, and immune systems, ranging from 2.1 ± 1.9 to 1.0 ± 2.3 years. The artery AgeGap was most strongly associated with cognitive decline, with conventional and organismal AgeGaps showing similar patterns. Higher baseline AgeGap z-scores (i.e., greater biological age) in the artery and brain were associated with poorer cognition, as measured by the Repeatable Battery for the Assessment of Neuropsychological Status Total Scores (Coeff. −3.0, 95 % CI: −3.4, −2.5; and −1.1, 95 % CI: −1.5, −0.6) and the Preclinical Alzheimer's Cognitive Composite (Coeff. −0.5, 95 % CI: −0.6, −0.4; and −0.14, 95 % CI: −0.3, −0.03).
CONCLUSIONS: These findings highlight the interplay between neurological function and cardiovascular aging in cognitive decline. Organ-specific biological age assessments may aid in the early detection of age-related changes, informing personalized interventions. Our study underscores the importance of proteomic aging signatures in elucidating Alzheimer’s disease mechanisms and other neurodegenerative conditions, advocating for an integrated approach to brain and cardiovascular health.
CITATION:
Sujin Kang ; Susan Baker ; Benedict Hayhoe ; Geraint Price ; Gerald Novak ; Janice Wong ; Lefkos Middleton ; Oliver Robinson (2025): Organ-specific proteomic aging and cognitive performance: Implications for risk prediction of Alzheimer’s disease and related dementias in older adults. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100274
TEMPORAL ASSOCIATIONS OF NEUROPSYCHIATRIC SYMPTOMS, DEMOGRAPHICS AND AMYLOID WITH SUBSEQUENT TAU BURDEN IN OLDER ADULTS
Pablo Aguilar-Dominguez, Eleni Palpatzis, Muge Akinci, Anna Canal-Garcia, Joana B. Pereira, Alexandre Bejanin, Eider M. Arenaza-Urquijo, Alzheimer’s Disease Neuroimaging Initiative
J Prev Alz Dis 2025;9(12)
Show summaryHide summaryBACKGROUND: Psychiatric symptoms are increasingly recognized as early manifestations of Alzheimer’s disease (AD). These symptoms may reflect or contribute to underlying neurobiological changes, including tau burden, which represents more advanced AD pathology. Understanding factors associated with tau burden may help identify individuals at elevated risk and improve early detection strategies.
OBJECTIVES: To investigate the temporal relationships between neuropsychiatric symptoms, demographic factors, and tau burden, by examining amyloid (Aβ)-dependent, -independent, and interactive associations.
DESIGN: Retrospective cohort study.
SETTING: Alzheimer’s Disease Neuroimaging Initiative.
PARTICIPANTS: We included 681 participants without dementia (mean age = 71.2 years, 51.8 % female).
MEASUREMENTS: The participants underwent tau PET scanning with prior amyloid PET and Neuropsychiatric Inventory (NPI) interview assessments clustered around three time periods relative to tau PET: closest (0 − 2 years), mid (3 − 5 years), and furthest (6 − 8 years). Linear regression analyses, adjusting for age and APOE ε4 alleles, examined associations of NPI scores, sex, education, and their Aβ-status interactions with tau burden.
RESULTS: Higher total NPI scores up to 2 years prior to tau PET were associated with greater tau burden independently of Aβ status, whereas anxiety symptoms demonstrated an Aβ-dependent relationship with tau. (NPI: β=0.117, 95 % CI: 0.049 to 0.185, p = 0.001, Anxiety: β=0.249, 95 % CI: 0.073 to 0.424, p = 0.006). NPI measured up to 5 years prior to tau PET interacted with Aβ on tau burden (0–2 years: β=0.272, 95 % CI: 0.136 to 0.407, p < 0.001, 3–5 years: β=0.336, 95 % CI: 0.127 to 0.544, p = 0.002). Sex and education showed minimal associations with tau at uncorrected statistical levels.
CONCLUSIONS: Neuropsychiatric symptoms were associated with tau burden up to two years before tau sampling, independently of Aβ, and interacted with Aβ status up to five years prior, suggesting that neuropsychiatric symptoms are related to tau in the short term and may represent manifestations of advancing AD pathology. Demographic factors showed minimal associations. These findings highlight the importance of evaluating neuropsychiatric and anxiety symptoms as potential indicators of increased tau pathology.
