Ahead of print articles
AMYLOID-RELATED IMAGING ABNORMALITIES IN JAPANESE PATIENTS WITH ALZHEIMER’S DISEASE TREATED WITH LECANEMAB: A REAL-WORLD STUDY
Ryosuke Shimasaki, Masanori Kurihara, Taro Bannai, Keiko Hatano, Fumio Suzuki, Aya Midori Tokumaru, Kenji Ishii, Ryoko Ihara, Atsushi Iwata
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BACKGROUND: Although clinical trials have suggested a lower incidence of adverse events associated with Lecanemab in Asian populations compared to global cohorts, longitudinal real-world data across broader clinical indications are necessary to confirm these findings in routine practice.
OBJECTIVES: This study aimed to provide real-world evidence regarding the safety profile of Lecanemab in Japanese patients in a clinical setting.
DESIGN: A real-world observational study with a follow-up period of up to 18 months.
SETTING: A single center in Japan.
PARTICIPANTS: We included 120 Japanese patients who received Lecanemab between December 2023 and November 2025 and underwent at least one brain MRI before the fifth infusion.
MEASUREMENTS: Safety outcomes included amyloid-related imaging abnormalities (ARIA), infusion-related reactions (IRRs), and treatment discontinuation.
RESULTS: The mean age was 74.2 ± 7.9 years, and 89 (74%) were female. The majority of patients (88%) had a baseline CDR global score of 0.5. During follow-up, 81 patients completed the 12-month assessment. ARIA occurred in 24 patients (20%); ARIA-E with or without ARIA-H occurred in 5 patients (4%), and isolated ARIA-H occurred in 19 patients (16%). Crucially, no patients experienced symptomatic ARIA. All patients with ARIA-E who had available APOE data were ε4 carriers. Patients with ARIA had significantly lower baseline MMSE scores (p = 0.04), alongside non-significant trends toward higher plasma GFAP levels (p = 0.11) and higher deep white matter Fazekas scores (p = 0.05). IRRs occurred in 34 patients (28%), all of which were mild. Treatment was discontinued in 19 patients (16%), mainly due to disease progression (n = 8).
CONCLUSION: In this Japanese AD cohort, Lecanemab demonstrated a manageable safety profile in a real-world setting. In exploratory analyses, potential trends toward a higher frequency of ARIA were observed in patients with lower MMSE scores, higher plasma GFAP levels, and higher Fazekas scores, underscoring the importance of individualized risk assessment prior to therapy.
CITATION:
Ryosuke Shimasaki ; Masanori Kurihara ; Taro Bannai ; Keiko Hatano ; Fumio Suzuki ; Aya Midori Tokumaru ; Kenji Ishii ; Ryoko Ihara ; Atsushi Iwata (2025): Amyloid-related imaging abnormalities in Japanese patients with Alzheimer’s disease treated with Lecanemab: A real-world study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100562
DEMENTIA RISK FACTOR ASSESSMENT IN A LOCAL ALZHEIMER’S PREVENTION POPULATION: A GERMAN CROSS-SECTIONAL, OBSERVATIONAL STUDY
Lena Sannemann, Michelle Gerards, Lara Bohr, Frederic Brosseron, Claus Escher, Franziska Kalthegener, Theresa Müller, Alfredo Ramírez, Philip Zeyen, Frank Jessen, Ayda Rostamzadeh
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BACKGROUND: The risk for dementia is to a significant extent driven by potentially modifiable factors. Prevention strategies are increasingly aiming at individually tailored risk reduction approaches, particularly in light of emerging Brain Health Services for dementia prevention (dBHS).
METHODS: The cross-sectional observational study “Individual Risk Profiling for Alzheimer's and Dementia Prevention” (INSPIRATION) assessed the individual risk factors of 162 participants of the local Cologne Alzheimer Prevention Registry and provided individual feedback on risk profiles during a single visit. We analysed the frequency and patterns of risk factors and explored their association with cognition and Alzheimer’s disease (AD) plasma biomarkers.
FINDINGS: The most common risk factors in this population were obesity, non-adherence to a Mediterranean diet, low subjective sleep quality, subjective experience of stress, and hearing impairment. A principal component analysis (PCA) revealed six principal components (PC), which we labeled as (1) psychosocial factors, (2) blood pressure, (3) physical condition, (4) hearing impairment, (5) lifestyle, and (6) substance use. We found isolated associations between PCs, cognition, and AD plasma biomarkers.
INTERPRETATION: These findings provide initial insights into which risk factors may be most relevant and actionable for highly-educated and prevention-motivated populations likely to seek dBHS. Interventions addressing the domains of psychosocial factors, physical condition, and lifestyle may be particularly relevant to consider for a personally tailored risk reduction approach in comparable populations.
FUNDING: The study was funded by research funds of the Medical Faculty and the University Hospital Cologne, University of Cologne and the non-profit association Kölner Verein für seelische Gesundheit e.V.
CITATION:
Lena Sannemann ; Michelle Gerards ; Lara Bohr ; Frederic Brosseron ; Claus Escher ; Franziska Kalthegener ; Theresa Müller ; Alfredo Ramírez ; Philip Zeyen ; Frank Jessen ; Ayda Rostamzadeh (2025): Dementia risk factor assessment in a local Alzheimer’s prevention population: a German cross-sectional, observational study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100556
GLOBAL, REGIONAL, AND NATIONAL BURDEN OF DEMENTIA ATTRIBUTABLE TO MOOD DISORDERS: A COMPARATIVE RISK ASSESSMENT STUDY
Jing Wu, Jiali Zhou, Shiyi Shan, Ke Tang, Longzhu Zhu, Jiayao Ying, Xinyu Liu, Peige Song
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BACKGROUND: Mood disorders, particularly depressive and bipolar disorders, have emerged as potentially modifiable risk factors for dementia. However, the burden of dementia attributable to mood disorders remains unquantified. We aimed to quantify that burden among adults aged 45 years and older using a comparative risk assessment approach.
METHODS: A literature search was performed in PubMed, Embase, and MEDLINE to identify cohort studies that assessed the association between mood disorders and subsequent dementia from database inception to 9th April 2025. Random-effects models were used to derive pooled risk ratios (RRs). Assuming a 5-year lag between mood disorders and dementia onset, we calculated population attributable fractions (PAFs) and age-standardized disability-adjusted life year (DALY) rates (ASDRs) at global, regional, and national levels. Temporal trends in ASDR were analyzed using joinpoint regression to estimate average annual percentage change.
RESULTS: 77 articles were included. The pooled RR for all-cause dementia was 1.90 (95% confidence interval [CI]: 1.70, 2.12) for depressive disorders, and 3.10 (95% CI: 2.21, 4.35) for bipolar disorder. For dementia subtypes, depressive disorders showed an association with Alzheimer’s disease (RR: 2.57, 95% CI: 2.05, 3.23), and bipolar disorder was associated with vascular dementia (RR: 3.67, 95% CI: 2.42, 5.57). In 2016, the global PAFs of dementia attributable to depressive disorders were 4.79% (95% CI: 3.19%, 6.58%) in males and 5.56% (95% CI: 3.56%, 7.84%) in females. PAFs for bipolar disorder were 1.22% (95% CI: 0.65%, 2.01%) in males and 1.34% (95% CI: 0.71%, 2.18%) in females. In 2021, the global ASDR of dementia attributable to depressive disorders was 89.61 (95% CI: 34.80, 192.24) per 100,000 population, while the global ASDR for bipolar disorder was 15.91 (95% CI: 5.56, 37.87) per 100,000 population.
CONCLUSION: Since mood disorders are a substantial contributor to dementia burden, integrating mental health management into public health policies is essential.
CITATION:
Jing Wu ; Jiali Zhou ; Shiyi Shan ; Ke Tang ; Longzhu Zhu ; Jiayao Ying ; Xinyu Liu ; Peige Song (2025): Global, regional, and national burden of dementia attributable to mood disorders: a comparative risk assessment study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2025.8
BARRIERS AND FACILITATORS TO RECRUITMENT, ENGAGEMENT, AND RETENTION OF UNDERREPRESENTED POPULATIONS IN DEMENTIA PREVENTION RESEARCH: A SCOPING REVIEW
A.F. Rirash, S. Franzen, R. Bourdage, E. Kreuk, N.C. Visser, G.M. Babulal, E. van den Berg, J.M. Papma
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Underrepresented populations in dementia prevention research, including minoritized racial/ethnic groups, individuals with lower socioeconomic status, and others facing social and structural disadvantages, are disproportionately affected by dementia risk. This scoping review examined barriers and facilitators to recruitment, engagement, and retention of these populations in Alzheimer’s disease and related dementias (ADRD) prevention studies, synthesizing evidence from both empirical studies and review articles. Guided by PRISMA-ScR and the conceptual structure described by Gilmore-Bykovskyi et al., findings were synthesized from 19 reviews and 53 empirical studies. Findings were interpreted with attention to how overlapping factors—such as ethnicity, age, gender, and structural inequities—may influence study participation. Studies originated primarily from the United States (U.S.). Five key themes were identified: 1) mistrust, 2) stigma and limited research literacy, 3) logistical and financial constraints, 4) communication gaps and lack of team diversity, and 5) systemic-level barriers. Facilitators included culturally tailored outreach, long-term community partnerships, and inclusive study design. Retention strategies remain underreported, and little is known about the non-U.S. context. These findings highlight the need for context-specific, multi-level strategies that address the intersecting barriers faced by underrepresented groups to support equitable participation in dementia prevention research, and ultimately, dementia prevention.
CITATION:
A.F. Rirash ; S. Franzen ; R. Bourdage ; E. Kreuk ; N.C. Visser ; G.M. Babulal ; E. van den Berg ; J.M. Papma (2025): Barriers and facilitators to recruitment, engagement, and retention of underrepresented populations in dementia prevention research: a scoping review. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100557
LATE-LIFE BODY MASS INDEX AND AMYLOID INTERACTION ON COGNITIVE DECLINE IN UNIMPAIRED OLDER ADULTS
Wai-Ying Wendy Yau, Rema Raman, Jasmeer Chhatwal, Jeremy J. Pruzin, Zahra Shirzadi, Neelum Aggarwal, Adam M. Brickman, Petrice M. Cogswell, Jonathan Graff-Radford, Jay J. Pillai, Prashanthi Vemuri, Michael S. Rafii, Roy Yaari, Paul Aisen, Reisa Sperling, The A4 and LEARN Study Teams
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BACKGROUND: The late-life “obesity paradox” of reduced Alzheimer’s disease (AD) risk is postulated to be driven by underlying preclinical/prodromal pathology. However, few studies have directly examined the joint associations of BMI and amyloid pathology with cognitive decline, especially in individuals with preclinical AD targeted in prevention trials.
OBJECTIVE: To determine whether late-life BMI and amyloid pathology have independent or interactive associations with cognition in clinically unimpaired older adults.
DESIGN: Secondary analyses of A4 randomized clinical trial and the companion observational LEARN Study (median follow-up 4.7 years).
SETTING: Multicenter across 67 sites in US, Canada, Australia, and Japan.
PARTICIPANTS: We included 1663 participants (Placebo n = 582, Solanezumab n = 563, LEARN n = 518) who were baseline cognitively unimpaired and medically stable, mean age 71.5 ± 4.7 years, 60% women.
MEASUREMENTS: BMI and global amyloid burden [Florbetapir PET] were measured at baseline. Cognition was measured longitudinally using Preclinical Alzheimer Cognitive Composite.
RESULTS: Higher BMI and amyloid burden were independently associated with worse baseline cognition. Longitudinally, a BMI*Amyloid*Time interaction emerged: lower/normal BMI was associated with more favorable cognitive trajectory at low amyloid levels, but with faster cognitive decline when amyloid was substantially elevated.
CONCLUSIONS: Our cross-sectional findings support a negative association between obesity and cognitive aging up to late-life. Longitudinally, we observed an “obesity paradox”, where higher/obese BMI was associated with more favorable cognitive trajectories in the presence of advanced amyloid pathology. Together, our findings suggest that future trials targeting obesity to slow late-life cognitive decline may benefit from preferentially enrolling younger individuals or those without substantial amyloid accumulation.
CITATION:
Wai-Ying Wendy Yau ; Rema Raman ; Jasmeer Chhatwal ; Jeremy J. Pruzin ; Zahra Shirzadi ; Neelum Aggarwal ; Adam M. Brickman ; Petrice M. Cogswell ; Jonathan Graff-Radford ; Jay J. Pillai ; Prashanthi Vemuri ; Michael S. Rafii ; Roy Yaari ; Paul Aisen ; Reisa Sperling ; The A4 and LEARN Study Teams (2025): Late-life body mass index and amyloid interaction on cognitive decline in unimpaired older adults. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100543
INCREASE IN HEALTHCARE UTILIZATION AND MEDICARE PAYMENT WITH PROGRESSION OF PRECLINICAL ALZHEIMER’S DISEASE
Julie Beyrer, Zachary Sheff, Nalin Payakachat, Julie M. Chandler, Yun-Fei Chen, Joanna Kubisiak, Angelina Lee, Karen C. Holdridge, Roy Yaari, Paul Aisen, Michael S. Rafii, Reisa A. Sperling, A4 and LEARN Study Teams
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BACKGROUND: Alzheimer’s disease (AD) begins with the preclinical stage (Stages 1 and 2) where individuals are cognitively unimpaired but have AD pathology. Healthcare utilization and medical cost of cognitively unimpaired (preclinical) AD have not been previously evaluated.
OBJECTIVES: To describe healthcare resource utilization (HRU) and Medicare payments among cognitively unimpaired individuals with and without elevated amyloid and to evaluate the association of AD progression with HRU and Medicare payments.
DESIGN: Retrospective cohort analysis of the randomized controlled trial (Anti-Amyloid Treatment in Asymptomatic AD [A4]) and companion observational study (Longitudinal Evaluation of Amyloid Risk and Neurodegeneration [LEARN]) linked with Medicare.
SETTING: Clinical trials sites in the United States.
PARTICIPANTS: 246 cparticipants with cognitively unimpaired AD in A4 and 121 amyloid-negative participants in LEARN Medicare cohorts.
MEASUREMENTS: Measures from Medicare claims included medical conditions (diagnosis codes), HRU (inpatient, emergency room, outpatient, professional, skilled nursing facility, home health), and Medicare payments. AD progression (or cognitive or functional decline) was measured using Clinical Dementia Rating Scale-Global Score (CDR-GS) in A4/LEARN and diagnosis codes for cognitive impairment, AD, and JEN Frailty Index (JFI) of ≥6 (high frailty) in Medicare data.
RESULTS: HRU and payments were overall similar between A4 and LEARN Medicare. Claims indicators suggesting AD progression in A4 Medicare were associated with higher inpatient, outpatient, emergency room, and home health utilization (any utilization) and increased number of inpatient stays. Payments were significantly greater in A4 Medicare with AD progression vs without progression: 45% payment increase for cognitive impairment (p=0.035) with a mean incremental cost of $140 per person per month (PPPM) (95% confidence interval [CI] $125-$155), 66% payment increase for AD (p=0.011) with a mean incremental cost of $207 PPPM (95% CI $188-$226), and 103% payment increase for high frailty (p<0.001) with a mean incremental cost of $303 PPPM (95% CI $283-$323).
CONCLUSIONS: Overall, individuals with cognitively unimpaired AD in A4 Medicare did not have increased utilization and payments vs LEARN. HRU and payments were significantly greater in A4 Medicare participants with AD progression indicators in claims vs those without progression. These results highlight the need for additional research on both health and economic impacts of progression in a real-world (routine care) cohort of individuals with cognitively unimpaired AD and the potential cost savings associated with effective therapy that delays AD progression in cognitively unimpaired AD.
CITATION:
Julie Beyrer ; Zachary Sheff ; Nalin Payakachat ; Julie M. Chandler ; Yun-Fei Chen ; Joanna Kubisiak ; Angelina Lee ; Karen C. Holdridge ; Roy Yaari ; Paul Aisen ; Michael S. Rafii ; Reisa A. Sperling ; A4 and LEARN Study Teams (2025): Increase in healthcare utilization and Medicare payment with progression of preclinical Alzheimer’s disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100547
ASSOCIATION OF THE CUMULATIVE MODIFIED LIFE’S ESSENTIAL 8 SCORE WITH COGNITIVE CHANGE: RESULTS FROM TWO LONGITUDINAL CO-HORTS
Yiwen Dai, Yuling Liu, Yang Pan, Menghan Zhu, Xuyang Diao, Xinqing Yang, Jingya Ma, Darui Gao, Yanyu Zhang, Mengmeng Ji, Yichi Zhang, Wuxiang Xie, Fanfan Zheng
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INTRODUCTION: Although a higher baseline Life’s Essential 8 (LE8) score is linked to better cognitive performance and slower decline, it remains unclear whether the cumulative LE8 score is associated with cognitive change in later life.
