06/2026 journal articles
EDITORIAL : LIPID-LOWERING REGIMENS IN ALZHEIMER’S DISEASE DEMENTIA: SMALL EFFECTS WITH POTENTIAL LONG-TERM BENEFIT
Tobias Hartmann
J Prev Alz Dis 2026;6(13)
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CITATION:
Tobias Hartmann (2025): Editorial: Lipid-lowering regimens in Alzheimer’s disease dementia: small effects with potential long-term benefit. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100576
HYPOLIPIDEMICS REDUCE THE RATE OF ALZHEIMER\'S DISEASE DEVELOPMENT AND DEMENTIA PROGRESSION: A COHORT STUDY LINKED WITH GENETIC AND NEUROPATHOLOGICAL ANALYSES
Zohi Sternberg, Rebecca E. Podolsky, Jihnhee Yu, Shuangcheng Hua, Stanley Halvorsen, Bernhard J. Schaller
J Prev Alz Dis 2026;6(13)
Show summaryHide summaryBACKGROUND: High cholesterol contributes to the development and progression of dementia due to both Alzheimer's disease (A.D.) and vascular pathology. However, the effects of lipid-lowering regimen (LLR) on cognitive dysfunction and brain neuropathology are unknown.
OBJECTIVE: To investigate the effect of LLR on the conversion from normal to mild cognitive impairment (MCI), indicated by CDR-SOB of >0–2.5 (MCI), and the progression to dementia, indicated by CDR-SOB =>3 (10-year follow-up) and LLR effect on the rate of survival (15-year follow-up). Participants were stratified by age (≤70 years and >70 years), gender, and the presence of at least one copy of the APOE4 allele. We also analyzed the effect of LLR on brain neuropathology in participants, indicated by Braak staging, hippocampal atrophy, and CSF levels of total Tau. The differential effect of LLR, with or without cerebrovascular disease, lacunar infarct, or cystic infarction in the cognitive network, was analyzed.
METHODS: We have analyzed the National Alzheimer's Coordinating Center (NACC) Uniform Data Set (UDS).
RESULTS: In participants with CDR-SOB of >0–2.5, the use of hypolipidemic agents was associated with a reduced yearly increase in the CDR-SOB scores by 0.0088 (0.0038, 0.0138) unit (P < 0.001). This effect was more pronounced in participants with CDR-SOB =>3 showing a reduced yearly increase in the CDR-SOB scores by 0.1733 (0.1441, 0.2025) unit (P < 0.001) in LLR-users compared to non-users, and an increased rate of survival [HR: 0.822 (0.746, 0.906). P = 0.001]. The pattern persisted when participants were stratified based on age, gender, and the presence of APOE4. LLR had no significant effect on Braak staging scores, hippocampal atrophy, and total CSF Tau level, and was independent of the presence or absence of cerebrovascular disease, lacunar infarct, and cystic infarction in cognitive network.
CONCLUSION: Our results have implications for delaying cognitive dysfunction and halting the progression of dementia, regardless of the etiology being related to AD or vascular pathology.
CITATION:
Zohi Sternberg ; Rebecca E. Podolsky ; Jihnhee Yu ; Shuangcheng Hua ; Stanley Halvorsen ; Bernhard J. Schaller (2025): Hypolipidemics reduce the rate of Alzheimer's disease development and dementia progression: A cohort study linked with genetic and neuropathological analyses. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100555
EDITORIAL : BEYOND AMYLOID POSITIVITY: BIOLOGICAL HETEROGENEITY IN THE REAL-WORLD USE OF LECANEMAB
Michael S. Rafii
J Prev Alz Dis 2026;6(13)
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CITATION:
Michael S. Rafii (2025): Editorial: Beyond amyloid positivity: Biological heterogeneity in the real-world use of lecanemab. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100584
ATNIVS BIOMARKER HETEROGENEITY IN REAL-WORLD PATIENTS RECEIVING LECANEMAB
Masanori Kurihara, Ryoko Ihara, Gen Yoshii, Ryosuke Shimasaki, Keiko Hatano, Taro Bannai, Fumio Suzuki, Kenji Ishibashi, Ko Furuta, Katsuya Satoh, Aya Midori Tokumaru, Kenji Ishii, Atsushi Iwata
J Prev Alz Dis 2026;6(13)
Show summaryHide summaryBACKGROUND: While amyloid-β (Aβ) biomarker positivity is sufficient before initiating anti-Aβ antibody therapy, recent revised criteria also highlight the importance of other biomarkers (ATNIVS) to understand heterogeneity in AD.
DESIGN, SETTING, AND PARTICIPANTS: We reviewed patients who attended our specialty clinic between December 2023 and October 2024. Some participated in tau PET study (18F-MK6240). MRI was assessed using Fazekas score. Remaining samples were analyzed for plasma neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), and CSF α-synuclein seed amplification assay (SAA).
RESULTS: During the period, 200 attended and 147 proceeded to screening. Lecanemab was started in 93 of 108 A+ patients; mean age 74.2 years, 73.1% female. While all tested started on lecanemab were positive on amyloid PET, 21% had only regional positivity with lower Aβ burden (centiloid 31.3 ± 17.5 vs 67.6 ± 20.2) and higher age (79.2 ± 5.1 vs 73.3 ± 8.9). While all tested had CSF Aβ42/40 values below the single cut-off 0.067 in Japan, three (8.6%) had values close to the cutoff (0.059–0.067), all of whom were male. Other biomarkers also widely varied from normal to fully abnormal; CSF pTau181 (40.5–168 pg/mL, cut-off 56.5), tau PET-based Braak stage (0–VI), NfL (10.0–103.3 pg/mL), GFAP (121.9–652.5 pg/mL), Fazekas score (0–3), and positive α-synuclein SAA (25–33%). Some associations were indicated including higher Fazekas scores in amyloid PET regional-positive group and higher plasma NfL in CSF Aβ42/40 0.059–0.067 group.
