03/2026 journal articles
EDITORIAL: LOW NUMBER OF PATIENTS QUALIFYING FOR AMYLOID TARGETING IMMUNOTHERAPY
Frank Jessen
J Prev Alz Dis 2026;3(13)
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CITATION:
Frank Jessen (2026): Low number of patients qualifying for amyloid targeting immunotherapy. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100516
PREPARING FOR THE IMPLEMENTATION OF ANTI-AMYLOID THERAPIES IN EUROPE: ASSESSING REAL-WORLD ELIGIBILITY FOR LECANEMAB AND DONANEMAB IN A SWEDISH MEMORY CLINIC
Anna Rosenberg, Alina Solomon, Alexandre Bonnard, Makrina Daniilidou, Göran Hagman, Anette Hall, Anna Matton, Ulf Öhlund-Wistbacka, Eric Westman, Miia Kivipelto
J Prev Alz Dis 2026;3(13)
Show summaryHide summaryLecanemab and donanemab are the first anti-Aβ treatments to receive approval in Europe. Eligibility criteria are strict, eg., APOE ε4/4 carriers are excluded. Successful implementation in public healthcare hinges on accurate estimates of eligibility rates in settings which will be the first to roll out the treatments (specialized memory clinics with early disease stages). We applied the appropriate use recommendations (AUR) to assess treatment eligibility in a Swedish tertiary memory clinic where Aβ and APOE assessments are routinely performed. Of the full cohort (N = 410), 26 and 25 patients met the AUR criteria for lecanemab and donanemab, respectively (6 %; partial overlap between the groups). After excluding APOE ε4/4 carriers in line with the European guidelines, only 14 and 13 patients remained eligible (3 %). In clinics with younger populations, a significant percentage of potentially eligible patients are likely to have the APOE ε4/4 genotype. These findings are important to inform the implementation of anti-Aβ treatments.
CITATION:
Anna Rosenberg ; Alina Solomon ; Alexandre Bonnard ; Makrina Daniilidou ; Göran Hagman ; Anette Hall ; Anna Matton ; Ulf Öhlund-Wistbacka ; Eric Westman ; Miia Kivipelto (2025): Preparing for the implementation of anti-amyloid therapies in Europe: Assessing real-world eligibility for lecanemab and donanemab in a Swedish memory clinic. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100476
BRAIN HEALTH NAVIGATION IN A LARGE INTEGRATED HEALTHCARE SYSTEM
G.E. Cooper, S. Patton, D. Lockridge, S.W. Freeman, D. Drexler, K. Wasz
J Prev Alz Dis 2026;3(13)
Show summaryHide summaryAlzheimer’s Disease is a complex, chronic illness of increasing prevalence in the US and worldwide. The complexity of this illness, and its impact on caregivers make it an ideal candidate for navigation services. The development of billable navigation codes now make it possible to create a financially sustainable navigation program. We describe our initial experience with a brain health navigator program, partnering between primary and specialty memory care, in a large integrated healthcare system. While a number of challenges exist, and careful planning was required, we have successfully implemented a navigation program, enrolling greater than 100 patients in the initial 6 months. Patient and caregiver feedback has been highly positive. We have experienced no significant barriers to reimbursement and when accounting for incremental downstream revenue generation (e.g. MRI, labs), we are forecasting long-term financial sustainability and the opportunity for continued scaling over time.
CITATION:
G.E. Cooper ; S. Patton ; D. Lockridge ; S.W. Freeman ; D. Drexler ; K. Wasz (2025): Brain health navigation in a large integrated healthcare system. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100471
NO LONGITUDINAL ASSOCIATION BETWEEN HEARING LOSS AND ALZHEIMER’S DISEASE PATHOLOGY
Jordi H.C. Boons, Phuong Thuy Nguyen Ho, Anna van Houwelingen, M. Arfan Ikram, Gertjan Dingemanse, Bernd Kremer, Meike W. Vernooij, Andre Goedegebure, Julia Neitzel
J Prev Alz Dis 2026;3(13)
Show summaryHide summaryINTRODUCTION: Hearing loss (HL) is a potential risk factor for Alzheimer’s disease (AD), with animal studies suggesting a bidirectional relationship. This study examines whether HL links to changes in AD pathology and, whether AD biomarkers relate to subsequent HL progression.