METHODS: We included 1345 participants from the Health and Retirement Study (HRS) and 2865 participants from the English Longitudinal Study of Ageing (ELSA). A modified LE8 score was constructed based on sleep, physical activity, smoking, body mass index, blood lipids, blood glucose, and blood pressure. The cumulative modified LE8 score was calculated using 8 years of LE8 assessments. The association between cumulative modified LE8 score and cognitive change was examined using the linear mixed model.
RESULTS: Results from the HRS and the ELSA demonstrated general consistency. Pooled analysis showed that a per SD increase in cumulative modified LE8 score was associated with a slower rate of decline in global cognition (pooled Beta=0.089 SD/year), executive function (pooled Beta=0.093 SD/year), memory (pooled Beta=0.050 SD/year), and orientation (pooled Beta=0.040 SD/year).
DISCUSSION: A higher cumulative modified LE8 score was associated with better late-life cognition, highlighting the importance of maintaining long-term optimal cardiovascular health for preventing cognitive decline.
CITATION:
Yiwen Dai ; Yuling Liu ; Yang Pan ; Menghan Zhu ; Xuyang Diao ; Xinqing Yang ; Jingya Ma ; Darui Gao ; Yanyu Zhang ; Mengmeng Ji ; Yichi Zhang ; Wuxiang Xie ; Fanfan Zheng (2025): Association of the cumulative modified life’s Essential 8 score with cognitive change: Results from two longitudinal cohorts. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100548
MODIFIABLE LIFESTYLE FACTORS FOR DEMENTIA RISK IN AN ONLINE COHORT ASSESSED BY THE MOCA COGNITIVE HEALTH ASSESSMENT INDEX (MOCA-CHAI)
Laura Klaming, Hans-Aloys Wischmann, Murray Gillies, Ziad Nasreddine
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BACKGROUND: The growing prevalence of dementia highlights the need for a risk assessment tool that is accessible, facilitates the identification of at-risk individuals, and provides evidence-based guidance on how to reduce dementia risk.
OBJECTIVES: We developed, deployed, and evaluated the MoCA-CHAI, a self-administered, online dementia risk assessment for the general public. We provide a brief overview of its development, the self-enrolled population that has completed it, and a preliminary evaluation of its predictive performance.
METHODS: Drawing on the 2024 Lancet report, we developed the MoCA-CHAI translating the 14 identified risk factors into a questionnaire. We used the MoCA XpressO as a measure of cognitive impairment and a proxy measure for the probability of having or developing dementia.
FINDINGS: The MoCA-CHAI was completed by 3886 people. Based on their XpressO score, 11.3% showed a high probability of cognitive impairment. Using a logistic regression analysis, we found that each 1-point increase in MoCA-CHAI score decreases the odds of having cognitive impairment by 1%. Physical inactivity and exposure to air pollution are the most prevalent risk factors across the lifespan. Depression is more prevalent in young adults, while high cholesterol, hypertension, diabetes, and excessive alcohol consumption are more prevalent in middle-aged and older adults.
CONCLUSIONS: These findings demonstrate that the MoCA-CHAI provides insight into modifiable lifestyle factors and dementia risk. Differences in prevalences of risk factors indicate that prevention strategies need to be tailored to age-specific risk profiles. The MoCA-CHAI may help identify at-risk individuals who could benefit from targeted prevention and monitoring.
CITATION:
Laura Klaming ; Hans-Aloys Wischmann ; Murray Gillies ; Ziad Nasreddine (2025): Modifiable lifestyle factors for dementia risk in an online cohort assessed by the MoCA Cognitive Health Assessment Index (MoCA-CHAI). The Journal of Prevention of Alzheimer’s Disease (JPAD). Laura Klaming
SCREENING FOR ALZHEIMER’S DISEASE IN THE COMMUNITY USING AN AI-DRIVEN SCREENING PLATFORM: DESIGN OF THE PREDICTOM STUDY
Anna-Katharine Brem, Zunera Khan, Jonas Radermacher, Kostas Georgiadis, Ioulietta Lazarou, Margarita Grammatikopoulou, Ellie Pickering, Johanna Mitterreiter, Jon Arild Aakre, Nicholas J. Ashton, Miguel Baquero, Maria Beser-Robles, Claire Braboszcz, Sigurd Brandt, James Brown, Federica Cacciamani, Sarah Campill, Christopher Collins, Pushkar Deshpande, Ana Diaz, Stanley Durrleman, Sebastiaan Engelborghs, Laura Ferré-González, Giovani B. Frisoni, Martha Therese Gjestsen, Dianne Gove, Lee Honigberg, Bin Huang, Anett Hudak, Sandeep Kaushik, Tamas Letoha, Gaby Marquardt, Augusto J. Mendes, Matthias Müllenborn, Lucas Paletta, Nuno Pedrosa de Barros, Martin Pszeida, Audun Osland Vik-Mo, Hossein Rostamipour, Robert Perneczky, Boris-Stephan Rauchmann, Silvia Russegger, Timo Schirmer, Amied Shadmaan, Ana Beatriz Solana, Aureli Soria-Frisch, Paulina Tegethoff, Annemie Ribbens, Sara De Witte, Mark van der Giezen, Spiros Nikolopoulos, Anne Corbett, Holger Fröhlich, Dag Aarsland, the PREDICTOM Consortium
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BACKGROUND: Recent developments in physiological, imaging and digital biomarkers combined with the approval of new disease-modifying drugs against Alzheimer’s disease (AD) and diagnostic blood tests provide an opportunity to shift the first diagnostic steps to the home-setting. While these novel biomarkers enable scalable screening and earlier detection and treatment of AD, they require an evaluation of their accuracy, feasibility, and safety in primary care and the community setting.
OBJECTIVES: The aim of PREDICTOM is to develop and test the accuracy of an artificial intelligence (AI) driven screening platform for the risk assessment and early detection of AD to extend the clinical pathway to home-based screening using established and novel biomarkers.
DESIGN/SETTING: PREDICTOM is a European (Norway, UK, Belgium, France, Switzerland, Germany, Spain) observational, prospective cohort study using a cloud-based platform that stores a digitalised journey for each participant and provides a collection of artificial-intelligence (AI) algorithms and tools for risk assessment and early diagnosis and prognosis.
PARTICIPANTS: Cohort 1 consists of 4000 adults aged 50 years or older at risk of developing AD. Cohort 2 consists of 615 participants selected from Cohort 1 based on estimates indicating high (N = 415) or low (N = 200) risk of AD. Data from existing cohorts will guide the analytic strategy of the study.
MEASUREMENTS: Cohort 1 will undergo home-based assessments (Level 1), Cohort 2 will undergo in-clinic assessments (Levels 2 and 3). Level 1 includes at-home screening, collecting digital and physiological data (questionnaires, cognition, hearing, eye-tracking) and biofluids (capillary blood via finger-stick and saliva) for biomarker analysis. Level 2 comprises a more complex biomarker collection, most of which can be completed in primary care, including EEG, MRI, venous blood, microbiome from stool, cognition, hearing, and eye-tracking. Level 3 includes a diagnostic evaluation to confirm or rule out AD pathology using established biomarkers (cerebrospinal fluid, or amyloid PET).
CONCLUSIONS: PREDICTOM will develop AI-driven algorithms for the early detection of AD using biomarkers that can be collected at home or in the community care setting, and evaluate their integration into a well-defined and comprehensive clinical pathway.
CITATION:
Anna-Katharine Brem ; Zunera Khan ; Jonas Radermacher ; Kostas Georgiadis ; Ioulietta Lazarou ; Margarita Grammatikopoulou ; Ellie Pickering ; Johanna Mitterreiter ; Jon Arild Aakre ; Nicholas J. Ashton ; Miguel Baquero ; Maria Beser-Robles ; Claire Braboszcz ; Sigurd Brandt ; James Brown ; Federica Cacciamani ; Sarah Campill ; Christopher Collins ; Pushkar Deshpande ; Ana Diaz ; Stanley Durrleman ; Sebastiaan Engelborghs ; Laura Ferré-González ; Giovani B. Frisoni ; Martha Therese Gjestsen ; Dianne Gove ; Lee Honigberg ; Bin Huang ; Anett Hudak ; Sandeep Kaushik ; Tamas Letoha ; Gaby Marquardt ; Augusto J. Mendes ; Matthias Müllenborn ; Lucas Paletta ; Nuno Pedrosa de Barros ; Martin Pszeida ; Audun Osland Vik-Mo ; Hossein Rostamipour ; Robert Perneczky ; Boris-Stephan Rauchmann ; Silvia Russegger ; Timo Schirmer ; Amied Shadmaan ; Ana Beatriz Solana ; Aureli Soria-Frisch ; Paulina Tegethoff ; Annemie Ribbens ; Sara De Witte ; Mark van der Giezen ; Spiros Nikolopoulos ; Anne Corbett ; Holger Fröhlich ; Dag Aarsland ; the PREDICTOM Consortium (2025): Screening for Alzheimer’s disease in the community using an AI-driven screening platform: design of the PREDICTOM study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100545
PLASMA GFAP OUTPERFORMS CSF GFAP IN DETECTING AMYLOID PATHOLOGY AND IS ASSOCIATED WITH INCREASED RISK OF CLINICAL PROGRESSION IN EARLY ALZHEIMER’S DISEASE
Arda C. Cetindag, Carola G. Schipke, Hermann Esselmann, Niels Kruse, Jens Wiltfang, Anja Schneider, Klaus Fliessbach, Carolin Miklitz, Franziska Maier, Katharina Buerger, Daniel Janowitz, Michael Ewers, Sophia Stöcklein, Robert Perneczky, Boris-Stephan Rauchmann, Carolin Kurz, Stefan Teipel, Ingo Kilimann, Doreen Goerss, Christoph Laske, Sebastian Sodenkamp, Elham Najafpour, Michael Wagner, Sandra Roeske, Ingo Frommann, Melina Stark, Frederic Brosseron, Alfredo Ramirez, Luca Kleineidam, Josef Priller, Eike Jakob Spruth, Maria Gemenetzi, Slawek Altenstein, Emrah Düzel, Wenzel Glanz, Enise I. Incesoy, Michaela Butryn, Chris Bauer, Frank Jessen, Oliver Peters
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BACKGROUND: Early and accurate detection of Alzheimer’s disease (AD) is essential for timely intervention and development of disease-modifying treatments. The DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE) provides a deeply phenotyped cohort covering preclinical and early clinical stages, including subjective cognitive decline (SCD) and mild cognitive impairment (MCI). Astrocyte reactivity and its biomarkers, particularly glial fibrillary acidic protein (GFAP), have gained increasing attention in AD research; however, the relationship between GFAP and amyloid in early disease, as well as its potential prognostic value beyond its association with amyloid status, remains insufficiently understood.
OBJECTIVES: To evaluate the performance of CSF and plasma GFAP across early disease stages, compare these measures according to amyloid status, and assess the prognostic value of GFAP for clinical progression across diagnostic stages during longitudinal follow-up.
SETTING: This study used data from the multicenter DELCODE cohort in Germany, including participants with available plasma and/or CSF samples and standardized clinical, cognitive, imaging, and biomarker assessments.
MEASUREMENTS: GFAP concentrations in plasma and CSF were quantified using validated immunoassay platforms. Standard CSF AD biomarkers and ApoE genotype were measured using established assays. Amyloid status was defined by the CSF Aβ42/40 ratio. Longitudinal follow-up occurred annually for up to ∼10 years, with clinical conversion determined according to NIA-AA criteria.
RESULTS: Plasma and CSF GFAP increased across the AD continuum, with higher levels in MCI and AD (p < 0.001). Plasma GFAP showed a stronger association with amyloid status than CSF GFAP across all groups. In MCI, plasma GFAP combined with age and ApoE4 yielded an AUC of 0.87. Elevated plasma GFAP predicted increased risk of conversion to MCI (HR = 2.19, p < 0.001; adjusted HR = 1.70, p = 0.0056) and AD dementia (HR = 3.5; adjusted HR = 2.49 both p < 0.001).
CONCLUSION: Plasma GFAP is a sensitive, minimally invasive biomarker with diagnostic relevance for amyloid detection and prognostic relevance for clinical progression in early AD.
CITATION:
Arda C. Cetindag ; Carola G. Schipke ; Hermann Esselmann ; Niels Kruse ; Jens Wiltfang ; Anja Schneider ; Klaus Fliessbach ; Carolin Miklitz ; Franziska Maier ; Katharina Buerger ; Daniel Janowitz ; Michael Ewers ; Sophia Stöcklein ; Robert Perneczky ; Boris-Stephan Rauchmann ; Carolin Kurz ; Stefan Teipel ; Ingo Kilimann ; Doreen Goerss ; Christoph Laske ; Sebastian Sodenkamp ; Elham Najafpour ; Michael Wagner ; Sandra Roeske ; Ingo Frommann ; Melina Stark ; Frederic Brosseron ; Alfredo Ramirez ; Luca Kleineidam ; Josef Priller ; Eike Jakob Spruth ; Maria Gemenetzi ; Slawek Altenstein ; Emrah Düzel ; Wenzel Glanz ; Enise I. Incesoy ; Michaela Butryn ; Chris Bauer ; Frank Jessen ; Oliver Peters (2025): Plasma GFAP outperforms CSF GFAP in detecting amyloid pathology and is associated with increased risk of clinical progression in early Alzheimer’s disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100544
RIGHT-LATERALIZED CEREBELLAR CORTICAL THICKENING IS ASSOCIATED WITH MILD BEHAVIORAL IMPAIRMENT IN MILD COGNITIVE IMPAIRMENT
Sohee Kim, Young-Chul Jung, Eosu Kim, Keun You Kim, for the Alzheimer\'s Disease Neuroimaging Initiative
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BACKGROUND: Mild Behavioral Impairment (MBI) reflects later-life emergence of persistent neuropsychiatric symptoms and is increasingly recognized as an early manifestation of neurodegenerative disease, yet cerebellar correlates remain underexplored. We tested whether cerebellar morphometry is associated with incident MBI in mild cognitive impairment (MCI).
METHODS: Using longitudinal Alzheimer’s Disease Neuroimaging Initiative data, MBI was derived from Neuropsychiatric Inventory/ Neuropsychiatric Inventory-Questionnaire items mapped to five diagnostic domains and defined as new symptoms persisting for ≥2 consecutive visits after a symptom-free baseline. Of 530 MCI participants without baseline symptoms, 181 who developed MBI were matched 1:1 to controls by age, sex, and education. DeepCERES quantified lobular cerebellar cortical thickness and asymmetry from 3T T1-weighted MRI. We used logistic regression with false discovery rate correction and conducted domain-specific analyses (affective dysregulation, impulse dyscontrol, decreased motivation).
RESULTS: MBI cases had lower Mini Mental State Examination scores and higher dementia conversion than controls. Greater thickness in right cerebellar lobules IV (OR 1.215), V (OR 1.122), and VIIIB (OR 1.169), and greater asymmetry in right lobule V (OR 1.035), were associated with incident MBI. Affective dysregulation showed the strongest, largely right-lateralized associations and greater interhemispheric asymmetry. Main results were unchanged after separate sensitivity adjustments for Mini Mental State Examination scores and for index-visit psychiatric medication use.
CONCLUSION: Incident MBI in MCI is linked to right-lateralized cerebellar cortical thickening and asymmetry, most prominently for affective dysregulation. These patterns may reflect early compensatory and/or neuroinflammatory processes within cerebello–cortical circuits relevant to affect regulation.