CONCLUSIONS: We identified substantial heterogeneity in ATNIVS biomarker profiles among patients receiving lecanemab in a real-world setting.
CITATION:
Masanori Kurihara ; Ryoko Ihara ; Gen Yoshii ; Ryosuke Shimasaki ; Keiko Hatano ; Taro Bannai ; Fumio Suzuki ; Kenji Ishibashi ; Ko Furuta ; Katsuya Satoh ; Aya Midori Tokumaru ; Kenji Ishii ; Atsushi Iwata (2025): ATNIVS biomarker heterogeneity in real-world patients receiving lecanemab. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100567
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
J Prev Alz Dis 2026;6(13)
Show summaryHide summaryBACKGROUND: 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
ASSESSMENT OF CLINICAL AND NEUROIMAGING EFFICACY OF TREATMENT TARGETING TAU PATHOLOGY IN MILD COGNITIVE IMPAIRMENT AND MILD TO MODERATE ALZHEIMER’S DISEASE WITH HYDROMETHYLTHIONINE MESYLATE USING EXTERNAL CONTROL DATA
Bjoern O Schelter, Helen Shiells, Serena Lo, Nafeesa Nazlee, Emily Evans, Peter Bentham, Serge Gauthier, Henrik Zetterberg, Gordon K Wilcock, Lutz Froelich, Alistair Burns, Emer MacSweeney, Clive Ballard, Jin-Tai Yu, Tay Siew Choon, Vahe Asvatourian, Natalia Muehlemann, Jan Priel, Karin Kook, Tenecia Sullivan, Diane Downie, Sonya Miller, Carol Pringle, John M?D Storey, Tom Baddeley, Charles R Harrington, Roger Staff, Anca-Larisa Sandu, Claire Hull, Richard Stefanacci, Claude M Wischik, Alzheimer\'s Disease Neuroimaging Initiative
J Prev Alz Dis 2026;6(13)
Show summaryHide summaryBACKGROUND: Hydromethylthionine mesylate (HMTM) targets tau pathology and also has tau-independent symptomatic activity. A traditional randomised placebo-controlled trial (RCT) was precluded by loss of blinding due to urinary colouration and therapeutic activity at the minimum dose required to maintain blinding.
OBJECTIVE: To evaluate the efficacy of HMTM in participants with mild cognitive impairment (MCI) and mild to moderate dementia due to Alzheimer’s disease (AD).
METHODS: Because a traditional RCT was not feasible without loss of blinding, we compared HMTM 16 mg/day in TRx-237–039 with propensity score matched true placebo controls from the FDA-sponsored Critical Path for AD (CPAD) database with the same inclusion/exclusion criteria (protocol TRx-237–080). We also compared HMTM 16 mg/day with matched natural history controls from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and with a meta-analysis of placebo arms from trials in comparable populations in analyses specified prior to the 104-week database lock of TRx-237–039.
PARTICIPANTS: Propensity score matching yielded 127 pairs (HMTM n = 127; CPAD placebo n = 127) in the CPAD comparison, and 189 pairs in the ADNI comparison. A total of 218 receiving HMTM 16 mg/day were compared with meta-analytic controls (n = 1805–8567).
INTERVENTION: HMTM 16mg/day.
MEASUREMENTS: Primary outcomes in TRx-237–080 were change from baseline to 78 weeks in ADAS-Cog13 and whole brain volume (WBV). CDR-Sum of Boxes (CDR-SB) and CDR-Global were analysed at 104 weeks. ADAS-cog11 and WBV were analysed in ADNI comparisons, and ADAS-cog11, ADCS-ADL23, CDR-SB and WBV were analysed in meta-analytic comparisons.
RESULTS: Compared with matched CPAD placebo, HMTM 16 mg/day produced statistically significant differences in change on ADAS-Cog13 (p < 0.0001) and WBV at 78 (primary; p < 0.0001) and 104 weeks (p < 0.0001), and CDR-SB differed significantly overall (104-weeks; p < 0.001) and in MCI (p = 0.007). The odds of progressing to a more advanced CDR-Global stage were lower with HMTM (overall OR 0.31) and particularly in MCI (OR 0.15) versus CPAD placebo. Clinical and brain atrophy outcomes were similarly statistically significant in comparisons with ADNI case-matched natural history data and in meta-analytic comparisons.
CONCLUSION: Comparisons of HMTM treatment with CPAD, ADNI, and meta-analytic controls provide evidence consistent with clinical benefit HMTM. It has the potential to offer an accessible oral treatment option which could be delivered with minimal patient/physician burden.