CITATION:
Pablo Aguilar-Dominguez ; Eleni Palpatzis ; Muge Akinci ; Anna Canal-Garcia ; Joana B. Pereira ; Alexandre Bejanin ; Eider M. Arenaza-Urquijo ; Alzheimer’s Disease Neuroimaging Initiative (2025): Temporal associations of neuropsychiatric symptoms, demographics and amyloid with subsequent tau burden in older adults. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100294
THE ROLE OF TAU, AMYLOID-Β AND NEUROINFLAMMATION IN THE ASSOCIATION BETWEEN COGNITION AND WHITE MATTER HYPERINTENSITIES IN A SOUTHEAST ASIAN COHORT
Gurveen Kaur Sandhu, Ashwati Vipin, Jacklyn Leonardo, Fatin Zahra Zailan, Pricilia Tanoto, Faith Phemie Hui En Lee, Xin Ying Sim, Smriti Ghildiyal, Yi Jin Leow, Shan Yao Liew, Gursimar Bhalla, Rasyiqah Binte Shaik Mohamed Salim, Bocheng Qiu, Nagaendran Kandiah
J Prev Alz Dis 2025;9(12)
Show summaryHide summaryBACKGROUND: Elevated Glial Fibrillary Acidic Protein (GFAP) is associated with increased Phosphorylated Tau 181 (pTau181) induced neurodegeneration in Alzheimer’s Disease.
OBJECTIVES: However, the role of GFAP and pTau181 in vascular/mixed dementias requires elucidation within the Southeast Asian context, where their burden is considerable.
DESIGN: Population based cross-sectional study.
SETTING: Biomarkers and Cognition Study, Singapore (BIOCIS).
PARTICIPANTS: Baseline data from n = 583 (40.3 % male), non-demented but at risk, Southeast Asian community participants, were included in this analysis. All participants displayed cognitive symptoms on the Subjective Memory Complaints Questionnaire, although they may or may not have objective cognitive deficits and did not meet the criteria for dementia as per the DSM – 5.
METHODS: Neuropsychological assessments for executive function evaluation, volumetric White Matter Hyperintensities (WMH) measurement and plasma biomarker expression, were determined in non-demented but at risk, Southeast Asian research participants. Partial correlation analysis demonstrated variable associations. Simple moderation analysis revealed the ability for plasma biomarkers to influence the relationship between executive function and WMH.
RESULTS: WMH burden positively correlated to Neurofilament-Light (NfL) and pTau181. Executive function and processing speed negatively correlated to WMH burden. GFAP positively correlated to pTau181 and negatively correlated to executive function. NfL, GFAP, pTau181, and Amyloid beta 42/Amyloid beta 40 (Aβ42/Aβ40) ratio independently moderated, the relationship between executive function/processing speed and WMH burden.
CONCLUSIONS: Inflammatory mechanisms represented by GFAP were linked to tau pathology and WMH and also moderated the association between WMH on cognitive performance.
CITATION:
Gurveen Kaur Sandhu ; Ashwati Vipin ; Jacklyn Leonardo ; Fatin Zahra Zailan ; Pricilia Tanoto ; Faith Phemie Hui En Lee ; Xin Ying Sim ; Smriti Ghildiyal ; Yi Jin Leow ; Shan Yao Liew ; Gursimar Bhalla ; Rasyiqah Binte Shaik Mohamed Salim ; Bocheng Qiu ; Nagaendran Kandiah (2025): The role of Tau, amyloid-β and neuroinflammation in the association between cognition and white matter hyperintensities in a southeast Asian cohort. The Journal of Prevention of Alzheimer’s Disease (JPAD).https://doi.org/10.1016/j.tjpad.2025.100300
CHILDHOOD MALTREATMENT CONFERS LONG-TERM RISK FOR COGNITIVE IMPAIRMENT: A PROSPECTIVE INVESTIGATION
Stephanie Assuras, Kellie Courtney, Molly Maxfield, Shaina Shagalow, Sara Sherer, Jennifer J. Manly, Cathy Spatz Widom
J Prev Alz Dis 2025;9(12)
Show summaryHide summaryIMPORTANCE: Childhood maltreatment has been associated with greater risk for Alzheimer's disease and related dementias. Better understanding of this association will have implications for prevention and intervention efforts.
OBJECTIVE: To determine whether individuals with documented histories of childhood maltreatment and matched controls differ in cognitive functioning in late midlife and whether maltreatment leads to higher rates of cognitive impairment.
DESIGN: Prospective cohort design.
SETTING: Metropolitan Midwestern county area.
PARTICIPANTS: Children with documented maltreatment histories and demographically matched controls were followed up into late midlife (N = 447, Mage = 59.4). Control group children were matched to maltreated children on age, sex, race and ethnicity, and approximate family social class during the time the cases were processed.
EXPOSURE: Children with documented cases of physical and sexual abuse and neglect during 1967 to 1971 in the county juvenile (family) or adult criminal courts. Cases were restricted to children ages 0–11 at the time of the maltreatment to ensure that the temporal direction of consequences was clear.
MAIN OUTCOME AND MEASURES: Using a comprehensive neuropsychological assessment battery, multiple tests of cognitive functioning and the Functional Activities Questionnaire were administered. Participants were categorized as having cognitive impairment with no dementia (CIND) or dementia.