CITATION:
Sohee Kim ; Young-Chul Jung ; Eosu Kim ; Keun You Kim ; for the Alzheimer's Disease Neuroimaging Initiative (2025): Right-lateralized cerebellar cortical thickening is associated with mild behavioral impairment in mild cognitive impairment. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100540
PERFORMANCE OF A FULLY AUTO-MATED PLASMA TAU PHOSPHORY-LATED AT THREONINE 217 IMMU-NOASSAY TO REFLECT AMYLOID-BETA BURDEN IN AN UNSELECTED COHORT REPRESENTATIVE OF CLI-NICAL PRACTICE
Sayuri Hortsch, Annunziata Di Domenico, Niels Borlinghaus, David Caley, Laura Kaminioti-Dumont, Sara Bohn Jeppesen, Armand González-Escalante, Craig Ritchie, Kristian Steen Frederiksen, Marc Suárez-Calvet
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BACKGROUND: With the emergence of disease-modifying anti-amyloid-beta (Aβ) therapies for Alzheimer’s disease (AD), early and accurate quantitative measures of Aβ burden are critical. Blood-based biomarkers are a scalable and minimally invasive diagnostic solution; plasma tau phosphorylated at threonine 217 (pTau217) is a promising marker for Aβ pathology. The clinical performance of the prototype ElecsysⓇ Phospho-Tau (217P) Plasma immunoassay (Roche Diagnostics) to detect Aβ burden was investigated in an unselected cohort reflective of clinical practice.
METHODS: Plasma was prospectively collected from participants aged 55 to 80 years with objective or subjective cognitive decline under evaluation for AD. Participants were recruited at multiple clinical sites spanning primary and secondary care. Plasma pTau217 concentrations measured using the prototype pTau217 plasma immunoassay were compared with amyloid positron emission tomography centiloid-based classification at different cutoffs, with further analyses performed at centiloid cutoff 30.
OUTCOMES: Among 588 participants, plasma pTau217 demonstrated high concordance with centiloid-based classification at selected cutoffs. The discriminative ability of plasma pTau217 to detect Aβ pathology peaked at centiloid cutoff 32 (area under the curve=0.933). Subgroup analyses at centiloid cutoff 30 demonstrated good discrimination of Aβ positivity/negativity by clinical diagnosis, age, and sex. Moderately decreased kidney function to kidney failure was found to influence plasma pTau217 levels.
INTERPRETATION: The prototype pTau217 plasma immunoassay showed high accuracy in reflecting Aβ burden among individuals presenting with cognitive complaints across diverse clinical settings. These findings support its potential implementation into routine clinical practice for early detection of AD, alongside standard clinical and neuropsychologic assessments.
CITATION:
Sayuri Hortsch ; Annunziata Di Domenico ; Niels Borlinghaus ; David Caley ; Laura Kaminioti-Dumont ; Sara Bohn Jeppesen ; Armand González-Escalante ; Craig Ritchie ; Kristian Steen Frederiksen ; Marc Suárez-Calvet (2026): Performance of a fully automated plasma tau phosphorylated at threonine 217 immunoassay to reflect amyloid-beta burden in an unselected cohort representative of clinical practice. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100534
CHARACTERISTICS OF INFUSION-RELATED REACTIONS TO LECANEMAB IN EARLY ALZHEIMER’S DISEASE: A MULTICENTER REAL-WORLD STUDY IN NORTHWESTERN CHINA
Peijie Liu, Jie Liu, Jin Wang, Ying Du, Zhirong Liu, Hong Zhang, Aiqin Zhu, Gejuan Zhang, Xinling Meng, Chunmei Zhao, Weiping Zhang, Liangjun Dang, Wei Zhang, Qiumin Qu, Yan Qu
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BACKGROUND: Infusion-related reactions (IRRs) represent the most common adverse events associated with lecanemab. However, real-world data on IRR characteristics and risk factors in Asian populations, particularly Chinese, remain scarce.
METHODS: In a multicenter prospective registry, 139 patients with early Alzheimer’s disease (AD) receiving lecanemab were included. IRRs were physician-confirmed. Multivariable logistic regression identified independent predictors.
RESULTS: The cumulative IRR incidence was 12.36 %, highest at the first infusion (17.3 %) and decreased significantly thereafter (P < 0.001). Fever (54.2 %) and dizziness (16.7 %) were the most common symptoms. 45.8 % of IRRs occurred 2–24 hours after infusion. All IRRs were mild (Grade 1) and self-limited. Hypertension (OR = 5.017, P = 0.007) and higher Fazekas score (OR = 2.734, P = 0.017) were independently associated with IRR.
DISCUSSION: In this Chinese real‑world cohort, lecanemab‑associated IRRs were less frequent, mild, and delayed. Hypertension and white‑matter hyperintensity severity emerged as key risk factors, underscoring the potential role of cerebrovascular health in IRR susceptibility.
CITATION:
Peijie Liu ; Jie Liu ; Jin Wang ; Ying Du ; Zhirong Liu ; Hong Zhang ; Aiqin Zhu ; Gejuan Zhang ; Xinling Meng ; Chunmei Zhao ; Weiping Zhang ; Liangjun Dang ; Wei Zhang ; Qiumin Qu ; Yan Qu (2026): Characteristics of infusion-related reactions to lecanemab in early Alzheimer’s disease: A multicenter real-world study in Northwestern China. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100542
INTERIM ANALYSIS OF ALL-CASE POST-MARKETING SURVEILLANCE STUDY IN JAPAN: LECANEMAB IN PATIENTS WITH EARLY ALZHEIMER’S DISEASE
Atsushi Iwata, Yukinori Sakata, Kinuyo Koizumi, Akira Endo, Weijie Kuang, Kenta Sumitomo, Mika Ishii
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BACKGROUND: Lecanemab is a monoclonal antibody targeting amyloid-beta protofibrils, indicated for patients with mild cognitive impairment (MCI) and mild dementia due to Alzheimer’s disease.
OBJECTIVES: This study reports interim findings of an ongoing, multicenter, prospective, observational post-marketing study for all patients treated with lecanemab in routine clinical practice in Japan, focusing on amyloid-related imaging abnormalities (ARIAs) and infusion-related reactions primarily observed during up to 28 weeks after treatment initiation.
METHODS: Patients treated with lecanemab at any medical institutions across Japan are included in the study. Data are collected using an electronic data capture system via standardized case report forms (CRFs). Study items included the incidence of ARIA, ARIA-edema or effusion (-E), ARIA-hemorrhage (-H: cerebral microhemorrhages, superficial siderosis, and macrohemorrhage), and infusion-related reactions, reported as adverse drug reactions.
RESULTS: As of July 5, 2025, CRFs from 2675 patients were collected, of whom 2672 had data available for the interim analysis. The median age was 76.0 years, and 62.6 % (1672/2672) of patients were diagnosed with MCI. At Week 28, 7.3 % (195/2672) of patients discontinued treatment, with a mean treatment duration of 189.6 ± 34.4 days. Among 2634 patients confirmed to have undergone MRI scans after treatment initiation, ARIA was observed in 7.1 % (188/2634) of patients, ARIA-E in 3.0 % (78/2634), and ARIA-H in 5.2 % (137/2634). Serious ARIA-H (macrohemorrhage) occurred in two patients (0.1 %). Infusion-related reactions were observed in 17.0 % (455/2672), including 0.7 % (18/2672) serious cases. The proportion of patients who experienced ARIA was highest in patients with apolipoprotein E (APOE) ε4 homozygotes.
CONCLUSION: This interim analysis represents one of the largest real-world lecanemab cohorts reported globally to date. Although absolute rates are not directly comparable with those from clinical trials, the trends in ARIA distributions across APOE genotypes and infusion-related reactions were comparable to those observed in clinical trials.
CITATION:
Atsushi Iwata ; Yukinori Sakata ; Kinuyo Koizumi ; Akira Endo ; Weijie Kuang ; Kenta Sumitomo ; Mika Ishii (2026): Interim analysis of all-case post-marketing surveillance study in Japan: lecanemab in patients with early Alzheimer’s disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100541
LIVING ARRANGEMENTS AND COGNITIVE RESILIENCE IN AGING: UNRAVELING DISTINCT PATHWAYS THROUGH PLASMA BIOMARKERS
Yuanyuan Peng, Heqianxi Dong, Yu Luo, Wen Zhou, Lu Liu, Ming Chen, Na Liu, Jiwen Che, Feifei Hu, Yifeng Cheng, Xinyan Xie, Yan Zeng
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BACKGROUND: Global aging and changing family structures necessitate identifying modifiable factors for cognitive health. While social isolation is a known risk, the protective role of specific living arrangements and their interplay with neurobiology is unclear.
OBJECTIVES: This study aimed to: (1) examine the longitudinal association between living arrangements and cognitive function in older adults, and (2) investigate the potential moderating roles of plasma Alzheimer’s disease (AD) biomarkers in this relationship.
METHODS: Using data from the Hubei Memory and Aging Cohort Study, we followed 3403 older adults aged 65 years and above with different living arrangements. Participants underwent standardized cognitive assessments and plasma biomarker measurements, including amyloid-beta (Abeta) 40, Abeta 42, glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), phosphorylated tau (p-tau) 181, and p-tau 217. Linear mixed-effects models were employed to analyze cognitive trajectories.
RESULTS: Compared to older adults living separately from their families, those in two specific living arrangements, living with a spouse only or in multigenerational living, demonstrated significantly better cognitive performance across multiple domains. These protective associations proved robust even after comprehensive adjustment for plasma AD biomarkers. Importantly, we found that higher plasma GFAP levels significantly attenuated the cognitive benefits conferred by favorable living arrangements. In a separate, distinct pathway, higher plasma Abeta40 levels were independently associated with better-preserved language function over time.
CONCLUSIONS: Favorable living arrangements may benefit cognitive health through pathways independent of typical AD pathology. Incorporating living arrangements and plasma biomarkers, particularly GFAP, could enhance risk assessment and targeted interventions for cognitive decline in older adults.
CITATION:
Yuanyuan Peng ; Heqianxi Dong ; Yu Luo ; Wen Zhou ; Lu Liu ; Ming Chen ; Na Liu ; Jiwen Che ; Feifei Hu ; Yifeng Cheng ; Xinyan Xie ; Yan Zeng (2026): Living arrangements and cognitive resilience in aging: unraveling distinct pathways through plasma biomarkers. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100536
INTEGRATIVE SMR PRIORITIZES OXIDATIVE STRESS–RELATED REGULATORY GENES FOR ALZHEIMER’S DISEASE WITH BRAIN-TISSUE VALIDATION
Liu Wu, Yu-Ting Dong, Xin Mu, Xiao Luo, Ze-Jun Chen
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Oxidative stress (OS) plays a critical role in the pathogenesis of Alzheimer’s disease (AD), yet its genetic and epigenetic regulatory mechanisms remain unclear. In this study, we applied a three-step summary-based Mendelian randomization (SMR) framework to integrate Alzheimer’s disease (AD) GWAS summary statistics with peripheral-blood eQTL and mQTL datasets, and further evaluated brain-tissue relevance using GTEx v8 and AMP-AD resources. Across the three-step SMR analyses, we prioritized multiple OS-related candidate genes (e.g., CRLS1, PRKAA1, CYP2E1, GPX1, and APP) associated with AD risk, and brain-tissue analyses further highlighted KEAP1, SIRT1, and PRDX5 as region-relevant signals. Functional enrichment analyses highlighted critical pathways such as "Nrf2-mediated antioxidant response" and "PI3K-AKT signaling," emphasizing the roles of oxidative stress, mitochondrial function, and neuroinflammation in AD. Novel regulatory mechanisms were uncovered at methylation sites (e.g., cg20211653 associated with ABCA1), linking epigenetic regulation to transcriptional mechanisms and providing candidates for brain-tissue follow-up. This study provides new insights into the molecular underpinnings of AD, bridging genetic variation, epigenetic regulation, and transcription, and identifies potential therapeutic targets for mitigating oxidative damage and neurodegeneration.
CITATION:
Liu Wu ; Yu-Ting Dong ; Xin Mu ; Xiao Luo ; Ze-Jun Chen (2026): Integrative SMR prioritizes oxidative stress–related regulatory genes for Alzheimer’s disease with brain-tissue validation. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100535
DISCORDANCE IN AMYLOID POSITIVITY BETWEEN VISUAL READS AND CENTILOIDS: IMPACT OF WHITE MATTER UPTAKE
Arnaud Charil, Todd M. Nelson, Anthonin Reilhac, Viswanath Devanarayan, Shobha Dhadda, Michael C. Irizarry, Lynn D. Kramer, Larisa Reyderman
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BACKGROUND: The visual interpretation of amyloid PET scans, or visual read (VR), is the most common technique used in clinical practice to identify the presence of cerebral amyloid plaques. Amyloid status (positive or negative) determined by VR or using a Centiloid (CL) cut-off shows high overall concordance. However, discordant cases can occur where the VR is positive, but the CL is below the positivity cut-off, or vice versa.
OBJECTIVES: The objective of this analysis was to evaluate the rate of discordance and explore potential causes, particularly the role of amyloid tracer uptake in the white matter (WM), when determining amyloid status using VR and CL in screening for the elenbecestat phase 3 studies in early Alzheimer's disease (AD).
DESIGN: Amyloid PET scans using either Florbetapir (Amyvid™), Florbetaben (Neuraceq™) or Flutemetamol (Vizamyl™) from 3,232 participants (1507 VR- and 1725 VR+) with cognitive impairment screened for the elenbecestat phase 3 studies in early AD were visually interpreted at screening by trained neuroradiologists and quantified using CL values.
SETTING: Academic and clinical centers.
INTERVENTIONS/MEASUREMENTS: Quantitatively, amyloid positivity was defined as CL > 32.21. The number of positive cortical regions was determined by counting the number of regions with a standardized uptake value ratio (SUVr) that exceeded 1.17. PET SUVr levels in the cerebral WM were measured using an eroded WM region of interest (ROI). Statistical tests were conducted to detect differences among the four concordance groups, defined by the relationship of VR and CL status (positive or negative). Additionally, tests examined the relationship between uptake in the WM and rates and type of discordance. Receiver operating characteristic (ROC) analysis and DeLong’s test were also used to examine the effect of different tracers on the discordant rates.
RESULT: Discordance was observed in 6.53% of cases (n=211), with VR+/CL- in 4.61% (n=149) and VR-/CL+ in 1.92% (n=62). VR+/CL- discordant cases had significantly fewer amyloid-positive cortical regions compared to both VR+/CL+ and VR-/CL+ cases. VR-/CL+ cases had a significantly higher WM uptake than VR-/CL- and VR+/CL- cases. Our findings revealed a relationship between WM uptake and rates and types of discordance. High WM uptake can erroneously lead to CL+, due to gray matter (GM) contamination from the WM, and VR- status, due to reduced contrast between WM and GM, resulting in VR-/CL+ cases. Conversely, low WM uptake can result in an underestimation of CL values, inaccurately classifying a scan as CL-, and at the same time, the increased contrast may result in a VR+, thereby increasing the occurrence of discordant VR+/CL- cases.
CONCLUSION: Variations in WM uptake significantly contribute to discordances by introducing positive or negative bias in CL values and altering the GM to WM contrast, which forms the basis of the VR. Nevertheless, the rates of discordant cases are low and VR represents a robust and validated method to determine the presence of amyloid deposition. VR enables enrolling patients with amyloid beta pathology, as seen on amyloid PET scans, whereas CL scaling was developed to provide standardized units that more consistently characterize longitudinal amyloid‑β change. These findings reflect the complementary roles of VR and CL in amyloid PET evaluation, with implications for refining diagnostic accuracy and disease monitoring in AD clinical trials and practice.
CITATION:
Arnaud Charil ; Todd M. Nelson ; Anthonin Reilhac ; Viswanath Devanarayan ; Shobha Dhadda ; Michael C. Irizarry ; Lynn D. Kramer ; Larisa Reyderman (2026): DISCORDANCE IN AMYLOID POSITIVITY BETWEEN VISUAL READS AND CENTILOIDS: IMPACT OF WHITE MATTER UPTAKE. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100530
EVALUATING EVIDENCE-BASED RECRUITMENT STRATEGIES FOR ALZHEIMER’S DISEASE AND RELATED DEMENTIAS CLINICAL TRIAL RESEARCH: A LITERATURE REVIEW
Mireille Jacobson, Christina Deuschle, Desi Peneva, Alice Nuo-Yi Wang, Cooper Roache, Meghan Walsh, Phyllis Barkman Ferrell, Maria-Alice Manetas, Rema Raman, Paul Aisen, Dana Goldman
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BACKGROUND: With the prevalence of Alzheimer’s disease and related dementias (ADRD) rising, prevention and treatment clinical trials are increasingly important. Yet inadequate participant recruitment to ADRD research—a leading cause of trial delays, suspensions, or discontinuations—continues to hinder innovation and increase costs. This literature review aimed to identify ADRD recruitment strategies that are effective and ineffective, based on quantitative outcomes, with the goal of optimizing recruitment and advancing recruitment science.