CITATION:
Bjoern O Schelter ; Helen Shiells ; Serena Lo ; Nafeesa Nazlee ; Emily Evans ; Peter Bentham ; Serge Gauthier ; Henrik Zetterberg ; Gordon K Wilcock ; Lutz Froelich ; Alistair Burns ; Emer MacSweeney ; Clive Ballard ; Jin-Tai Yu ; Tay Siew Choon ; Vahe Asvatourian ; Natalia Muehlemann ; Jan Priel ; Karin Kook ; Tenecia Sullivan ; Diane Downie ; Sonya Miller ; Carol Pringle ; John M․D Storey ; Tom Baddeley ; Charles R Harrington ; Roger Staff ; Anca-Larisa Sandu ; Claire Hull ; Richard Stefanacci ; Claude M Wischik ; Alzheimer's Disease Neuroimaging Initiative (2025): Assessment of clinical and neuroimaging efficacy of treatment targeting tau pathology in mild cognitive impairment and mild to moderate Alzheimer’s disease with hydromethylthionine mesylate using external control data. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100560
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
J Prev Alz Dis 2026;6(13)
Show summaryHide summaryBACKGROUND: 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
COST ANALYSES OF PLASMA P-TAU217 VERSUS P-TAU217/AΒ42 RATIO USING TWO-STEP APPROACH IN THE JAPANESE HEALTH CARE SYSTEM
Masanori Kurihara, Ryoko Ihara, Kenichiro Sato, Atsushi Iwata
J Prev Alz Dis 2026;6(13)
Show summaryHide summaryPlasma p-tau217 may offer a cost-saving effect in diagnosing Alzheimer’s disease. However, each healthcare system has different costs, and its impact on evaluating anti-amyloid β (Aβ) therapies in Japan remains unclear. We conducted cost analyses using a two-step approach with a recently released application, assuming that measuring two analytes (p-tau217/Aβ42) would reduce the intermediate zone to 7%, despite doubling the price. Plasma biomarker costs were simulated from 100 to 800 USD. Cost savings ranged 34–79% compared with positron electron tomography (PET) and -5.6%–74% compared with in-patient cerebrospinal fluid (CSF) Aβ42/40 when 14.7% were in the intermediate zone. Savings were comparably high by measuring two analytes at 100 or 200 USD per analyte and gradually differed (one analyte better savings than two) as the cost per analyte increased. Both plasma p-tau217 and p-tau217/Aβ42 showed substantial cost-saving effects, with comparably high savings at lower costs (100, 200 USD) per analyte.
CITATION:
Masanori Kurihara ; Ryoko Ihara ; Kenichiro Sato ; Atsushi Iwata (2025): Cost analyses of plasma p-tau217 versus p-tau217/Aβ42 ratio using two-step approach in the Japanese health care system. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100572
PATHWAYS TO PARTICIPATION – A SCOPING REVIEW OUTLINING BARRIERS AND ENABLERS TO PARTICIPATION IN DEMENTIA RESEARCH
Lukas A. Duffner, Soraya Moradi-Bachiller, Dianne Gove, Ana M. Diaz-Ponce, Angela Bradshaw, Jean Georges
J Prev Alz Dis 2026;6(13)
Show summaryHide summaryBACKGROUND: Ongoing participant recruitment challenges in dementia research highlight the need to understand public perspectives on research participation. This scoping review explored existing literature on barriers and enablers to the recruitment and retention of participants in dementia studies.
METHODS: A scoping review was conducted in PubMed and PsycINFO, following the Arksey and O’Malley framework, using a keyword profile informed by a pilot search (full protocol available at osf.io/n8j4u). Abstract and full text screening were performed in duplicate and data were extracted using predefined criteria. Reported barriers and enablers were grouped into overarching themes. A panel of people with dementia and carers subsequently shared their perspectives on recruitment challenges and reflected on the review findings.
RESULTS: Forty-five publications were included for narrative synthesis, representing 112,011 participants (pooled mean age = 69.3 years; 64.8 % female). Most studies originated from the U.S. and focused on clinical dementia research, with an emphasis on recruitment rather than long-term retention. Barriers were grouped into eight themes: mistrust; fears, worries and concerns; awareness; beliefs and attitudes; practical and logistical constraints; study-related factors; informational barriers; and barriers related to carers and support systems. Enablers included internal motivators (e.g. altruism) and external facilitators (e.g. financial compensation or flexible scheduling).
CONCLUSIONS: While significant research gaps remain, many barriers to participation in dementia research appear modifiable. Targeted actions addressing these modifiable factors may enhance recruitment and retention, which may strengthen the inclusivity and impact of dementia research.
CITATION:
Lukas A. Duffner ; Soraya Moradi-Bachiller ; Dianne Gove ; Ana M. Diaz-Ponce ; Angela Bradshaw ; Jean Georges (2025): Pathways to participation – a scoping review outlining barriers and enablers to participation in dementia research. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100558
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
J Prev Alz Dis 2026;6(13)
Show summaryHide summaryUnderrepresented 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
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
J Prev Alz Dis 2026;6(13)
Show summaryHide summaryBACKGROUND: 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
KNOWLEDGE AND PERCEPTION OF DEMENTIA RISK AND PROTECTIVE FACTORS: A SYSTEMATIC REVIEW AND META-ANALYSIS
Muhammed L. Sambou, Jolanda H.M. Dobbe, Elaine A.C. Albers, Kay Deckers, Lidia R. Arends, M. Arfan Ikram, Ellen M.A. Smets, Wichor M. Bramer, Jeremy A. Labrecque, Leonie N.C. Visser, Frank J. Wolters
J Prev Alz Dis 2026;6(13)
Show summaryHide summaryBACKGROUND: Optimal dementia risk reduction strategies benefit from sufficient public knowledge of risk factors and risk perception, but current public awareness is uncertain.
METHODS: In a systematic literature review on public knowledge and perception of dementia risk factors, we searched relevant databases for original research articles until 2024. When possible, we pooled study results using random effects meta-analysis, and explored sources of heterogeneity through meta-regression. Qualitative studies and studies about risk perception were analysed using narrative synthesis.