RESULTS: Individuals with histories of childhood maltreatment performed worse on all 12 neuropsychological tests, compared to matched controls (Cohen’s d 0.28 to 0.42) and had significantly higher risk for CIND [AOR = 1.86), amnestic CIND [AOR = 1.68) and non-amnestic [AOR = 1.48). About 13 % of maltreated individuals met criteria for amnestic CIND. Few met criteria for dementia. Males, females, Blacks, Whites, older and younger individuals, and those physically or sexually abused or neglected showed the effects of maltreatment.
CONCLUSIONS AND RELEVANCE: Cognitive repercussions of childhood maltreatment continue into late midlife. Findings reinforce the importance of early detection and preventive interventions that may decrease risks associated with childhood maltreatment in later adulthood. Because we use documented court cases from childhood, this design reduces potential biases associated with reliance on retrospective self-reports of childhood adversities. To our knowledge, this is the first study to examine long-term consequences of childhood neglect for cognitive impairment.
CITATION:
Stephanie Assuras ; Kellie Courtney ; Molly Maxfield ; Shaina Shagalow ; Sara Sherer ; Jennifer J. Manly ; Cathy Spatz Widom (2025): Childhood maltreatment confers long-term risk for cognitive impairment: A prospective investigation. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100303
COMPARATIVE ANALYSIS OF THE BURDEN OF YOUNG-ONSET AND LATE-ONSET DEMENTIA IN CHINA FROM 1990 TO 2021: A STUDY BASED ON GBD 2021 DATA
Ke-qiang Lu, Ke-jia Lu, Zheng-jun Ji
J Prev Alz Dis 2025;9(12)
Show summaryHide summaryBACKGROUND: Most epidemiological studies on dementia in China have focused on the elderly population, with a lack of systematic comparisons between the burden of young-onset dementia (YOD) and late-onset dementia (LOD).
METHODS: Based on data from the Global Burden of Disease (GBD) study, this research systematically evaluated changes in the burden of YOD and LOD in China over different time periods. The analysis employed average annual percentage change (AAPC), Bayesian age-period-cohort (BAPC) modeling, decomposition analysis, risk factor attribution analysis, health inequality analysis, and frontier analysis.
RESULTS: AAPC analysis showed that the growth rate of YOD has significantly outpaced that of LOD since 2012. Forecasting results indicated that the age-standardized rates for both YOD and LOD are expected to continue rising in the future. Decomposition analysis revealed that between 1990 and 2021, the main drivers of the increasing YOD burden shifted from population growth to epidemiological changes and population aging, whereas population growth remained the dominant driver for LOD. Risk factor analysis indicated that the impact of high BMI on both YOD and LOD has become increasingly pronounced. Health inequality and frontier analyses suggested that, although disparities in YOD and LOD burden across different SDI regions were not significant, there remains substantial room for improvement in managing both conditions in China.
CONCLUSION: In recent years, YOD has exhibited a more rapid increase compared to LOD, with its driving forces gradually shifting from population-related factors to epidemiological transitions. This highlights the need to strengthen identification and intervention strategies targeting younger and middle-aged populations. Tobacco use, high fasting plasma glucose, and high BMI are key modifiable risk factors shared by both YOD and LOD, with particular attention needed on the sustained impact of high BMI. Although international disparities in health inequality are not pronounced, China still holds considerable potential for improvement in the prevention and control of both YOD and LOD. Future interventions should be more forward-looking, systematic, and tailored to specific population groups.
CITATION:
Ke-qiang Lu ; Ke-jia Lu ; Zheng-jun Ji (2025): Comparative analysis of the burden of young-onset and late-onset dementia in China from 1990 to 2021: A study based on GBD 2021 data. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100307
LETTER TO THE EDITOR: REEVALUATING THE NEUROPROTECTIVE PROMISE OF DIETARY NITRATE: COMMENTARY ON RAJENDRA ET AL. (2025)
Parth Aphale, Himanshu Shekhar, Shashank Dokania
J Prev Alz Dis 2025;9(12)
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CITATION:
Parth Aphale ; Himanshu Shekhar ; Shashank Dokania (2025): Letter to the Editor: Reevaluating the neuroprotective promise of dietary nitrate: Commentary on Rajendra et al. (2025). The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100339
REPLY TO LETTER TO THE EDITOR: “REEVALUATING THE NEUROPROTECTIVE PROMISE OF DIETARY NITRATE: COMMENTARY ON RAJENDRA ET AL. (2025)
Catherine Bondonno
J Prev Alz Dis 2025;9(12)
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CITATION:
Catherine Bondonno (2025): Reply to letter to the editor: “Reevaluating the Neuroprotective promise of dietary nitrate: Commentary on Rajendra et al. (2025). The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100338