METHODS: PubMed, Google Scholar, relevant ADRD websites, and references were searched for studies meeting inclusion criteria—those reporting quantitative outcomes aimed at improving recruitment rates, timely recruitment, or representation. Reference lists from relevant systematic reviews and meta-analyses, including publications from leading researchers, were also examined. The Mixed Methods Appraisal Tool (MMAT) was used to assess evidence quality.
RESULTS: The search yielded 965 publications, of which 50 met inclusion criteria. Few studies reported recruitment methods for pharmacological trials, and many lacked sufficient detail or standardized reporting to assess quality using MMAT criteria, making it difficult to determine effectiveness. Recruitment efforts deemed successful by study authors often relied on multi-pronged approaches integrating community engagement, structured outreach, and digital tools. However, evidence for effective and scalable strategies remains limited.
CONCLUSION: Advancing ADRD recruitment science requires progress in two key areas: embedding recruitment evaluation directly into trial protocols and encouraging broader sharing of recruitment data. Routine practices, such as publishing recruitment outcomes and adopting standardized reporting, can help close the evidence gap. These approaches enable comparison, replication, and generalizability of effective strategies, ultimately accelerating progress in ADRD research.
CITATION:
Mireille Jacobson ; Christina Deuschle ; Desi Peneva ; Alice Nuo-Yi Wang ; Cooper Roache ; Meghan Walsh ; Phyllis Barkman Ferrell ; Maria-Alice Manetas ; Rema Raman ; Paul Aisen ; Dana Goldman (2026): Evaluating evidence-based recruitment strategies for Alzheimer’s disease and related dementias clinical trial research: A literature review. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100532
AMYLOID SPATIAL EXTENT WITH FLORBETAPIR-PET FOR EARLY DETECTION OF PRECLINICAL ALZHEIMER’S DISEASE
Emma G. Thibault, Grace Del Carmen Montenegro, J?Alex Becker, Julie C? Price, Brian C. Healy, Bernard J. Hanseeuw, Rachel F. Buckley, Heidi I.L. Jacobs, Michael J. Properzi, Reisa A. Sperling, Keith A. Johnson, Michelle E. Farrell
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BACKGROUND: Prevention of Alzheimer’s disease (AD) requires biomarkers sensitive to the earliest amyloid-β (Aβ) deposits.
OBJECTIVES: To characterize performance of a recently-developed Aβ-PET spatial extent metric (EXT) for early Aβ detection using 18[F]-florbetapir (FBP)-PET, evaluating its sensitivity, reliability, and associations with plasma pTau217, tau-PET, and cognition.
DESIGN: Longitudinal study with up to 5.5 years of PET, plasma and cognitive measures.
SETTING: The Anti-Amyloid Treatment in Asymptomatic Alzheimer’s disease (A4) Study and its companion screen-fail study Longitudinal Evaluation of Amyloid and Neurodegeneration Risk (LEARN) conducted across 67 international sites.
PARTICIPANTS: 1118 cognitively unimpaired older adults from the A4 placebo arm and LEARN.
MEASUREMENTS: EXT (% of neocortex above region-specific thresholds), global Aβ SUVR, plasma pTau217, medial temporal (MTL) and temporal neocortical (nTEMP) tau-PET SUVR, and Preclinical Alzheimer Cognitive Composite (PACC).
RESULTS: EXT showed high cross-sectional reliability and longitudinal stability. Using EXT reclassified 21.4% of SUVR-participants from Aβ− to Aβ+ and predicted who would progress to SUVR+ 5.5 years later with 83% sensitivity and 94% specificity. In SUVR− individuals, higher pTau217 associated with greater SUVR only within EXT+ individuals. Baseline EXT outperformed SUVR in predicting MTL tau proliferation. For neocortical tau SUVR and PACC change, EXT was the better predictor in earlier Aβ stages (while Aβ spread) while SUVR was superior later (after Aβ was widespread).
CONCLUSIONS: EXT is a robust, generalizable PET metric that detects Aβ before global positivity and early Aβ-related changes in tau and cognition, supporting its relevance for trial enrichment and early therapeutic monitoring in AD prevention trials.
CITATION:
Emma G. Thibault ; Grace Del Carmen Montenegro ; J․Alex Becker ; Julie C․ Price ; Brian C. Healy ; Bernard J. Hanseeuw ; Rachel F. Buckley ; Heidi I.L. Jacobs ; Michael J. Properzi ; Reisa A. Sperling ; Keith A. Johnson ; Michelle E. Farrell (2026): Amyloid spatial extent with florbetapir-PET for early detection of preclinical Alzheimer’s disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100529
LETTER TO THE EDITOR: DONANEMAB THERAPY IN ALZHEIMER’S DISEASE WITH MILD COGNITIVE IMPAIRMENT: CONVERGENT AMYLOID, TAU, AND PLASMA BIOMARKER NORMALIZATION WITH COGNITIVE IMPROVEMENT
Limoran Tang, Yun Xu, Hui Zhao
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CITATION:
Limoran Tang ; Yun Xu ; Hui Zhao (): Letter to the Editor: Donanemab therapy in Alzheimer’s disease with mild cognitive impairment: Convergent amyloid, tau, and plasma biomarker normalization with cognitive improvement. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100533
VALIDATION OF A NOVEL COGNITIVE-FUNCTIONAL OUTCOME MEASURE OPTIMIZED FOR EARLY ALZHEIMER’S DISEASE: EVIDENCE FROM THE VIVA-MIND TRIAL
Jasmin A. Duehring, Diane M. Jacobs, David P. Salmon, Andrew J. MacKelfresh, Carolyn Revta, Antje Meyer, Michael Schaeffer, Sylvia Schell-Mader, Tanja Wassmann, Christine Wenzkowski, Howard H. Feldman, Steven D. Edland, ADCS VIVA-MIND Study Group
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BACKGROUND: Cognitive-functional composite measures are increasingly used as primary efficacy endpoints in early Alzheimer’s disease (AD) trials, where greater sensitivity to decline can improve trial efficiency and reduce sample size requirements.
OBJECTIVES: To compare sensitivity to decline of the Cognitive Functional Component 2 (CFC2), a novel cognitive-functional composite measure described by Raghavan et al. (2013), against the Clinical Dementia Rating - Sum of Boxes (CDR-SB) and other standard cognitive and functional outcomes including MMSE, FAQ, ADAS Cog 13 and ADCOMS using prospective randomized clinical trial data.
DESIGN: The VIVA-MIND trial was a phase 2A/2B randomized controlled trial investigating the safety and efficacy of varoglutamstat in patients with mild cognitive impairment and mild dementia due to AD.
SETTING: The VIVA-MIND trial was conducted between 2021–2024. It was prematurely terminated in mid-2024 by the study sponsor.
PARTICIPANTS: This secondary analysis uses data from 98 participants in the modified intention-to-treat population from the VIVA-MIND trial with complete neuropsychological test data.
MEASUREMENTS: Standard power calculations informed by parameters estimated from linear mixed-effects models were used to determine the relative efficiency of outcome measures.
RESULTS: The CFC2 was more sensitive to decline than the CDR-SB in this population. Use of the CFC2 would yield a 15% reduction in required sample size relative to the CDR-SB. Application of an optimal weighting scheme further improved the sensitivity of the CFC2.
CONCLUSIONS: Practically significant differences in the efficiency of clinical trials in early AD may be realized by the choice of clinical outcome measure and weighting scheme. Although further verification is needed, we replicate a previous finding that the CFC2 may outperform the CDR-SB in the early AD population.
CITATION:
Jasmin A. Duehring ; Diane M. Jacobs ; David P. Salmon ; Andrew J. MacKelfresh ; Carolyn Revta ; Antje Meyer ; Michael Schaeffer ; Sylvia Schell-Mader ; Tanja Wassmann ; Christine Wenzkowski ; Howard H. Feldman ; Steven D. Edland ; ADCS VIVA-MIND Study Group (2026): Validation of a novel cognitive-functional outcome measure optimized for early Alzheimer’s Disease: Evidence from the VIVA-MIND trial. The Journal of Prevention of Alzheimer’s Disease (JPAD).https://doi.org/10.1016/j.tjpad.2026.100531
SOCIODEMOGRAPHIC DIFFERENCES IN DEMENTIA PREVENTION KNOWLEDGE IN GERMANY: IMPLICATIONS FOR TARGETED HEALTH COMMUNICATION
Pauline Albus, Ann-Kristin Folkerts, Josef Kessler, Sebastian Köhler, Elke Kalbe
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BACKGROUND: Dementia is a leading cause of disability and mortality worldwide. While the disorder is widely recognized, public awareness of modifiable risk and potentially protective factors remains limited. This is despite evidence that a substantial proportion of cases could be prevented or delayed by modifying personal risk factors. To date, the influence of sociodemographic factors on knowledge about dementia prevention has not been sufficiently examined, particularly in Germany, leaving a critical gap for targeted public health strategies.
OBJECTIVES: To assess awareness of the preventability of dementia and to evaluate knowledge of risk and protective factors in the German population, with particular focus on the influence of age, sex, and education.
DESIGN: Online, cross-sectional survey study.
SETTING: German population. A link to the survey was distributed nationwide via e-mail, flyers, and social media.
PARTICIPANTS: Adults aged ≥18 years without diagnosed cognitive impairment. A total of 2610 individuals completed the survey, of whom 2515 (mean age 52.5 years, range 18–95, 69.8% female) were included in the analysis.
MEASUREMENTS: Awareness of dementia, risk factors, and preventability was assessed using two dichotomous and three Likert-scale items. Knowledge of 23 evidence-based risk and protective factors (plus sham items) was measured with Likert-scale items. Composite knowledge scores were derived from these items, including separate subscores for medical and lifestyle-related risk factors. Preferred information dissemination sources were assessed using a multiple-choice item. Analyses included descriptive statistics and regression models with age, sex, and education as predictors.
RESULTS: While almost all respondents (98.2%) affirmed knowing what dementia is, only 73% affirmed awareness of risk-modifying factors, with substantial subgroup differences. Nearly 38% did not agree that dementia can be prevented, including a higher proportion of those aged ≥75 years (52%). Lifestyle factors, such as physical, mental, and social activity and diet, were most frequently recognized (>75%), whereas medical and environmental risks (e.g., cardiovascular disease, kidney disease, air pollution) were consistently underrecognized (<50%). Overall, younger age, female sex, and higher education were predictors of significantly higher knowledge scores, with education showing the strongest effect. Preferred information sources also differed systematically; lower-educated participants and men were more likely to rely on general practitioners, while higher-educated groups preferred digital resources and specialized organizations.
CONCLUSIONS: Compared with findings from previous German surveys, awareness of dementia preventability is higher in the present sample; however, knowledge about specific influencing factors—particularly medical—remains limited. As awareness, knowledge, and preferred information channels differ across age, sex, and education groups, educational efforts should be tailored accordingly.
CITATION:
Pauline Albus ; Ann-Kristin Folkerts ; Josef Kessler ; Sebastian Köhler ; Elke Kalbe (2026): Sociodemographic differences in dementia prevention knowledge in Germany: Implications for targeted health communication. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100517
PREVENTION OF DEMENTIA USING MOBILE PHONE APPLICATIONS (PRODEMOS) – A HEALTH-ECONOMIC COST-UTILITY ANALYSIS IN PEOPLE AGED 55–75 YEARS WITH LOW SOCIO-ECONOMIC STATUS
Ron Handels, Marieke Hoevenaar-Blom, Manshu Song, Carol Brayne, Eric Moll van Charante, Fiona E. Matthews, Junfang Xu, Linus Jönsson, Nicola Coley, Rachael Brooks, Xuening Jian, Tingting Qin, Youxin Wang, Wei Wang, Edo Richard, Anders Wimo, PRODEMOS study group
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INTRODUCTION: We aimed to explore the potential incremental cost-effectiveness of the PRODEMOS coach-supported mobile health intervention for primary prevention of dementia versus standard of care provided to people aged 55–75 years with low socio-economic status (SES) in the United Kingdom (UK), and any SES in China.
METHODS: 12–18-month PRODEMOS trial (ISRCTN15986016) efficacy outcomes on hypertension, obesity, hypercholesterolemia, physical inactivity and smoking were extrapolated to lifetime impact on dementia onset, myocardial infarction, stroke and death using a health-economic open-source simulation model.
RESULTS: Simulated outcomes showed dementia cases were avoided (UK = -206 (-658 to 281), China = -140 (-456 to 205) per 100,000 persons) and disease-free time was gained for dementia, myocardial infarction and stroke (mean months per person UK = 0.4, 0.0 and 0.0; China = 0.2, 0.0 and 0.0 respectively). Assuming a maximum intervention duration of 10 years with a 10 % annual non-adherence rate, the incremental net health benefit in the UK (-0.190) and China (-0.009) indicated a potential lack cost-effectiveness.
LIMITATIONS: Our method was limited by strong assumptions regarding causality and sustained effectiveness, lack of some country-specific input estimates, and the lack of probabilistic analysis.
CONCLUSION: The PRODEMOS coach-supported mobile health intervention for the primary prevention of dementia, aimed at people aged 55 to 75 years with low SES in the UK and those of any SES in China, may potentially lack cost-effectiveness in both countries. However, lack of data required strong assumptions regarding causality and sustained effectiveness, which limited policy recommendations.
CITATION:
Ron Handels ; Marieke Hoevenaar-Blom ; Manshu Song ; Carol Brayne ; Eric Moll van Charante ; Fiona E. Matthews ; Junfang Xu ; Linus Jönsson ; Nicola Coley ; Rachael Brooks ; Xuening Jian ; Tingting Qin ; Youxin Wang ; Wei Wang ; Edo Richard ; Anders Wimo ; PRODEMOS study group (2026): Prevention of dementia using mobile phone applications (PRODEMOS) – a health-economic cost-utility analysis in people aged 55–75 years with low socio-economic status. The Journal of Frailty and Aging (JFA). https://doi.org/10.1016/j.tjpad.2026.100526
MEMORY CONSOLIDATION AND ARIA IN INDIVIDUALS RECEIVING ANTI-AMYLOID MONOCLONAL ANTIBODIES
Marc W Haut, Camila Vieira Ligo Teixeira, Patrick D. Worhunsky, Rashi I. Mehta, Joseph E. Malone, Melanie Ward, Cierra M. Keith, Holly E. Phelps, Stephanie Pockl, Nafiisah Rajabalee, Khalid Sharif, Gary Marano, Pierre-Francois D’Haese, Ali R. Rezai
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Amyloid related imaging abnormalities (ARIA) are the most significant risk associated with the use of anti-amyloid monoclonal antibodies (MAB) for Alzheimer’s disease (AD). Currently, the presence of the APOE ε4 allele is the best predictor for the development of ARIA. However, the degree of baseline memory impairment has not been fully explored as a risk factor for ARIA. Here, we examined MAB outcomes in a memory clinic population and compared patients with AD who developed ARIA to a case-matched group who did not develop ARIA. Participants who developed ARIA had greater numbers of recall intrusions and false positives, both markers for memory consolidation, at baseline than those who did not develop ARIA. We also observed greater baseline hippocampal and supplementary motor cortical atrophy with ARIA. These differences remained when controlling for the APOE ε4 allele and the presence of pretreatment microhemorrhages. Further investigation of memory impairment and associated brain atrophy is warranted to understand ARIA risk and MAB outcomes in AD.
CITATION:
Marc W Haut ; Camila Vieira Ligo Teixeira ; Patrick D. Worhunsky ; Rashi I. Mehta ; Joseph E. Malone ; Melanie Ward ; Cierra M. Keith ; Holly E. Phelps ; Stephanie Pockl ; Nafiisah Rajabalee ; Khalid Sharif ; Gary Marano ; Pierre-Francois D’Haese ; Ali R. Rezai (2026): Memory Consolidation and ARIA in Individuals Receiving Anti-amyloid Monoclonal Antibodies. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100519
NUTRITIONAL SUPPLEMENTS AND COGNITION IN HEALTHY AGING AND MILD COGNITIVE IMPAIRMENT PATIENTS: A SYSTEMATIC REVIEW AND NETWORK META-ANALYSIS
Xing Liu, Chenyi Yang, Xinyi Wang, Huihui Liao, Huan Liu, Ji Ma, Yi Sun, Haiyun Wang
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BACKGROUND: Nutritional supplementation is increasingly regarded as a potential strategy to preserve or enhance cognitive function in individuals with healthy aging and mild cognitive impairment (MCI). However, its overall efficacy remains uncertain due to inconsistent findings across clinical trials.