FINDINGS: Of 4996 articles screened, 155 were eligible for inclusion. Of these, 125 reported on knowledge of risk factors and 50 on risk perception, jointly providing data from 164,644 participants in 41 countries across 6 continents. Recognition of the 28 queried risk and protective factors was moderate, somewhat higher for lifestyle factors (medians: 38.5–71.5%) than for cardiovascular (9.9–66.9%) and environmental (25.4–44.4%) factors, but with large heterogeneity across queried factors. With the exception of physical activity (71.5%, IQR:46.9–88.3%), social isolation (66.6% [23.7–84.0%]) and traumatic brain injury (65.0% [18.0–76.7%]), recognition of all established modifiable risk factors for dementia from prespecified lists was below 50%, lowest for education (19.5% [7.8–54.9%]), air pollution (25.4% [16.3–41.0%]), and obesity (30.4% [27.0–43.0%]). Recall of risk factors (7 studies) was markedly lower than recognition. Meta-regression analyses showed no consistent differences by year of publication, or by participants’ age, gender, and educational attainment. Among 23 qualitative studies, limited knowledge emerged particularly regarding dementia-specific risk factors like hearing loss. Perceived risk was measured inconsistently across studies, but was generally moderate to high, along with notable worry about dementia in a large part of the older population.
CONCLUSIONS: Knowledge of dementia risk and protective factors in the general population remains limited. These findings call for population-level interventions, including educational campaigns, to enhance preventive strategies.
CITATION:
Muhammed L. Sambou ; Jolanda H.M. Dobbe ; Elaine A.C. Albers ; Kay Deckers ; Lidia R. Arends ; M. Arfan Ikram ; Ellen M.A. Smets ; Wichor M. Bramer ; Jeremy A. Labrecque ; Leonie N.C. Visser ; Frank J. Wolters (2025): Knowledge and perception of dementia risk and protective factors: a systematic review and meta-analysis. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100565
COMPARATIVE EFFECTS OF SOME PHARMACOLOGICAL AND NON-PHARMACOLOGICAL INTERVENTIONS ON COGNITIVE FUNCTION IN ALZHEIMER’S DISEASE: A BAYESIAN NETWORK META-ANALYSIS
Yuning Zhao, Guangxin Luo, Can Huang, Zhenyang Chen, Yu Wei, Qiaosen Chen, Fang Wang, Yong Gan, Xiaoxv Yin
J Prev Alz Dis 2026;6(13)
Show summaryHide summaryBACKGROUND: Given the growing global public health burden of Alzheimer’s disease, this study used the Bayesian network meta-analysis to assess the effects of pharmacological and non-pharmacological interventions on cognitive function in the population with Alzheimer’s disease.
METHODS: Two investigators screened the literature from English databases (PubMed, MEDLINE, Embase, Cochrane CENTRAL, and Web of Science) and three major Chinese bibliographical databases (China National Knowledge Infrastructure Database, Wanfang Database, and VIP Database). We assessed the risk of bias and publication bias of the selected literature. Subsequently, a Bayesian network meta-analysis and meta-regression were conducted to further investigate the comparative efficacy of different interventions on cognitive outcomes.
RESULTS: A total of 4788 cases were initially identified. Photobiomodulation [SMD=0.66, 95%CrI (0.29, 1.02)], enriching environment [SMD=0.69, 95%CrI (0.08, 1.31)], pharmacological therapy [SMD=0.36, 95%CrI (0.17, 0.55)], cognitive stimulation therapy [SMD=0.32, 95%CrI (0.11, 0.55)] and exercise therapy [SMD=0.28, 95%CrI (0.06, 0.51)] showed considerable enhancements in cognitive function among individuals with Alzheimer’s disease. Photobiomodulation and enriching environment stood out, with their effects more potent than those of other therapies, as indicated by the surface under the cumulative ranking curve — photobiomodulation clocked in at 87.3%, while enriching environment scored 83.8%, versus pharmacological therapy’s 54.7%.
CONCLUSIONS: Among the interventions evaluated, photobiomodulation and enriching environment were associated with better improvements in cognitive function than pharmacological therapy. Exercise therapy and cognitive stimulation therapy also demonstrated beneficial effects. Music therapy showed no statistical difference from the control group. In addition, the research developed an innovative approach to contrast pharmacological and non-pharmacological treatments for Alzheimer’s disease.
CITATION:
Yuning Zhao ; Guangxin Luo ; Can Huang ; Zhenyang Chen ; Yu Wei ; Qiaosen Chen ; Fang Wang ; Yong Gan ; Xiaoxv Yin (2025): Comparative effects of some pharmacological and non-pharmacological interventions on cognitive function in Alzheimer’s disease: A Bayesian network meta-analysis. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100564
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
J Prev Alz Dis 2026;6(13)
Show summaryHide summaryINTRODUCTION: 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
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
J Prev Alz Dis 2026;6(13)
Show summaryHide summaryBACKGROUND: 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
STRUCTURAL SOCIAL FACTORS MODIFY THE ASSOCIATION BETWEEN ALZHEIMER’S PATHOLOGY AND COGNITIVE FUNCTION
Michelle Gerards, Lena Sannemann, Frank Jessen
J Prev Alz Dis 2026;6(13)
Show summaryHide summaryBACKGROUND: Social factors have been linked to cognitive decline and risk of dementia. However, our understanding of their impact on cognition in the context of Alzheimer’s disease (AD) pathology is still limited.
OBJECTIVES: This study examined whether two structural social factors, relationship status (RS) and living situation (LS), modify the association between AD pathology and cognition.
DESIGN: Observational, analysis of existing cohort data.
SETTING: Data were obtained from the National Alzheimer's Coordinating Center (NACC) and the Imaging Dementia–Evidence for Amyloid Scanning (IDEAS) study.
PARTICIPANTS: Participants with available data on cognitive performance, AD pathology, and structural social factors.
MEASUREMENTS: We used the Mini-Mental State Examination (MMSE), a widely used brief screening measure of global cognitive status. For the description of AD, postmortem neuropathology (NACC) reports, or amyloid PET (IDEAS) were used. RS and LS were coded according to the respective datasets. Group comparisons and regression models were used to evaluate interactions between RS or LS with AD pathology on cognition.
RESULTS: Across cohorts, up to 31% of individuals were not in a relationship, and up to 22% lived alone. Individuals in a relationship (RS+) or those who lived with someone (LS+) showed poorer cognitive performance than those not in a relationship (RS-) or living alone (LS-) at comparable levels of AD pathology. Interaction analyses indicated that the association between AD pathology and MMSE differed by LS, with LS+ being associated with slightly lower MMSE scores across pathology levels, an effect primarily driven by participants living with someone who is not a partner. In contrast, within the NACC cohort, RS+ individuals showed overall lower MMSE scores, while the association between AD pathology and MMSE was weaker compared to RS− individuals.
DISCUSSION: LS and RS showed differences in how AD pathology related to global cognitive status. Being in a relationship was linked to a weaker association between AD pathology and global cognitive status, whereas living with someone was associated with a lower global cognitive status at comparable levels of pathology. While the direction of these associations remains unclear, our findings suggest that the relationship between AD pathology and cognitive status may vary across different structural social contexts.
CITATION:
Michelle Gerards ; Lena Sannemann ; Frank Jessen (2025): Structural social factors modify the association between Alzheimer’s pathology and cognitive function. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100563
THE ASSOCIATION BETWEEN OMEGA-3 SUPPLEMENTATION AND COGNITIVE DECLINE IN OLDER ADULTS
Zheng-Bin Liao, Zi-Cheng Hu, Gui-Hua Zeng, Jia Chen, Xin-Peng Li, Yu-Hui Liu, Xiu-Qing Yao, Ye-Ran Wang, Alzheimer’s Disease Neuroimaging Initiative
J Prev Alz Dis 2026;6(13)
Show summaryHide summaryBACKGROUND: While omega-3 fatty acid supplementation is widely used for cognitive protection, its efficacy remains controversial, and its impact on core Alzheimer's disease (AD) pathologies in humans is not well-established.
METHODS: This longitudinal study utilized data from the Alzheimer's Disease Neuroimaging Initiative (ADNI). We employed linear mixed-effects models to assess the association between omega-3 supplementation and longitudinal cognitive decline, and mediation analyses to examine whether this relationship was mediated by core AD pathologies (Aβ-PET, tau-PET, T1-MRI, FDG-PET).
RESULTS: Omega-3 supplementation was associated with significantly accelerated cognitive decline, as evidenced by a faster decrease in MMSE scores (β = -0.266, p < 0.001) and a faster increase in both ADAS-Cog13 (β = 0.823, p < 0.001) and CDR-SB scores (β = 0.205, p < 0.001). This association was not mediated by Aβ deposition, tau pathology, or gray matter atrophy. Instead, longitudinal FDG hypometabolism within AD-vulnerable regions served as a significant mediating pathway, accounting for 30.8%, 40.8%, and 19.0% of the total effect on the decline in MMSE, ADAS-Cog13, and CDR-SB, respectively.
CONCLUSIONS: Omega-3 supplementation may be associated with accelerated cognitive decline in older adults, potentially through adverse effects on cerebral synaptic function rather than classical AD proteinopathies. These findings challenge the prevailing view of omega-3 as uniformly beneficial and highlight the need for a cautious reassessment of its widespread use for cognitive protection.
CITATION:
Zheng-Bin Liao ; Zi-Cheng Hu ; Gui-Hua Zeng ; Jia Chen ; Xin-Peng Li ; Yu-Hui Liu ; Xiu-Qing Yao ; Ye-Ran Wang ; Alzheimer’s Disease Neuroimaging Initiative (2025): The association between omega-3 supplementation and cognitive decline in older adults. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100569
SPEECH-BASED DIGITAL BIOMARKERS FOR EARLY ETIOLOGICAL STRATIFICATION OF ALZHEIMER’S DISEASE AND FRONTOTEMPORAL DEGENERATION: A BIOMARKER-CONFIRMED PROSPECTIVE STUDY
Eloïse Da Cunha, Valeria Manera, Frédéric Chorin, Justine Lemaire, Alexandra Plonka, Aurélie Mouton, Raphaël Zory, Auriane Gros
J Prev Alz Dis 2026;6(13)
Show summaryHide summaryBACKGROUND: Early differentiation between Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD) is a prerequisite for secondary prevention and targeted trial enrollment, yet remains challenging at disease onset. We investigated whether automated speech analysis could serve as a digital biomarker for early etiological stratification across clinically heterogeneous presentations.
METHODS: In this prospective biomarker-confirmed prognostic study, 172 participants (108 patients with biomarker-confirmed AD or FTLD and 64 controls) completed a standardized speech protocol at initial clinical assessment. Acoustic, temporal, and phonatory features were automatically extracted. Machine learning models and a stacking ensemble were trained using stratified, repeated 5-fold cross-validation to discriminate between AD and FTLD pathology, with exploratory analysis extending to atypical and rare phenotypes crossed with physiopathology, including primary progressive aphasia (PPA) variants.
RESULTS: Speech-based models achieved high sensitivity and specificity in distinguishing physiopathology independently (mean area under the curve (AUC)=0.986) and crossed phenotype and physiopathological diagnostic association (mean AUC=0.966).The ensemble identified 82% of cases with clinicopathological discordance. Interpretability analyses revealed distinct speech signatures: AD was associated with global speech slowing and phonatory instability, while FTLD was characterized by reduced verbal output and acoustic hypo-expressivity.