METHODS: In accordance with the guidelines outlined by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses of Network Meta-Analyses, we conducted a comprehensive systematic search. Our inclusion criteria focused on randomized controlled trials (RCTs) that examined the impact of nutrient supplementation on cognitive function within healthy aging and MCI patients. The primary outcome of interest was the change in cognitive function, while the secondary outcome involved alterations in blood biochemical markers (e.g., homocysteine, vitamin B12, and serum folate levels).
RESULTS: The meta-analysis results indicated that docosahexaenoic acid (DHA)+eicosapentaenoic acid (EPA)+vitamin E+tryptophan+melatonin, as well as melatonin alone, significantly enhanced global cognitive function. Additionally, DHA, folic acid+DHA, and the DHA+EPA+vitamin E+tryptophan+melatonin were all effective in augmenting memory. DHA alone was found to be beneficial in improving processing speed, whereas vitamin D3 was associated with improvements in visuospatial function. Notably, sensitivity analyses revealed that while most domain-specific effects remained stable, the rankings of certain small-sample interventions were sensitive to study duration and sample size. Supplementation with folic acid, vitamin B12, and vitamin B6, whether administered individually or in combination, resulted in varying improvements in blood biomarkers, including homocysteine, vitamin B12, and serum folate levels.
CONCLUSIONS: Nutritional supplementation demonstrates nuanced, domain-specific benefits rather than universal cognitive enhancement. While specific multi-nutrient combinations show potential, their effects are significantly influenced by baseline cognitive status, age, and intervention duration. Our findings suggest that nutritional strategies should be tailored to individual cognitive profiles, emphasizing the need for personalized interventions and further high-quality, longitudinal trials to confirm long-term clinical impact.
CITATION:
Xing Liu ; Chenyi Yang ; Xinyi Wang ; Huihui Liao ; Huan Liu ; Ji Ma ; Yi Sun ; Haiyun Wang (2026): Nutritional supplements and cognition in healthy aging and mild cognitive impairment patients: a systematic review and network meta-analysis. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100518
NEURONAL AUTOANTIBODIES IN NEURODEGENERATIVE DEMENTIA: FROM EVIDENCE TO CLINICAL FRAMEWORK
Heya Luan, Xiaodong Han, Chang Xu, Aidi Shan, Xin Wang, Shaoqi Li, Qi Yao, Tong Cui, Jinxuan Guo, Boye Wen, Yao Sun, Chuqiao Li, Qingyuan Sun, Cuibai Wei
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Neuronal autoantibodies, including against neuronal surface receptors or intracellular antigens, are established pathogenic mediators and therapeutic targets in autoimmune encephalitis (AIE) and paraneoplastic neurological syndromes (PNS). These antibodies are now increasingly reported in patients with clinically diagnosed neurodegenerative dementia, prompting re-evaluation of a neurodegenerative etiology. Within neurodegenerative trajectories, whether such antibodies act as pathogenic drivers, non-causal markers, or immune modulators remains unresolved, and heterogeneous cohorts, assays, and endpoints limit inference and clinical translation. This review integrates current research at the intersection of autoimmunity and neurodegeneration and highlights accumulating evidence for a biological continuum. This model suggests that antibody-mediated mechanisms may extend beyond acute inflammation, with sustained exposure contributing to time-dependent neurodegeneration. To facilitate clinical translation, we advance a standardized diagnostic workflow comprising three sequential stages: (i) a pretest-probability triage that defines high-risk constellations prompting antibody testing, stratifies patients accordingly; (ii) a specimen-and-assay pathway for standardized testing workflow and structured interpretation of results; and (iii) post-test integrated analysis to adjudicate pathogenic relevance based on phenotype-antibody concordance. By bridging observational research to clinical decision-making, the framework supports identification of an immunologically modulated neurodegenerative subtype with potential for therapeutic intervention, while reducing false positives and avoiding non-essential immunotherapy in low-probability contexts.
CITATION:
Heya Luan ; Xiaodong Han ; Chang Xu ; Aidi Shan ; Xin Wang ; Shaoqi Li ; Qi Yao ; Tong Cui ; Jinxuan Guo ; Boye Wen ; Yao Sun ; Chuqiao Li ; Qingyuan Sun ; Cuibai Wei (2026): Neuronal autoantibodies in neurodegenerative dementia: From evidence to clinical framework. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100515
VISUOSPATIAL MEMORY DEFICIT, PLASMA P-TAU217, AND AΒ42/AΒ40 RATIO ENHANCE SENSITIVITY TO IDENTIFY AΒ PET POSITIVITY IN INDIVIDUALS WITH SCD
Qinjie Li, Lin Huang, Ying Wang, Yihui Guan, Fang Xie, Qihao Guo
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INTRODUCTION: We hypothesize that specific cognitive assessments and plasma biomarkers may exhibit heightened sensitivity during the stage of subjective cognitive decline (SCD). The integration of these plasma biomarkers and cognitive assessments could enhance the ability to predict beta-amyloid (Aβ) pathology in individuals with SCD.
METHODS: A total of 231 participants, including 74 normal controls (NC) and 157 SCD, underwent Aβ and tau PET scans and blood testing for Aβ40, Aβ42, p-tau181, p-tau217, NfL, and GFAP. Cognitive assessments, plasma biomarkers, tau PET SUVr, and demographics were compared between Aβ+ and Aβ− groups within NC and SCD. The least absolute shrinkage and selection operator (LASSO) and logistic regression were employed to perform variable selection and develop predictive models.
RESULTS: We observed significantly worse global cognition, visuospatial memory performance, executive function, and metamemory, as well as higher tau PET SUVr, elevated levels of p-tau217, p-tau181, and GFAP, and lower Aβ42/Aβ40 ratios in SCD Aβ+ compared to SCD Aβ-. The model incorporating BVMT-LD and p-tau217 achieved a slightly higher AUC than the model using p-tau217 and Aβ42/Aβ40 (0.94 vs. 0.93). Partial correlation analyses indicated that both auditory verbal memory (AVLT-LD) and visuospatial memory (BVMT-LD) were significantly negatively associated with p-tau217, whereas only AVLT-LD demonstrated a significant negative association with tau pathology severity.
CONCLUSION: Visuospatial memory deficit and plasma p-tau217 are powerful biomarkers for identifying Aβ+ in SCD. Auditory verbal memory links to tau pathology severity, while visuospatial memory is more sensitive to Aβ deposition, supporting early intervention to prevent AD progression.
CITATION:
Qinjie Li ; Lin Huang ; Ying Wang ; Yihui Guan ; Fang Xie ; Qihao Guo (2026): Visuospatial memory deficit, plasma p-tau217, and Aβ42/Aβ40 ratio enhance sensitivity to identify Aβ PET positivity in individuals with SCD. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100525
JPAD Volume 13, N°04 - 2026
EDITORIAL: REMOTE OUTCOME MEASURES IN ALZHEIMER\'S DISEASE CLINICAL TRIALS: A CALL TO ACTION
Gustavo A. Jimenez-Maggiora
J Prev Alz Dis 2026;4(13)
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CITATION:
Gustavo A. Jimenez-Maggiora (2026): Editorial: Remote outcome measures in Alzheimer's disease clinical trials: A call to action. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100528
DIGITAL MEMORY ASSESSMENTS AND PLASMA PTAU217 ENABLE EFFICIENT PRECLINICAL ALZHEIMER’S TRIALS
Casey R. Vanderlip, Daniel L. Gillen, Joshua D. Grill, Craig E.L. Stark
J Prev Alz Dis 2026;4(13)
Show summaryHide summaryBACKGROUND: Preclinical Alzheimer’s disease (AD) trials enroll cognitively unimpaired, amyloid-positive older adults; however, most remain clinically stable over typical trial durations. Limited near-term decline reduces statistical power and drives large sample sizes and high costs. Scalable enrichment strategies capable of identifying individuals most likely to decline are critically needed.
OBJECTIVES: To determine whether a brief digital memory assessment (DMA) and plasma phosphorylated tau 217 (pTau217), individually or combined, identify preclinical AD participants at elevated risk for cognitive and biological progression, and whether such enrichment reduces clinical trial sample-size requirements.
DESIGN: Analysis of data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4) Study, a multicenter randomized clinical trial with 240 weeks of follow-up.
SETTING: Secondary-prevention trial conducted across sites in the United States, Canada, Australia, and Japan.
PARTICIPANTS: A total of 1,169 cognitively unimpaired adults aged 65–85 years who were amyloid-positive and completed both a baseline DMA and plasma pTau217 measurement.
MEASUREMENTS: Primary outcome was change in the Preclinical Alzheimer Cognitive Composite (PACC) over 240 weeks. Secondary outcomes included Clinical Dementia Rating–Sum of Boxes, Mini-Mental State Examination, Cognitive Function Instrument, and annualized change in amyloid PET, plasma pTau217, and tau PET.
RESULTS: Participants with both elevated pTau217 and low DMA exhibited the greatest cognitive decline and reached the 240-week PACC decline of the overall cohort 83 weeks earlier. Participants with neither marker showed minimal decline. Dual enrichment reduced sample-size estimates for a clinical trial from 3,252 to 818 participants per arm (75 % reduction). These individuals also demonstrated faster increases in plasma pTau217 and neocortical tau PET.
CONCLUSIONS: A brief DMA combined with plasma pTau217 identifies a subset of cognitively unimpaired, amyloid-positive older adults at highest risk for cognitive and biomarker progression. This dual-marker enrichment strategy enables smaller, shorter, and more cost-efficient preclinical AD trials and supports more targeted evaluation of preventive therapies.
CITATION:
Casey R. Vanderlip ; Daniel L. Gillen ; Joshua D. Grill ; Craig E.L. Stark (2026): Digital memory assessments and plasma pTau217 enable efficient preclinical Alzheimer’s trials. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100503
LECANEMAB FOR TREATMENT OF INDIVIDUALS WITH EARLY ALZHEIMER’S DISEASE (AD) WHO ARE APOLIPOPROTEIN E Ε4 (APOE Ε4) NON-CARRIERS OR HETEROZYGOTES
Richard Perry, Christopher Kipps, Maria Eugenia Soto Martín, Marco Bozzali, Giancarlo Logroscino, Sarah Trafford, Shobha Dhadda, Michio Kanekiyo, Amanda Goodwin, Mark Hodgkinson, Steven Hersch, Michael Irizarry, Lynn Kramer, Lutz Froelich
J Prev Alz Dis 2026;4(13)
Show summaryHide summaryBACKGROUND: Lecanemab, an antibody directed at Aβ-protofibrils and plaque, showed meaningful delay in disease progression and biological effects consistent with disease modification in the phase 3 Clarity AD trial.
OBJECTIVE: The objective of this paper is to present efficacy and safety results in ApoE ε4 non-carriers or heterozygotes population of Clarity AD.
DESIGN: Clarity AD is an 18-month, randomized study (core) in participants with early AD, with an open-label extension phase (OLE) phase.
SETTING: Academic and clinical centers.
PARTICIPANTS: All eligible ApoE ε4 participants were randomized 1:1 across 2 treatment groups (placebo and lecanemab 10 mg/kg biweekly); the results presented herein are for the ApoE4 heterozygote or non-carrier participants.
MEASUREMENTS: Endpoints included change from baseline at 18 months in the global cognitive and functional scale, CDR-SB, amyloid positron emission tomography (PET), Alzheimer’s Disease Assessment Scale-Cognitive Subscale 14 (ADAS-Cog14), Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS-MCI-ADL), and health-related quality-of-life (HRQoL) assessments. Amyloid imaging related abnormalities (ARIA) occurrence was monitored throughout the study by central reading of magnetic resonance imaging. Following 18 months treatment in the Core, eligible participants transitioned to the OLE where they received open-label lecanemab. Clinical outcomes (CDR-SB, ADAS-Cog14, and ADCS-MCI-ADL) were evaluated by examining ‘delayed start’ (core:placebo followed by OLE:lecanemab) and ‘early start’ (core:lecanemab followed by OLE:lecanemab) cohorts as well as natural history cohorts. Time to progression to next stage of AD was also evaluated through 36 months.
RESULTS: 1795 participants with early AD were enrolled in Clarity AD, of which 1521 were ApoE ε4 heterozygotes or non-carriers (85 %). Lecanemab significantly reduced clinical decline on CDR-SB at 18 months compared to placebo in the ApoEε4 heterozygotes or non-carriers subgroup. Amyloid PET, ADAS-Cog14, ADCS-MCI-ADL, and HRQoL results were consistent with the CDR-SB findings. In the analysis subgroup, the most common adverse reactions for lecanemab were infusion-related reactions (26 %), ARIA-H (13 %), fall (11 %), headache (11 %), and ARIA-E (9 %). In the OLE, lecanemab-treated participants continued to accrue benefit in CDR-SB through 36 months, with continued separation through 36 months relative to the ADNI natural history cohort. Delayed start results follow a parallel trajectory relative to early start results, but do not catch up, confirming a disease modifying effect and reflecting importance of early treatment initiation. Results were similar for ADAS-Cog14 and ADCS-MCI-ADL. Lecanemab reduced the risk of progression to next stage of AD by 28 % on lecanemab as compared to the ADNI natural history cohort.
CONCLUSION: In the ApoE ε4 heterozygotes or non-carrier subgroup of Clarity AD, lecanemab slowed decline in disease progression and reduced markers of amyloid, with expanding benefit over time.
CITATION:
Richard Perry ; Christopher Kipps ; Maria Eugenia Soto Martín ; Marco Bozzali ; Giancarlo Logroscino ; Sarah Trafford ; Shobha Dhadda ; Michio Kanekiyo ; Amanda Goodwin ; Mark Hodgkinson ; Steven Hersch ; Michael Irizarry ; Lynn Kramer ; Lutz Froelich (2026): Lecanemab for treatment of individuals with early Alzheimer’s Disease (AD) who are apolipoprotein E ε4 (ApoE ε4) non-carriers or heterozygotes. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100507
PRECLINICAL AMYLOID PATHOLOGY IS ASSOCIATED WITH ANXIETY BUT NOT DEPRESSION IN COGNITIVELY NORMAL OLDER ADULTS: EVIDENCE FOR DIFFERENTIAL NEUROPSYCHIATRIC PATHWAYS
Jonathan Vogelgsang, Clara Beck, Regan Patrick, Ipsit Vahia, Sara Weisenbach
J Prev Alz Dis 2026;4(13)
Show summaryHide summaryINTRODUCTION: Neuropsychiatric symptoms may represent early Alzheimer's disease (AD) manifestations, but their relationship with amyloid pathology in cognitively unimpaired individuals remains unclear.
METHODS: We analyzed 4,492 cognitively unimpaired adults (aged 65-85) from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Study. Participants completed amyloid-PET imaging and assessments of anxiety, depression, memory complaints, and AD concerns.
RESULTS: 1,231 participants (27.4%) were amyloid-positive. While anxiety and depression scores remained within normal ranges, amyloid-positive participants reported higher memory complaints (p = 0.008) and AD concerns (p < 0.001) before status disclosure. Regression analyses showed amyloid burden associated with anxiety (β = 0.04, standardized, p = 0.003) but not depression (p = 0.68). Mediation analyses revealed anxiety was directly associated with amyloid, while depression was mediated through subjective cognitive concerns.
DISCUSSION: Preclinical amyloid pathology directly associates with subclinical anxiety but only indirectly with depression through subjective stress, suggesting distinct neuropsychiatric pathways in early AD that could inform detection strategies.