CONCLUSIONS: Automated speech analysis provides a promising non-invasive digital biomarker for the early etiological stratification of AD and FTLD, including atypical phenotypes, with high accuracy in a monocentric biomarker-confirmed cohort. These findings support the feasibility of speech-based etiological stratification and its potential to complement existing biomarker frameworks, particularly in cases of clinicopathological discordance. External validation is required before clinical deployment can be considered.
CITATION:
Eloïse Da Cunha ; Valeria Manera ; Frédéric Chorin ; Justine Lemaire ; Alexandra Plonka ; Aurélie Mouton ; Raphaël Zory ; Auriane Gros (2025): Speech-based digital biomarkers for early etiological stratification of Alzheimer’s disease and frontotemporal degeneration: a biomarker-confirmed prospective study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100573
AMYLOID PATHOLOGY AND MODIFIABLE RISK FACTORS IN COGNITIVE DECLINE AMONG COGNITIVELY UNIMPAIRED OLDER ADULTS
Ying-Hsin Hsu, Chih-Kuang Liang, Ming-Yueh Chou, Jaysón Davidson, Yu-Chun Wang, Mike A. Nalls, Luigi Ferrucci, Mark Cookson, Hirotaka Iwaki
J Prev Alz Dis 2026;6(13)
Show summaryHide summaryBACKGROUND: Alzheimer’s disease (AD) pathology, particularly amyloid-β (Aβ) deposition, occurs years before clinical symptoms. Modifiable risk factors may influence cognitive trajectories during this preclinical stage, but whether amyloid status alters their effects remains unclear.
OBJECTIVES: To investigate interactions between amyloid pathology and modifiable risk factors in predicting longitudinal cognitive decline among cognitively unimpaired older adults.
DESIGN AND SETTING: This study was a secondary analysis of data derived from two large multicenter longitudinal cohort studies, the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease (A4) Study and the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) Study.
PARTICIPANTS: A total of 1707 cognitively unimpaired adults aged 65–85 years were included, comprising 1169 amyloid-positive participants from the A4 Study (Aβ+) and 538 amyloid-negative participants from the LEARN Study (Aβ–).
MEASUREMENTS: Cognitive function was assessed every six months using the Preclinical Alzheimer’s Cognitive Composite (PACC) over a mean follow-up of 4.9 years. Eight established modifiable risk factors—low education, alcohol use, diabetes, high cholesterol, high blood pressure, obesity, depressive symptoms, and physical inactivity—were evaluated. Linear mixed-effects models were applied to examine associations between each risk factor and longitudinal PACC decline, and to test interactions with amyloid status, adjusting for demographic and genetic covariates.
RESULTS: Significant interactions between amyloid status and modifiable risk factors were observed for diabetes (adjusted β = −0.206, p = 0.032), high cholesterol (adjusted β = −0.155, p < 0.001), and physical inactivity (adjusted β = −0.161, p = 0.046), indicating combined effects rather than additive effects on cognitive decline among Aβ+ individuals. In the A4 study (Aβ+), low education, diabetes, high cholesterol, and physical inactivity were independently associated with accelerated cognitive decline, whereas obesity was linked to slower decline. In contrast, in the LEARN study (Aβ-), these associations were not statistically significant.
CONCLUSIONS: In conclusion, the significant interactions with amyloid status were observed for diabetes, high cholesterol, and physical inactivity, indicating that these risk factors were associated with faster cognitive decline specifically in Aβ+ individuals. The results suggest that consideration of amyloid status may be important when evaluating the potential role of metabolic and lifestyle risk factors in preclinical cognitive decline. In Aβ+ individuals, obesity was associated with slower cognitive decline, while low education was linked to lower baseline cognition or a reduced symptom threshold, without a significant interaction with amyloid status. Future studies should incorporate amyloid status and longitudinal biomarkers to assess whether modifying these factors can slow preclinical cognitive decline.
CITATION:
Ying-Hsin Hsu ; Chih-Kuang Liang ; Ming-Yueh Chou ; Jaysón Davidson ; Yu-Chun Wang ; Mike A. Nalls ; Luigi Ferrucci ; Mark Cookson ; Hirotaka Iwaki (2025): Amyloid pathology and modifiable risk factors in cognitive decline among cognitively unimpaired older adults. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100574
ASSOCIATIONS OF PLASMA BIOMARKERS WITH AGE IN THE PRESENILIN-1 E280A AUTOSOMAL DOMINANT ALZHEIMER\'S DISEASE KINDRED
Vincent Malotaux, Vivian Ku, Paula Ospina Lopera, Yi Su, Yinghua Chen, Alpana Singh, Jonathan Ruiz-Triviño, María José Hidalgo, Laura Osorio, Laura Serna, Daniela Giraldo, Diana Alzate, Bing He, Catarina Tristão-Pereira, Liliana Ramirez Gomez, Sonia Do Carmo, A. Claudio Cuello, Nicholas J. Ashton, Eric M. Reiman, David Aguillón, Yakeel T. Quiroz
J Prev Alz Dis 2026;6(13)
Show summaryHide summaryBACKGROUND: Autosomal-dominant Alzheimer’s disease (ADAD) offers a model to define early biological changes in Alzheimer’s disease due to its predictable age at symptom onset. Although ultrasensitive plasma assays are available, their associations with age in ADAD remain incompletely characterized.
OBJECTIVES: To characterize age-related changes in plasma biomarkers and examine associations with cognition in PSEN1 E280A ADAD.
DESIGN AND SETTING: Cross-sectional observational study in members of the Colombian PSEN1 E280A kindred.
PARTICIPANTS: A total of 164 individuals were included, comprising 83 mutation carriers (mean age 34.36±9.82 years; 54% female) and 81 non-carriers (mean age 33.75±9.84 years; 52% female).