CITATION:
Jonathan Vogelgsang ; Clara Beck ; Regan Patrick ; Ipsit Vahia ; Sara Weisenbach (2026): Preclinical amyloid pathology is associated with anxiety but not depression in cognitively normal older adults: Evidence for differential neuropsychiatric pathways. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100497
PREDICTING COGNITIVE DECLINE: COMPARATIVE ANALYSIS OF ANU-ADRI, CAIDE, COGDRISK, LIBRA, LIBRA2, UKBDRS AND LANCET BASED DEMENTIA RISK SCORES IN THE HUNT STUDY
Josephine Stubs, Geir Selbæk, Bjørn Heine Strand, Gill Livingston, Kaarin J. Anstey, Kay Deckers, Mika Kivimäki, Steinar Krokstad, Fiona E. Mathews, Ellen Melbye Langballe
J Prev Alz Dis 2026;4(13)
Show summaryHide summaryOBJECTIVE: To evaluate and compare the predictive value of eight dementia risk scores for late-life cognitive function and cognitive decline; ANU-ADRI, CAIDE, CogDrisk, LIBRA, LIBRA2, UKBDRS(-APOE), and a Lancet commission-based risk score.
METHODS: Using Norwegian Trøndelag Health Study (HUNT) data, we calculated risk scores from lifestyle and health data of 7221 dementia-free participants (mean age: 76.8 years, 54.1% female) collected in HUNT3 (2006–2008). Cognitive function was assessed using the Montreal Cognitive Assessment scale (MoCA) 11 years later in HUNT4 70+, and reassessed in 4716 participants 4 years thereafter. Associations between continuous risk scores or risk score tertiles, cognition and cognitive decline were examined using linear mixed-effects models. Logistic regression models were used to test associations between risk scores and a ≥ 3-point decline in MoCA scores.
RESULTS: All risk scores were significantly associated with cognitive function and cognitive decline. Associations with cognitive function ranged from UKBDRS β per 1SD=-1.61(95%CI:-1.72,-1.51) to CAIDE (β=-0.74;95%CI:-0.82,-0.67), and with yearly cognitive decline from Lancet (β=-0.23;95%CI:-0.27,-0.18) to CAIDE (β=-0.04;95%CI:-0.07,-0.02). High-low risk group differences in cognitive function were largest for CogDrisk (β=-3.04;95%CI:-3.27,-2.81), LIBRA (β=-3.04;95%CI:-3.27,-2.80) and lowest for CAIDE (β=-1.65;95%CI:-1.86,-1.44). High-risk groups showed the steepest decline for UKBDRS-APOE (β=-0.43;95%CI:-0.52,-0.34), Lancet (β=-0.39;95%CI:-0.48,-0.30), and LIBRA (β=-0.38;95%CI:-0.47,-0.28). All scores predicted ≥3-point decline modestly: AUCs were highest for UKBDRS (AUC=0.61;95%CI:0.60,0.63), UKBDRS-APOE (0.61;95%CI:0.60,0.63), CogDrisk (0.60;95%CI:0.58,0.62), and Lancet (0.60;95%CI:0.58,0.61), but none outperformed a model including age and education alone (0.61;95%CI:0.60,0.63).
CONCLUSION: Risk scores captured meaningful gradients in cognition and decline but offered limited discriminatory accuracy beyond demographics, supporting their use for prevention-oriented risk profiling rather than prediction.
CITATION:
Josephine Stubs ; Geir Selbæk ; Bjørn Heine Strand ; Gill Livingston ; Kaarin J. Anstey ; Kay Deckers ; Mika Kivimäki ; Steinar Krokstad ; Fiona E. Mathews ; Ellen Melbye Langballe (2026): Predicting cognitive decline: Comparative analysis of ANU-ADRI, CAIDE, CogDrisk, LIBRA, LIBRA2, UKBDRS and Lancet based dementia risk scores in the HUNT study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100524
ESTIMATED PREVALENCE OF UNDERDIAGNOSED DEMENTIA IN A MULTIETHNIC COMMUNITY-BASED STUDY
Lydia Trudel, Joseph Therriault, Arthur C. Macedo, Meredith N. Braskie, Karin L. Meeker, Arthur W. Toga, Serge Gauthier, Paolo Vitali, Sid E. O’Bryant, Pedro Rosa-Neto
J Prev Alz Dis 2026;4(13)
Show summaryHide summaryDementia frequently goes undetected in community settings, particularly among socially disadvantaged populations. Here, we estimated the prevalence of underdiagnosed dementia across diverse sociodemographic determinants of health in the Health and Aging Brain Study–Health Disparities (HABS-HD), a community-based cohort of adults recruited through community outreach in Fort Worth, Texas. We estimated age-specific probabilities of underdiagnosis using Poisson regression models with a log link, including age and sex as covariates. Robust (sandwich) variance estimators were used to obtain standard errors and 95% confidence intervals (CI). Group differences or trends for continuous measures were assessed using robust variance estimates. The prevalence of underdiagnosed dementia was higher among individuals without physician access (98.1% vs. 78.1%, p<.0001), non-English speakers (97.9% vs. 76.8%, p<.0001), and the uninsured (91.5% vs. 79.5%, p=.03). Black and Hispanic participants also showed higher prevalence (85.8% and 90.9%) compared to non-Hispanic White participants (64.9%; p=.02 and p=.002, respectively). Each additional year of education was associated with a 2.5% lower risk of underdiagnosis (p<.0001). No differences were observed by sex, marital status, income or social support. Our results highlight that several sociodemographic factors contribute to the likelihood of living with undiagnosed dementia.
CITATION:
Lydia Trudel ; Joseph Therriault ; Arthur C. Macedo ; Meredith N. Braskie ; Karin L. Meeker ; Arthur W. Toga ; Serge Gauthier ; Paolo Vitali ; Sid E. O’Bryant ; Pedro Rosa-Neto (2026): Estimated prevalence of underdiagnosed dementia in a multiethnic community-based study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100510
LONGITUDINAL SUBCORTICAL VOLUME CHANGES AND THEIR CORRELATIONS WITH MULTIPLE PET AND FLUID BIOMARKERS IN DOMINANTLY INHERITED ALZHEIMER’S DISEASE
IL Han Choo, Hoyoung Park, Brian A. Gordon, Randall J. Bateman, the Dominantly Inherited Alzheimer Network
J Prev Alz Dis 2026;4(13)
Show summaryHide summaryBACKGROUND: Alzheimer's disease postmortem studies demonstrate that amyloid plaques and neurofibrillary tangles are present in subcortical regions.
OBJECTIVE: To investigate longitudinal subcortical structural changes in autosomal dominant Alzheimer’s disease in relation to multiple PET and fluid biomarkers.
DESIGN: Dominantly Inherited Alzheimer’s Network (DIAN) Observational study.
SETTING: Multicenter study.
PARTICIPANTS: Participants were identified as mutation-carriers of pathologic variants in presenilin-1, presenilin-2, or amyloid precursor protein and as non-carriers from the same families as the mutation-carriers. They underwent baseline and 2 and more times longitudinal follow-up assessments of multiple biomarkers
MEASUREMENTS: Participants underwent structural MRI, ¹¹C-Pittsburgh Compound B PET, ¹⁸F-fluorodeoxyglucose PET, and CSF and plasma assessments. Rates of biomarker change as a function of estimated years to symptom onset were estimated using multivariate linear mixed-effects models, and longitudinal associations between subcortical atrophy and multiple biomarkers were evaluated.
RESULTS: A total of 601 participants completed one or more clinical evaluations, with up to eight annual visits. Mutation carriers showed significantly greater longitudinal atrophy in the left amygdala, bilateral thalamus, putamen, nucleus accumbens, and hippocampus compared with non-carriers (Bonferroni-corrected p < 0.05). The earliest divergence was observed 13.2 years before the expected symptom onset in the right nucleus accumbens, following amyloid-β (Aβ) accumulation in the right thalamus that began 23.8 years before onset. Among carriers, atrophy in the right thalamus, bilateral putamen, and bilateral nucleus accumbens was significantly associated with region-specific or cortical Aβ accumulation, as well as with CSF Aβ42, Aβ42/Aβ40 ratio, total tau, and phosphorylated tau (Bonferroni-corrected p < 0.05).
CONCLUSIONS: The present findings may provide a unique and well-characterized model for investigating the temporal ordering of Alzheimer’s disease biomarkers.
CITATION:
IL Han Choo ; Hoyoung Park ; Brian A. Gordon ; Randall J. Bateman ; the Dominantly Inherited Alzheimer Network (2026): Longitudinal subcortical volume changes and their correlations with multiple PET and fluid biomarkers in dominantly inherited Alzheimer’s disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100513
VASCULAR STIFFNESS PREDICTS PLASMA MARKERS OF NEURODEGENERATION AMONG OLDER AFRICAN AMERICANS
Miray Budak, Kevin S. Heffernan, Victoria Paruzel, Soodeh Moallemian, Bernadette A. Fausto, Nicholas Ashton, Henrik Zetterberg, Fanny M. Elahi, Mark A. Gluck
J Prev Alz Dis 2026;4(13)
Show summaryHide summaryBACKGROUND: Vascular health is a critical and potentially modifiable determinant of Alzheimer’s disease (AD) risk, yet its contribution to early neurodegenerative processes remains incompletely understood, particularly among African Americans, who experience a disproportionate AD burden. Estimated pulse wave velocity (ePWV), derived from age and blood pressure, provides a scalable index of vascular stiffness.
OBJECTIVES: To examine associations between vascular stiffness and plasma biomarkers of AD-related neurodegeneration in older African Americans.
DESIGN: Cross-sectional observational study.
SETTING: Community-based aging cohort study conducted at an academic research center.
PARTICIPANTS: A total of 145 cognitively unimpaired older African Americans (mean age=71.18±6.83 years; 110 women).
MEASUREMENTS: ePWV was calculated using validated equations based on age and blood pressure. Plasma biomarkers included phosphorylated tau217 (p-tau217; N=145), phosphorylated tau231 (p-tau231; N=126), glial fibrillary acidic protein (GFAP; N=126), neurofilament light chain (NfL; N=126), and amyloid-β42/40 ratio (Aβ42/40; N=126). Multivariable regression models adjusted for sex, education, pulse pressure, waist-to-hip ratio, global cognition, and hypertension status.
RESULTS: Higher ePWV was significantly associated with higher plasma concentrations of p-tau217 (β=0.34, p=.006), GFAP (β=0.55, p<.001), and NfL (β=0.52, p<.001), but not with p-tau231 and Aβ42/40 (p>.05).
CONCLUSIONS: Greater vascular stiffness, indexed by elevated ePWV, was associated with circulating markers of tau-related neurodegeneration, astrocytic activation, and axonal injury in cognitively unimpaired older African Americans. The absence of association with p-tau231 and Aβ42/40 suggests preferential effects on neurovascular damage and later tau-related processes, but no primary effect on biomarkers related to Aβ pathology, still highlighting vascular health as a modifiable target for AD prevention.
CITATION:
Miray Budak ; Kevin S. Heffernan ; Victoria Paruzel ; Soodeh Moallemian ; Bernadette A. Fausto ; Nicholas Ashton ; Henrik Zetterberg ; Fanny M. Elahi ; Mark A. Gluck (2026): Vascular stiffness predicts plasma markers of neurodegeneration among older African Americans. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100523
EXPERIMENTAL AND TRANSLATIONAL MODELS OF ALZHEIMER’S DISEASE: FROM NEURODEGENERATION TO NOVEL THERAPEUTIC INSIGHTS
Nadeemullah Khan, Somnath De, Suhasini Boddu, Navya Pravala
J Prev Alz Dis 2026;4(13)
Show summaryHide summaryNeurodegeneration on demand represents a groundbreaking approach to modeling Alzheimer’s disease (AD) in animals, enabling precise study of its molecular and behavioral hallmarks. Novel techniques, including optogenetic activation of amyloidogenic pathways, viral vector-mediated delivery of mutated human genes (e.g., APP, MAPT), and synthetic tau fibril analogs, induce AD-like pathology, including amyloid-beta plaques, tau hyperphosphorylation, neuroinflammation, and synaptic loss in diverse species, ranging from transgenic rodents to cephalopods and cannies. Emerging platforms, such as bioengineered neural organoids grafted into immunocompromised hosts, allowed for the controlled onset of AD-like features, providing unique insights into disease progression. Advanced tools like real-time neuroimaging and single-cell multi-omics help elucidate the temporal and cellular dynamics of neurodegeneration. These models provided unparalleled opportunities to dissect AD’s complex mechanisms, including protein misfolding, glial dysregulation, and cognitive decline. However, challenges remained, including interspecies molecular disparities, incomplete replication of human AD complexity, and ethical concerns surrounding cognitive impairment in sentient models. This review explores these innovative strategies, their contributions to understanding AD’s pathogenesis, and their potential to accelerate the development of transformative therapies, while also addressing limitations and future directions for refining these pioneering models.
CITATION:
Nadeemullah Khan ; Somnath De ; Suhasini Boddu ; Navya Pravala (2026): Experimental and translational models of Alzheimer’s disease: From neurodegeneration to novel therapeutic insights. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100498
EVALUATION OF PLASMA P-TAU217 BIOMARKERS IN DETECTING AMYLOID PATHOLOGY AND PREDICTING COGNITIVE OUTCOMES: OBSERVATIONS FROM JAPANESE ALZHEIMER’S DISEASE NEUROIMAGING INITIATIVE COHORT
Kensaku Kasuga, Masataka Kikuchi, Emiko Kikkawa-Saito, Tamao Tsukie, Takanobu Ishiguro, Akinori Miyashita, Takeshi Iwatsubo, the Japanese Alzheimer’s Disease Neuroimaging Initiative, Takeshi Ikeuchi
J Prev Alz Dis 2026;4(13)
Show summaryHide summaryBACKGROUND AND OBJECTIVES: Plasma phosphorylated tau 217 (p-tau217) has shown strong potential as a blood-based biomarker for detecting amyloid pathology in Alzheimer’s disease. This study evaluated the diagnostic and prognostic utility of plasma biomarkers, including p-tau217, in participants from the Japanese Alzheimer’s Disease Neuroimaging Initiative (J-ADNI) cohort.
METHODS: We analyzed paired plasma and CSF samples from 172 J-ADNI participants. CSF and plasma biomarkers were quantified using the LUMIPULSE platform, and the same plasma samples were analyzed using the Simoa platform. The diagnostic accuracy for detecting amyloid pathology and the prognostic value of plasma p-tau217 biomarkers were assessed. Associations between plasma p-tau217 and polygenic risk scores (PRS), as well as potential confounding factors, were examined.
RESULTS: Plasma p-tau217 levels measured using Lumipulse and Simoa assays were highly correlated (p < 0.001). All plasma p-tau217 assays showed high diagnostic accuracy for CSF Aβ42/Aβ40-defined amyloid pathology (AUC = 0.98). A single cutoff point based on the Youden index for p-tau217 and p-tau217/Aβ42 achieved >90% specificity and >90% sensitivity. The predefined FDA-approved two-cutoff model for p-tau217/Aβ42 was applicable to this cohort. PRS was significantly associated with plasma p-tau217 independently of APOE genotypes. Subjects with higher plasma p-tau217 levels showed a significantly increased risk of conversion to dementia and larger longitudinal cognitive declines. Plasma p-tau217 levels were significantly influenced by the body mass index, estimated glomerular filtration rate, and high-density lipoprotein cholesterol.
CONCLUSIONS: Plasma p-tau217 and p-tau217/Aβ42 are robust biomarkers for AD diagnosis and prognosis in the Japanese population.
CITATION:
Kensaku Kasuga ; Masataka Kikuchi ; Emiko Kikkawa-Saito ; Tamao Tsukie ; Takanobu Ishiguro ; Akinori Miyashita ; Takeshi Iwatsubo ; the Japanese Alzheimer’s Disease Neuroimaging Initiative ; Takeshi Ikeuchi (2026): Evaluation of plasma p-tau217 biomarkers in detecting amyloid pathology and predicting cognitive outcomes: Observations from Japanese Alzheimer’s disease neuroimaging initiative cohort. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100502
LONG-TERM FASTING INSULIN VARIABILITY AND COGNITIVE FUNCTION: INSIGHTS FROM THE CARDIA STUDY
Bo-Shui Huang, Zuo-Yu Huang, Yu-Hong Zeng, Kun-Hao Bai, Jing-Bin Guo, Jun Weng, Ze-Hua Li, Qing-Yun Hao
J Prev Alz Dis 2026;4(13)
Show summaryHide summaryBACKGROUND AND AIM: Fasting insulin variability has emerged as a potential marker of metabolic dysregulation, but its long-term implications for cognitive function remain unclear. This study aimed to clarify the role of long-term fasting insulin variability in predicting individual cognitive function risk.