MEASUREMENTS: Plasma Aβ42/Aβ40, phospho-tau217 (p-tau217), brain-derived tau (BD-tau), glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) were quantified. Sex-adjusted associations with age, divergence ages between groups, classification performance (ROC curves), and associations with cognition (MMSE and CERAD delayed recall) were assessed.
RESULT: All plasma biomarkers were associated with age (p < .01). Divergence between carriers and non-carriers began with Aβ42/Aβ40 before age 18, followed by p-tau217 (26.0 years), GFAP (26.1 years), BD-tau (27.9 years), and NfL (38.7 years). Aβ42/Aβ40 showed the highest discrimination of mutation status (AUC=0.99), followed by p-tau217 (AUC=0.87) and GFAP (AUC=0.84). Among carriers, p-tau217, GFAP, BD-tau, and NfL were associated with MMSE, while p-tau217, GFAP, and NfL predicted CERAD delayed recall.
CONCLUSION: Plasma biomarkers exhibit a temporal cascade in PSEN1 E280A ADAD. P-tau217 and GFAP show the strongest associations with early cognitive decline, suggesting their potential utility for tracking disease progression and monitoring treatment effects in E280A carriers.
CITATION:
Vincent Malotaux ; Vivian Ku ; Paula Ospina Lopera ; Yi Su ; Yinghua Chen ; Alpana Singh ; Jonathan Ruiz-Triviño ; María José Hidalgo ; Laura Osorio ; Laura Serna ; Daniela Giraldo ; Diana Alzate ; Bing He ; Catarina Tristão-Pereira ; Liliana Ramirez Gomez ; Sonia Do Carmo ; A. Claudio Cuello ; Nicholas J. Ashton ; Eric M. Reiman ; David Aguillón ; Yakeel T. Quiroz (2025): Associations of plasma biomarkers with age in the presenilin-1 E280A autosomal dominant Alzheimer's disease kindred. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100578
MULTIDIMENSIONAL MODELING OF BIOLOGICAL AGING: INTEGRATING GAIT, EYE MOVEMENT, REST-STATE FUNCTIONAL CONNECTIVITY, AND PLASMA BIOMARKERS IN NON-DEMENTIA OLDER ADULTS
Jingyi Lin, Yiliang Liu, Ziyu Ouyang, Xuan Yang, Sizhe Zhang, Tianyan Xu, Qijie Yang, Yuan Zhu, Meidan Wan, Xuewen Xiao, Xiangmin Fan, Beisha Tang, Lu Shen, Bin Jiao, Shilin Luo
J Prev Alz Dis 2026;6(13)
Show summaryHide summaryAccurate modeling of biological age has clinical value for risk stratification, personalized prevention, and intervention planning, promoting proactive healthcare for aging and age-related diseases. Because aging is multidimensional, robust and interpretable multimodal approaches are needed. We studied 908 non-dementia older adults (> 60 years), collecting data on gait, eye movements, resting-state functional connectivity (rs-FC), and plasma biomarkers (neurofilament light chain, NfL, and glial fibrillary acidic protein, GFAP). Fourteen gait features, two eye movement features, 19 rs-FC features, and plasma GFAP levels were significantly correlated with age (p < 0.05). Among single-domain models, eye movement features showed the strongest predictive performance (R2 = 0.606; MAE = 3.060). A combined multimodal model achieved markedly higher accuracy (R2 = 0.814; MAE = 1.902). These findings demonstrate that integrating physiological, neurological, and biomarker data substantially improves biological age modeling, supporting the development of comprehensive frameworks to assess aging better and guide timely, targeted preventive strategies.
CITATION:
Jingyi Lin ; Yiliang Liu ; Ziyu Ouyang ; Xuan Yang ; Sizhe Zhang ; Tianyan Xu ; Qijie Yang ; Yuan Zhu ; Meidan Wan ; Xuewen Xiao ; Xiangmin Fan ; Beisha Tang ; Lu Shen ; Bin Jiao ; Shilin Luo (2025): Multidimensional modeling of biological aging: integrating gait, eye movement, rest-state functional connectivity, and plasma biomarkers in non-dementia older adults. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100566
THE CONCURRENT BURDEN OF ALZHEIMER’S PATHOLOGY, CEREBRAL AMYLOID ANGIOPATHY, AND MICROINFARCTS ON COGNITIVE DECLINE
Mingyao You, Chao Tang, Lianfei Liu, Dengpeng Chen, Yillin Wu, Dian He
J Prev Alz Dis 2026;6(13)
Show summaryHide summaryBACKGROUND: Alzheimer’s disease (AD) is frequently complicated by vascular co-morbidities. However, the specific mechanistic pathways by which vascular lesions interact with genetic susceptibility to accelerate cognitive decline remain unclear. This study investigated whether cerebral amyloid angiopathy (CAA) and cortical microinfarcts mediate the impact of AD pathology on cognition and evaluated the modifying role of APOE genotype.
METHODS: We conducted a retrospective clinico-pathological study using the National Alzheimer’s Coordinating Center (NACC) database. The cohort included autopsy-confirmed participants aged 50 and older. Structural Equation Modeling (SEM) was employed to quantify the pathways linking AD pathology (Thal phase) to CAA severity, microinfarcts, and cognitive performance (CDR-Sum of Boxes). We further assessed the cumulative burden of pathology by comparing "Pure AD" cases against those with a "Triple Hit" of AD, CAA, and microvascular injury.
RESULTS: SEM analysis identified a significant statistical mediation pathway wherein parenchymal amyloid is strongly associated with CAA, which correlates with an increased risk of microinfarcts and subsequent cognitive dysfunction. We observed a significant gene-pathology interaction: APOE ε4 carriers demonstrated a steeper trajectory of cognitive decline for a given severity of CAA compared to non-carriers. Furthermore, the "Triple Hit" group exhibited significantly worse cognitive impairment than the "Pure AD" group (P < 0.001), independent of age and education.