METHODS: We analyzed data from CARDIA study participants who underwent cognitive testing and had at least three insulin measurements. Fasting insulin was measured at 7 timepoints over 30 years. Intra-individual insulin variability was assessed using standard deviation (SD), coefficient of variation (CV), and average real variability (ARV). Cognitive function was evaluated using the Digit Symbol Substitution Test (DSST), Stroop Test, and Rey Auditory Verbal Learning Test (RAVLT), with results standardized to z-scores and combined into a global cognitive z-score. Multivariable linear models were used to assess associations with cognitive performance.
RESULTS: In the 25-year analysis (n = 2712), higher long-term insulin variability was significantly associated with poorer global cognitive performance at year 25 after adjustment for demographic, lifestyle, and cardiometabolic covariates (CV-insulin: β=–0.719; 95% CI: –1.161 to –0.276; P < 0.01; SD-insulin: β=–0.019; 95% CI: –0.036 to –0.002; P < 0.05). These associations remained significant after additional adjustment for either concurrent insulin at year 25 or mean insulin levels over 25 years. Domain-specific analyses showed that higher insulin variability was associated with lower DSST z-scores (worse attention) and higher Stroop interference z-scores (worse executive function). Extended analyses over 30 years (n = 2069) yielded consistent results: higher CV-insulin was inversely associated with global cognitive z-scores (β=–0.837; 95% CI: –1.347 to –0.327), as well as with DSST (β=–0.347; 95% CI: –0.581 to –0.112) and RAVLT z-scores (β=–0.276; 95% CI: –0.522 to –0.031). These associations persisted after full adjustment for year 30 covariates and time-varying confounders across the follow-up, supporting the temporal robustness and clinical relevance of insulin variability as an independent predictor of cognitive function.
CONCLUSIONS: Greater long-term insulin variability is independently associated with poorer midlife cognitive performance. These findings highlight insulin variability as a potential marker of cognitive health risk.
CITATION:
Bo-Shui Huang ; Zuo-Yu Huang ; Yu-Hong Zeng ; Kun-Hao Bai ; Jing-Bin Guo ; Jun Weng ; Ze-Hua Li ; Qing-Yun Hao (2026): Long-term fasting insulin variability and cognitive function: Insights from the CARDIA study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100487
ASSOCIATION OF CARDIAC BIOMARKERS WITH LONGITUDINAL COGNITIVE CHANGES IN THE GENERAL POPULATION
Fang-Fei Wei, Dubo Chen, Chaoxin Xu, Zhongping Yu, Zihao Chen, Chang Chen, Xin He, JingJing Zhao, Wenqing Li, Cuiping Zhao, Jiangui He, Yugang Dong, Jan A. Staessen, Chen Liu
J Prev Alz Dis 2026;4(13)
Show summaryHide summaryBACKGROUND: Little is known about the association of high-sensitivity cardiac troponin T (hs-cTnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) with changes in cognitive performance over time.
OBJECTIVES: To investigate the association of cardiac biomarkers with cognitive changes over time.
PARTICIPANTS: The study population consisted of 2540 stroke-free participants (56.1 % women; 21.2 % Black; mean age, 74.5 years) enrolled in the Atherosclerosis Risk in Communities study.
MEASUREMENTS: Associations of the changes in the Mini Mental State Examination (MMSE) scores with the log-transformed cardiac biomarkers were modelled using multivariable linear and restricted cubic spline regression.
RESULTS: Over 6.6 years (median), the MMSE score decreased by 0.57 (95 % CI, 0.46–0.67) and the frequency of an MMSE score <24 increased from 5.339 % to 9.69 % (P < 0.001). In multivariable-adjusted models, the cardiac biomarkers measured at baseline were linearly related to absolute MMSE changes with association sizes amounting to 0.47 (0.27–0.66) and 0.58 (0.19–0.97) for NT-proBNP and hs-cTnT, respectively. Classification-by-cardiac biomarker interactions were significant for race, age group and diabetes in relation to NT-proBNP (P ≤ 0.031) and for race, age group and hypertension in relation to hs-cTnT (P ≤ 0.041). For both biomarkers, associations were stronger in Blacks than Whites and in older than younger individuals; for NT-proBNP in diabetic than non-diabetic participants; and for hs-cTnT in normotensive than hypertensive individuals.
CONCLUSION: NT-proBNP and hs-cTnT were associated with MMSE changes. Although association studies cannot prove causality, the clinical implication might be that targeting the heart within the framework of a multifactorial approach might be strategy in reducing cognitive decline.
CITATION:
Fang-Fei Wei ; Dubo Chen ; Chaoxin Xu ; Zhongping Yu ; Zihao Chen ; Chang Chen ; Xin He ; JingJing Zhao ; Wenqing Li ; Cuiping Zhao ; Jiangui He ; Yugang Dong ; Jan A. Staessen ; Chen Liu (2026): Association of cardiac biomarkers with longitudinal cognitive changes in the general population. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100494
TRAJECTORIES OF SOCIAL PARTICIPATION AND RISK OF COGNITIVE IMPAIRMENT IN CHINESE OLDER ADULTS: A SIX-YEAR LONGITUDINAL STUDY
Kangle Wang, Ruihan Wan, Jiale Peng, Huanghao Zhou, Kaifeng Xu, Hao Liu, Lidian Chen, Zhizhen Liu
J Prev Alz Dis 2026;4(13)
Show summaryHide summaryBACKGROUND: The growing burden of cognitive decline represents a significant public health concern in aging populations, particularly in China. Social participation is a modifiable factor that may protect against cognitive decline, yet its long-term dynamic association with cognitive impairment remains insufficiently characterized.
OBJECTIVES: This study aimed to delineate long-term trajectories of social participation and determine their association with cognitive impairment in Chinese older adults.
DESING: Longitudinal cohort study.
SETTING: The study utilized data collected in 2013, 2015, and 2018 from the China Health and Retirement Longitudinal Study.
PARTICIPANTS: We included 3074 Chinese adults aged ≥60 years who were free of cognitive impairment in 2013, had complete social participation data in 2013/2015/2018, and completed cognitive assessments in 2018
INTERVENTION(S): Not applicable.
MEASUREMENTS: Social participation was derived from CHARLS self-reported activity items and frequency and summed into a composite score (range 0–33). Cognitive performance was assessed using episodic memory (immediate and delayed 10-word recall) and mental status (orientation, serial subtraction, and figure drawing), yielding a global score (range 0–31); cognitive impairment was defined as a score <11. Group-based trajectory modeling identified five social participation trajectories. Multivariable logistic regression estimated odds ratios (ORs) for cognitive impairment adjusting for sociodemographic, health, and behavioral covariates.
RESULTS: Five distinct social participation trajectories were identified. In the fully adjusted model, relative to the “stable low” group, those in the “low baseline–increasing” (OR = 0.66, 95% CI: 0.47–0.92), “stable intermediate” (OR = 0.75, 95% CI: 0.58–0.97), and “stable high” (OR = 0.41, 95% CI: 0.22–0.76) groups had markedly reduced chances of cognitive impairment, while no significant link was found for the “moderate decline” group (OR = 0.90, 95% CI: 0.71–1.17).
CONCLUSIONS: Maintaining or increasing one’s social activities was linked to a notably lower likelihood of cognitive decline. These results highlight the importance of social involvement patterns as a modifiable factor for fostering cognitive strength. Interventions to maintain or enhance participation are therefore a viable strategy for the primary prevention of cognitive decline in older adults.
CITATION:
Kangle Wang ; Ruihan Wan ; Jiale Peng ; Huanghao Zhou ; Kaifeng Xu ; Hao Liu ; Lidian Chen ; Zhizhen Liu (2026): Trajectories of social participation and risk of cognitive impairment in Chinese older adults: A six-year longitudinal study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100499
ASSOCIATION BETWEEN MRI INDICATORS OF THE GLYMPHATIC SYSTEM AND COGNITION IN HIGH-RISK POPULATIONS FOR ALZHEIMER\'S DISEASE
Li Jiang, Ling Zhang, Shu-Xian Wu, Qin-Qin Zhu, Wei Wang, Jia-Wei Gao, Yi Zhu, Shui Tian, Ming Qi
J Prev Alz Dis 2026;4(13)
Show summaryHide summaryBACKGROUND: Using the Diffusion Tensor Image Analysis Along the Perivascular Space (ALPS) method and perivascular space (PVS) burden to study glymphatic function in high-risk Alzheimer's disease (AD) populations, this research investigates the correlation between ALPS index and PVS volume with cognitive function respectively.
METHODS: This study enrolled 126 participants, including 21 cognitively unimpaired (CU) individuals, 68 with subjective cognitive decline (SCD), and 37 with mild cognitive impairment (MCI). All participants underwent MRI and cognitive assessments. MRI measures, including the PVS burden and the ALPS index, were compared across SCD, MCI, and CU groups. Additionally, correlations among the ALPS index, PVS burden, and cognitive scales were analyzed.
RESULTS: The PVS in the basal ganglia volume fraction (PVSVF-BG) in patients with MCI was significantly larger than the fraction in CUs (p < 0.05) and a higher PVSVF-BG was associated with poorer performance on the Trail Making Test A (TMTA) (r = 0.29, p < 0.05). Compared with the CU and SCD groups, patients with MCI exhibited a significantly lower ALPS index in both the left (p < 0.05) and right hemispheres (p < 0.001). Lower whole brain ALPS index in patients with MCI was correlated with worse performance in the Auditory Verbal Learning Test(AVLT) (N4, r = 0.33, p < 0.05; N7, r = 0.56, p < 0.001).
CONCLUSIONS: An increased PVS burden and a decreased ALPS index can be observed in the preclinical stage of AD, which may suggest impaired glymphatic system function. These impairments were further correlated with worse cognitive performance in terms of attention in SCD and memory in MCI.
CITATION:
Li Jiang ; Ling Zhang ; Shu-Xian Wu ; Qin-Qin Zhu ; Wei Wang ; Jia-Wei Gao ; Yi Zhu ; Shui Tian ; Ming Qi (2026): Association between MRI indicators of the glymphatic system and cognition in high-risk populations for Alzheimer's disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100504
CUMULATIVE BLOOD PRESSURE AND RISK OF DEMENTIA AND COGNITIVE DECLINE: A SYSTEMATIC REVIEW AND META-ANALYSIS
Ruirui Wang, Yijie Gao, Nicole Ee, Fope Akinyede, Xiaoyue Xu, Linan Chen, Shangzhi Xiong, Xiaoying Chen, Craig S. Anderson, Katie Harris, Ruth Peters
J Prev Alz Dis 2026;4(13)
Show summaryHide summaryBACKGROUND AND OBJECTIVE: Cumulative blood pressure (cBP), reflecting long-term BP exposure, is increasingly used to examine risk associations with dementia and cognitive function, but findings to date are inconsistent. This systematic review aimed to synthesize existing evidence to clarify risk associations in adults.
METHODS: We searched for articles in Medline, Embase (Ovid), Web of Science, Cochrane Library, and China National Knowledge Infrastructure from inception to January 2025 in any language. Longitudinal, observational studies involving participants aged over 18 years at the time of initial BP assessment were eligible for inclusion. cBP was defined as the area under the curve of BP values over time or an equivalent method, expressed in units of mmHg × time. Study outcomes were dementia, cognitive function assessments, and neuroimaging markers. This review is registered in PROSPERO (CRD42025640637).
RESULTS: From 6334 records identified, 10 independent prospective cohort studies from 9 publications were included in the review, of which four cohort studies were eligible for meta-analysis. Meta-analysis showed that higher cumulative systolic BP (cSBP) was associated with an increased risk of incident dementia (odds ratio [OR] 1.21, 95% CI 1.00–1.45; I² = 92.4%, P for heterogeneity<0.001), while cumulative diastolic BP (cDBP) was not associated with dementia risk (OR 0.97, 95% CI 0.72–1.32; I²=97.3%, P for heterogeneity<0.001). Among eight studies on cognitive function, five reported that higher cSBP was associated with poorer cognitive performance, while three reported non-significant results. In contrast, findings for higher cDBP were mixed, with two studies reporting adverse associations, two reporting protective associations, and three reporting null associations. Two studies linked higher cSBP and cDBP to greater white matter hyperintensity burden. Sensitivity and subgroup analyses suggested that the positive association between cSBP and dementia-related outcomes were more pronounced among middle-aged adults, whereas inverse or null associations for higher cDBP was observed in some cohorts among individuals aged ≥60 years.
CONCLUSION: Higher cSBP is associated with increased risk of incident dementia and cognitive decline, whereas associations for cDBP are mixed. Given the limited evidence, future studies should incorporate age-stratified analyses and consider including cumulative pulse pressure and mean arterial pressure to further clarify the relationship between cBP and cognition.
CITATION:
Ruirui Wang ; Yijie Gao ; Nicole Ee ; Fope Akinyede ; Xiaoyue Xu ; Linan Chen ; Shangzhi Xiong ; Xiaoying Chen ; Craig S. Anderson ; Katie Harris ; Ruth Peters (2025): Cumulative blood pressure and risk of dementia and cognitive decline: a systematic review and meta-analysis. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100500
SPATIAL AMYLOID–INFORMED MULTIMODAL BRAIN AGE AS AN EARLY MARKER OF ALZHEIMER’S-RELATED VULNERABILITY AND RISK STRATIFICATION
Liang Cui, Qing-Min Wang, Zhen Zhang, Min Wang, You-Yi Tu, Jie-Hui Jiang, Yi-Hui Guan, Yue-Hua Li, Fang Xie, Qi-Hao Guo
J Prev Alz Dis 2026;4(13)
Show summaryHide summaryBACKGROUND: Brain age gap (BAG)—the difference between predicted and chronological age—captures neurobiological aging, but MRI-only models insufficiently reflect Alzheimer’s disease (AD) pathology. Whether incorporating regional amyloid-β (Aβ) positron emission tomography (PET) improves sensitivity to early AD processes remains unknown.
OBJECTIVES: To develop an amyloid-informed multimodal BAG model and examine its associations with cognition, plasma biomarkers, and functional connectivity across the AD continuum.
DESIGN: Cross-sectional analysis using integrated machine-learning models.
SETTING: Chinese Preclinical Alzheimer’s Disease Study (CPAS), a cohort recruited from community settings and memory clinics.
PARTICIPANTS: Nine hundred ninety community-dwelling adults spanning normal cognition, subjective cognitive decline (SCD), mild cognitive impairment (MCI), and dementia.
MEASUREMENTS: Regional Aβ-PET and structural MRI informed BAG estimation. Cognitive tests, plasma biomarkers (p-tau217, p-tau181, neurofilament light [NfL], glial fibrillary acidic protein [GFAP], Aβ42/40), and hippocampus–default mode network (DMN) connectivity from resting-state fMRI were assessed.
RESULTS: Higher BAG was associated with greater odds of SCD, MCI, or dementia across the cohort, with stronger effects in Aβ-positive individuals. BAG explained more cognitive variance than global Aβ burden and was linked to multidomain cognitive deficits. Elevated BAG corresponded to higher p-tau217, p-tau181, NfL, and GFAP and lower Aβ42/40, indicating early biomarker alterations. BAG was also associated with reduced hippocampus–DMN connectivity.
CONCLUSIONS: An amyloid-informed multimodal BAG model captures convergent AD-related pathology, biomarker alterations, and cognitive vulnerability beyond amyloid burden alone, supporting its value for individualized risk s2tratification and prevention-focused assessment.
CITATION:
Liang Cui ; Qing-Min Wang ; Zhen Zhang ; Min Wang ; You-Yi Tu ; Jie-Hui Jiang ; Yi-Hui Guan ; Yue-Hua Li ; Fang Xie ; Qi-Hao Guo (2025): Spatial amyloid–informed multimodal brain age as an early marker of Alzheimer’s-related vulnerability and risk stratification. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100501
THE ROLE OF LIPIDS IN MEDIATING THE EFFECTS OF IMMUNE CELLS ON ALZHEIMER’S DISEASE RISK: A NETWORK MENDELIAN RANDOMIZATION STUDY
Xinyu Yang, Jingjing Jiang, Wenjing Li, Rui Pan, Yanjie Li
J Prev Alz Dis 2026;4(13)
Show summaryHide summaryBACKGROUND: Observational studies have shown associations between immune cells, lipids, and Alzheimer’s disease (AD), but their specific causal relationships and the mediating role of lipids remain unclear.