CONCLUSIONS: Vascular pathology is a critical mediator of cognitive failure in AD, particularly in APOE ε4 carriers. The concurrent "Triple Hit" of proteinopathy and vasculopathy is associated with a profound failure of cognitive reserve, likely reflecting a more advanced global disease state. These findings highlight the urgent need to target vascular resilience as a disease-modifying strategy in Alzheimer’s disease.
CITATION:
Mingyao You ; Chao Tang ; Lianfei Liu ; Dengpeng Chen ; Yillin Wu ; Dian He (2025): The concurrent burden of Alzheimer’s pathology, cerebral amyloid angiopathy, and microinfarcts on cognitive decline. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100568
DEPRESSIVE SYMPTOMS AS A RISK FACTOR OR PRODROME OF DEMENTIA: MULTI-STATE COGNITIVE TRANSITIONS MODIFIED BY AGE AND POLYGENIC RISK
Ziyang Ren, Ruyi Zhang, Shuai Guo, Yihao Zhao, Jufen Liu, Xiaoying Zheng
J Prev Alz Dis 2026;6(13)
Show summaryHide summaryBACKGROUND: Whether depressive symptoms signal a risk factor or a prodromal symptom of dementia, and how this depends on age, genetic susceptibility, and cognitive stages, remains controversial.
OBJECTIVES: To examine the association between depressive symptoms and incident dementia and cognitive transitions, and to test effect modification by age and AD genetic susceptibility (APOE and AD polygenic risk score [PRS]).
DESIGN: Longitudinal cohort study (1998–2020) using repeated assessments; incident dementia was modeled using Fine-Gray competing-risk models, and cognitive transitions were modeled with multi-state Markov models.
SETTING: The U.S. Health and Retirement Study.
PARTICIPANTS: For the main incident dementia analysis, 13,225 dementia-free participants were included at baseline; genetic and repeated-measures analyses were restricted to 12,089 participants with complete PRS/APOE data.
MEASUREMENTS: Depressive symptoms were assessed with the 8-item CES-D. Cognitive status was classified as normal cognition, subjective memory complaint (SMC), cognitive impairment no dementia (CIND), or dementia. AD genetic susceptibility was indexed by APOE and AD PRS. Outcomes included incident dementia and transitions across cognitive states.
RESULTS: Baseline depressive symptoms (prevalence 11.3%) were associated with a higher incidence of dementia (sHR 1.24, 95% CI 1.10–1.39), with stronger associations in late midlife (50–59y: sHR 1.65) than ≥60y (sHR 1.19; P for interaction=0.001). After excluding dementia occurring within 5–10y, the associations for late midlife (but not ≥60y) remained significant (sHR for 5y=1.57; for 10y=1.55, both P for interaction≤0.030). AD PRS modified this association: depressive symptoms predicted dementia only among individuals with lower AD PRS, whereas APOE ε4 showed no modification. Multi-state analyses showed depressive symptoms accelerated progression across the cognitive continuum (e.g., normal cognition → SMC, HR=1.49; SMC → CIND, HR=1.33; CIND → dementia, HR=1.17) and reduced reversion to normal cognition. Furthermore, AD genetic susceptibility was positively associated with depressive symptom burden, specifically at the SMC stage.
CONCLUSIONS: Depressive symptoms in late midlife, especially with lower AD PRS, are more consistent with a potentially modifiable risk marker for dementia, whereas depressive symptoms emerging at SMC in genetically susceptible adults may more often reflect prodromal disease activity.
CITATION:
Ziyang Ren ; Ruyi Zhang ; Shuai Guo ; Yihao Zhao ; Jufen Liu ; Xiaoying Zheng (2025): Depressive symptoms as a risk factor or prodrome of dementia: multi-state cognitive transitions modified by age and polygenic risk. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100577
LETTER TO THE EDITOR: HEALTH-ECONOMIC CHALLENGES FOR NEW ALZHEIMER’S DISEASE TREATMENTS
Jinjing Fu, Anders Sköldunger, Angela Bradshaw, Hana Marie Broulíková, Chiara C Brück, Jack M. Chapel, Sabine Grimm, Anna Hansson, William L. Herring, Jakub Hlávka, Men Thi Hoang, Linus Jönsson, Filipa Landeiro, Javier Mar, Alison McKean, Matej Misik, Peter Neumann, Thomas Rapp, Craig Ritchie, Anja Schiel, Yi Sun, Dominic Trépel, David Trueman, P.J. van der Veere, Lynn van Rosmalen, Jean L Vonsy, Lizzie Walker, Anders Wimo, Bengt Winblad, Xin Xia, Ron Handels
J Prev Alz Dis 2026;6(13)
Show summaryHide summary
CITATION:
Jinjing Fu ; Anders Sköldunger ; Angela Bradshaw ; Hana Marie Broulíková ; Chiara C Brück ; Jack M. Chapel ; Sabine Grimm ; Anna Hansson ; William L. Herring ; Jakub Hlávka ; Men Thi Hoang ; Linus Jönsson ; Filipa Landeiro ; Javier Mar ; Alison McKean ; Matej Misik ; Peter Neumann ; Thomas Rapp ; Craig Ritchie ; Anja Schiel ; Yi Sun ; Dominic Trépel ; David Trueman ; P.J. van der Veere ; Lynn van Rosmalen ; Jean L Vonsy ; Lizzie Walker ; Anders Wimo ; Bengt Winblad ; Xin Xia ; Ron Handels (2025): Letter to the Editor: Health-economic challenges for new Alzheimer’s disease treatments. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100575