METHODS: Within a network Mendelian randomization (MR) framework, we first applied two-sample univariable MR to assess the causal effects of immune cells and lipids on AD. Then, multivariable MR was used in mediation analyses to determine whether lipids mediate the effects of immune cells on AD. Finally, reverse MR analyses were performed to minimize potential bias from reverse causation. The inverse variance weighted method was used as the primary estimator.
RESULTS: The analysis revealed that elevated levels of CD33 on CD33dim HLA DR+ CD11b+ and CD33 on CD33dim HLA DR+ CD11b- were associated with an increased risk of AD. Mediation analysis further indicated that polyunsaturated fatty acids are protective lipid metabolites for AD and partially mediate the effects of the aforementioned immune cells on AD, with mediation proportions of 3.70 % and 3.67 %, respectively.
CONCLUSION: This study provides new insights into how immune cells may influence AD pathogenesis through lipid metabolism. It also offers a theoretical basis and potential direction for developing immune–lipid-based strategies for AD prevention and intervention.
CITATION:
Xinyu Yang ; Jingjing Jiang ; Wenjing Li ; Rui Pan ; Yanjie Li (2026): The role of lipids in mediating the effects of immune cells on Alzheimer’s disease risk: A network Mendelian randomization study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100509
DIAGNOSTIC AND PROGNOSTIC UTILITY OF SERUM Β-SYNUCLEIN IN ALZHEIMER’S DISEASE: A LONGITUDINAL COHORT STUDY
Siqi Xie, Yumei Liang, Ting Yang, Dandan Sheng, Lan Ding, Jianping Jia, Alzheimer’s Disease Neuroimaging Initiative
J Prev Alz Dis 2026;4(13)
Show summaryHide summaryBACKGROUND: Serum β-synuclein is an emerging blood-based biomarker for synaptic integrity in Alzheimer’s disease (AD). However, its comparative performance against the established CSF marker neurogranin and its prognostic utility for longitudinal disease progression remain to be fully characterized.
METHOD: We analyzed 475 participants from the Alzheimer’s Disease Neuroimaging Initiative. We compared serum β-synuclein and CSF neurogranin using receiver operating characteristic analysis and Cox proportional hazards models. We also assessed the cross-sectional associations of both biomarkers with cognitive and neuroimaging markers using linear regression. Linear mixed-effects models were applied to determine if baseline serum β-synuclein levels and longitudinal rate of change predicted disease progression. Finally, the trajectory of serum β-synuclein was modeled across the AD continuum.
RESULTS: Serum β-synuclein distinguished clinical AD dementia from controls with high accuracy (AUC = 0.84). Cross-sectionally, it exhibited robust associations with cognitive deficits and neuroimaging markers, comparable to or exceeding those of CSF neurogranin. Higher baseline serum β-synuclein, but not CSF neurogranin, significantly predicted the risk of conversion to dementia (hazard ratio = 1.83). Longitudinally, both elevated baseline levels and faster rates of increase in serum β-synuclein predicted accelerated cognitive decline and neurodegeneration, independent of baseline amyloid or tau pathology. Trajectory analysis revealed that serum β-synuclein levels accelerated significantly over time specifically in individuals with concurrent amyloid and tau pathology.
DISCUSSION: Serum β-synuclein serves as a robust prognostic biomarker for AD, demonstrating diagnostic accuracy for clinical dementia and superior predictive utility for disease conversion compared to CSF neurogranin. Its ability to track synaptic degeneration independent of core proteinopathies highlights its potential as a dynamic outcome measure for monitoring disease progression in clinical trials.
CITATION:
Siqi Xie ; Yumei Liang ; Ting Yang ; Dandan Sheng ; Lan Ding ; Jianping Jia ; Alzheimer’s Disease Neuroimaging Initiative (2026): Diagnostic and prognostic utility of serum β-synuclein in Alzheimer’s disease: a longitudinal cohort study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100514
HEALTHY LIFESTYLE AND ALZHEIMER’S DISEASE IN INDIVIDUALS WITH HYPERLIPIDEMIA: A PROSPECTIVE COHORT STUDY
Danyang Sun, Linling Yu, Chenqi Liao, Yuzhong Xu, Wei Liu, Xiong Wang
J Prev Alz Dis 2026;4(13)
Show summaryHide summaryBACKGROUND: Whether healthy lifestyle behaviors are associated with Alzheimer’s disease (AD) risk among individuals with hyperlipidemia remains unclear.
METHODS: We analyzed 241,642 dementia-free participants from the UK Biobank. A weighted lifestyle score (0–7) was derived from seven factors and categorized into five tiers. Hyperlipidemia was defined as lipid-lowering medication use or LDL-cholesterol ≥ 4.0 mmol/L. Cox regression estimated hazard ratios (HRs) and 95% confidence intervals (CIs).
RESULTS: Over a median follow-up of 14.5 years, 1728 AD cases occurred, including 977 cases among 104,082 individuals with hyperlipidemia. Compared with the intermediate tier, unhealthy lifestyle was associated with elevated AD risk (HR: 1.17; 95% CI: 1.02–1.35), while healtshy and very healthy tiers were associated with progressively lower risk (HR=0.85 and 0.74, respectively). These associations were evident among individuals with hyperlipidemia, but not statistically significant among those without hyperlipidemia.
CONCLUSIONS: Healthy lifestyle patterns were associated with lower AD risk among individuals with hyperlipidemia, with greater risk reductions observed for healthier lifestyle tiers.
CITATION:
Danyang Sun ; Linling Yu ; Chenqi Liao ; Yuzhong Xu ; Wei Liu ; Xiong Wang (2026): Healthy lifestyle and Alzheimer’s disease in individuals with hyperlipidemia: A prospective cohort study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100520
ASSOCIATIONS BETWEEN PLANT-BASED DIETARY PATTERNS AND RISKS OF COGNITIVE IMPAIRMENT AND DEMENTIA: A SYSTEMATIC REVIEW AND DOSE-RESPONSE META-ANALYSIS
Jui-Hsiu Tsai, Tou-Yuan Tsai, Hua Li, Cheng-Yu Wang, Yu-Kang Tu, Huei-Kai Huang, Hsin Ma, Yu-Lin Hsieh, Chuan-Sheng Hung, Shih-Chieh Shao, Eric H Chou, Chin-Lon Lin, Ming-Nan Lin
J Prev Alz Dis 2026;4(13)
Show summaryHide summaryBACKGROUND: Evidence remains inconclusive regarding plant-based diets preventing cognitive impairment and dementia, as certain plant-based foods, including refined carbohydrates, sweets, sugar-sweetened beverages, and trans fats, may increase dementia risk.
OBJECTIVES: To quantitatively synthesize prospective cohort studies on associations between adherence to plant-based diets and the risks of cognitive impairment and dementia.
DESIGN: Systematic review and meta-analysis. This study adhered to the PRISMA guidelines and was registered on PROSPERO (No: CRD42024501334).
SETTING: Studies published until December 2025 were systematically identified using AgeLine, CINAHL, Embase, MEDLINE, PsycINFO, Scopus, and Web of Science.
PARTICIPANTS: The study population comprised adults aged ≥ 20 years with no cognitive impairment at baseline.
INTERVENTION: Studies were enrolled if the participants (1) assessed dietary patterns characterized by higher plant-based food consumption and decreased or ceased consumption of animal-based foods or (2) used established dietary indices, including overall plant-based diet index (PDI), healthful plant-based diet index (hPDI), and unhealthful plant-based diet index (uPDI).
MEASUREMENTS: Data extraction, risk of bias assessment, and the GRADE approach for assessing certainty of evidence were performed independently by three reviewers. A random-effects model with restricted maximum likelihood was used to calculate pooled risk ratios and 95% confidence intervals. The dose-response meta-analysis used two-stage dose-response regression.
RESULTS: The meta-analysis based on seven studies (number of participants: 221,380; number of cases of incident cognitive impairment and dementia: 5668) indicated that participants with greater adherence to plant-based diets had significantly lower risks of cognitive impairment and dementia (pooled risk ratio, 0.74; 95% confidence interval, 0.56–0.97; I2 = 92.3%) than those with lower adherence. Dose-response relationships modeled using restricted cubic splines indicated that overall PDI and hPDI were negatively associated with risks of cognitive impairment and dementia, whereas uPDI was significantly positively associated with these risks.
CONCLUSIONS: This meta-analysis suggests that adherence to plant-based diets, particularly those rich in healthful plant foods, may be associated with a lower risk of cognitive impairment and dementia. However, given the residual heterogeneity and the inherent limitations of observational study designs, large randomised controlled trials are warranted to establish causality.
CITATION:
Jui-Hsiu Tsai ; Tou-Yuan Tsai ; Hua Li ; Cheng-Yu Wang ; Yu-Kang Tu ; Huei-Kai Huang ; Hsin Ma ; Yu-Lin Hsieh ; Chuan-Sheng Hung ; Shih-Chieh Shao ; Eric H Chou ; Chin-Lon Lin ; Ming-Nan Lin (2026): Associations between plant-based dietary patterns and risks of cognitive impairment and dementia: A systematic review and dose-response meta-analysis. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100521
LIFESTYLE FACTORS AND DNA METHYLATION-BASED AGING CLOCKS: CROSS-SECTIONAL AND LONGITUDINAL ASSOCIATIONS IN THE SINGAPORE DIET AND HEALTHY AGING COHORT
Jiatong Shan, Jian Hua Tay, Kaisy Xinhong Ye, Jiuyu Guo, Luwen Cao, Yan Zeng, Tih-Shih Lee, Kua Ee Heok, Brian K. Kennedy, Andrea B. Maier, Lei Feng
J Prev Alz Dis 2026;4(13)
Show summaryHide summaryBACKGROUND: Lifestyle factors play a critical role in healthy aging, yet their relationships with aging biomarkers remain insufficiently characterized, particularly in Asian populations. This study aimed to examine the cross-sectional and longitudinal associations between 15 modifiable lifestyle factors and two DNA methylation (DNAm) clocks (GrimAge acceleration [AgeDev] and DunedinPACE) in a cohort of older Asian adults.
METHODS: We conducted a cross-sectional analysis of 631 participants (median age 70.0 years; 72.6% female) and a longitudinal analysis of 114 participants (mean follow-up 3.96 years) from the Singapore Diet and Healthy Aging (DaHA) cohort. Lifestyle exposures were assessed using validated self-administered questionnaires. Peripheral blood DNAm profiles were generated using the Illumina MethylationEPIC array. Multivariable linear regression models were applied to evaluate associations between lifestyle factors and DNAm clocks, adjusting for sociodemographic covariates, health status, and immune cell-type proportions.
RESULTS: In cross-sectional analyses, smoking history showed robust positive associations with accelerated epigenetic aging (GrimAge AgeDev: β = 1.45, 95% CI 1.13–1.77, p < 0.0001; DunedinPACE: β = 0.63, 95% CI 0.22–1.05, p = 0.003). Conversely, weekly physical activity was associated with slower aging (GrimAge AgeDev: β = –0.22, 95% CI –0.40 to –0.04, p = 0.02), as was daily engagement in cognitively stimulating activities (GrimAge AgeDev: β = –0.16, 95% CI –0.31 to –0.01, p = 0.04). Weekly feelings of stress were initially associated with greater GrimAge AgeDev, but this relationship was attenuated after full adjustment. No significant longitudinal associations were detected, which may reflect limited statistical power and the stability of long-standing lifestyle behaviors over the follow-up period.
CONCLUSIONS: These findings highlight significant cross-sectional associations between key modifiable lifestyle factors, particularly smoking, physical activity, and cognitive engagement, and epigenetic aging in an older Asian cohort. The results suggest that interventions targeting these behaviors may modulate the pace of biological aging. The absence of significant longitudinal associations underscores the need for larger prospective studies with longer follow-up and continued validation of epigenetic clocks in diverse populations to confirm these relationships over time.
CITATION:
Jiatong Shan ; Jian Hua Tay ; Kaisy Xinhong Ye ; Jiuyu Guo ; Luwen Cao ; Yan Zeng ; Tih-Shih Lee ; Kua Ee Heok ; Brian K. Kennedy ; Andrea B. Maier ; Lei Feng (2026): Lifestyle factors and DNA methylation-based aging clocks: cross-sectional and longitudinal associations in the Singapore diet and healthy aging cohort. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100522
LETTER TO THE EDITOR : RE-THINKING FUNDING SUCCESS IN ALZHEIMER’S DISEASE RESEARCH: WHY GOOD SCIENCE IS NOT ENOUGH
Peter Fusdahl, Miguel G. Borda, Dag Aarsland
J Prev Alz Dis 2026;4(13)
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CITATION:
Peter Fusdahl ; Miguel G. Borda ; Dag Aarsland (2026): Long-term fasting insulin variability and cognitive function: Insights from tRe-thinking funding success in Alzheimer’s disease research: Why good science is not enoughhe CARDIA study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100496
LETTER TO THE EDITOR: REFLECTIONS ON THE ROLE OF AI IN ALZHEIMER’S DISEASE RESEARCH: ADDRESSING INCLUSIVITY, CAUSALITY, AND ETHICAL CONSIDERATIONS
Mingyue Chen, Yan Han
J Prev Alz Dis 2026;4(13)
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CITATION:
Mingyue Chen ; Yan Han (2026): Letter to the Editor: Reflections on the role of AI in Alzheimer’s disease research: Addressing inclusivity, causality, and ethical considerations. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100488
LETTER TO THE EDITOR : THE FUTURE OF HRT/MHT AND ALZHEIMER’S DISEASE RISK, ONSET AND PROGRESSION
Edwin D. Lephart, Dawson W. Hedges, Frederick Naftolin, Zoe D. Draelos
J Prev Alz Dis 2026;4(13)
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CITATION:
Edwin D. Lephart ; Dawson W. Hedges ; Frederick Naftolin ; Zoe D. Draelos (2026): Letter to the Editor: The future of HRT/MHT and Alzheimer’s disease risk, onset and progression. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100508
LETTER TO THE EDITOR : LONG-TERM EXTENSION DATA DO NOT ROBUSTLY SUPPORT CLINICAL DISEASE COURSE MODIFICATION WITH DONANEMAB
Jemma Hazan, Kathy Y. Liu, Robert Howard
J Prev Alz Dis 2026;4(13)
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CITATION:
Jemma Hazan ; Kathy Y. Liu ; Robert Howard (2026): Letter to the Editor: Long-term extension data do not robustly support clinical disease course modification with donanemab. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100511
LETTER TO THE EDITOR: LONG-TERM TREATMENT OF EARLY ALZHEIMER’S DISEASE WITH DONANEMAB
Vincenzo Solfrizzi, Bruno P. Imbimbo
J Prev Alz Dis 2026;4(13)
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CITATION:
Vincenzo Solfrizzi ; Bruno P. Imbimbo (2026): Letter to the Editor: Long-term treatment of early Alzheimer’s disease with donanemab. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100512
CORRIGENDUM TO “LECANEMAB FOR TREATMENT OF INDIVIDUALS WITH EARLY ALZHEIMER’S DISEASE (AD) WHO ARE APOLIPOPROTEIN E Ε4 (APOE Ε4) NON-CARRIERS OR HETEROZYGOTES” [THE JOURNAL OF PREVENTION OF ALZHEIMER\'S DISEASE (2026) 100507]
Richard Perry, Christopher Kipps, Maria Eugenia Soto Martín, Marco Bozzali, Giancarlo Logroscino, Sarah Trafford, Shobha Dhadda, Michio Kanekiyo, Amanda Goodwin, Mark Hodgkinson, Steven Hersch, Michael Irizarry, Lynn Kramer, Lutz Froelich
J Prev Alz Dis 2026;4(13)
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CITATION:
Richard Perry ; Christopher Kipps ; Maria Eugenia Soto Martín ; Marco Bozzali ; Giancarlo Logroscino ; Sarah Trafford ; Shobha Dhadda ; Michio Kanekiyo ; Amanda Goodwin ; Mark Hodgkinson ; Steven Hersch ; Michael Irizarry ; Lynn Kramer ; Lutz Froelich (2026): Corrigendum to “Lecanemab for treatment of individuals with early Alzheimer’s Disease (AD) who are apolipoprotein E ε4 (ApoE ε4) non-carriers or heterozygotes” [The Journal of Prevention of Alzheimer's Disease (2026) 100507]. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100527