MEHODS: Baseline Aβ42/Aβ40 and p-tau217 were measured using single-molecule arrays in 474 participants of the Rotterdam Study (mean age=62.37) between 2010-2016. HL was defined as the better-ear’s pure-tone threshold average. After seven years, participants underwent amyloid PET; HL and p-tau217 were reassessed two years after PET.
RESULTS: Baseline HL was not associated with amyloid PET positivity, Aβ42/Aβ40, or longitudinally with p-tau217. Likewise, HL progression did not predict PET outcomes. APOE4 carriership did not modify associations with Aβ PET. Similarly, baseline plasma biomarkers were also unrelated to longitudinal HL changes.
CONCLUSION: No bidirectional association was observed between HL and AD pathology, suggesting that HL may contribute to dementia through other pathways.
CITATION:
Jordi H.C. Boons ; Phuong Thuy Nguyen Ho ; Anna van Houwelingen ; Arfan Ikram ; Gertjan Dingemanse ; Bernd Kremer ; Meike W. Vernooij ; Andre Goedegebure ; Julia Neitzel (2026): No longitudinal association between hearing loss and Alzheimer’s disease pathology. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100481
ASSOCIATIONS OF SELF- AND INFORMANT-REPORTED FUNCTIONAL IMPAIRMENT WITH COGNITIVE PERFORMANCE AND INCIDENT DEMENTIA
Yaqing Gao, Paola Zaninotto, Andrew Steptoe
J Prev Alz Dis 2026;3(13)
Show summaryHide summaryINTRODUCTION: Functional impairment is central to dementia diagnosis, typically assessed through basic and instrumental activities of daily living (ADLs/IADLs) reported by participants or informants. However, it remains unclear which items and reporting sources best capture cognition-related functional impairment.
METHODS: We analysed data from 1,050 adults aged ≥65 years in the English Longitudinal Study of Ageing Harmonised Cognitive Assessment Protocol. Self- and informant-reported ADL and IADL impairments were examined at overall and item levels. Associations with general and domain-specific cognition were estimated using linear regression, and with incident dementia over 6.7 years using Cox models, both adjusted for socioeconomic, lifestyle, and health factors.
RESULTS: ADL and IADL impairment proportions were similar across self- and informant-reports, with modest concordance. Informant-reported, but not self-reported, impairments were consistently associated with poorer cognition across domains, particularly executive function (informant-reported ADL: β = –0.71 SD, 95% CI –0.89 to –0.53) and memory (informant-reported IADL: β = –0.46 SD, 95% CI –0.60 to –0.32), and higher dementia risk (ADL: HR = 3.13, 95% CI 1.23 to 7.96; IADL: HR = 5.00, 95% CI 2.40 to 10.43). The strongest associations were observed for managing money and tasks involving episodic or visuospatial memory, especially among individuals with intermediate education and when informants had higher education or daily contact.
DISCUSSION: Informant-reported IADLs, particularly those involving financial management and memory, may be strong indicators of cognitive impairment and dementia risk. Emphasising these items and informant characteristics may improve population surveillance of dementia and inform outcome selection in preclinical dementia trials targeting early functional decline. These findings should be interpreted in the context of a population-based sample with attrition.
CITATION:
Yaqing Gao ; Paola Zaninotto ; Andrew Steptoe (2026): Associations of self- and informant-reported functional impairment with cognitive performance and incident dementia. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100482
PHASE 3 RANDOMIZED CLINICAL TRIALS OF SIMUFILAM IN MILD-TO-MODERATE ALZHEIMER’S DISEASE
James W. Kupiec, Anton P. Porsteinsson, Raymond S. Turner, Suzanne Hendrix, Craig Mallinckrodt, Arifulla Khan, Ian Cohen, Jonathan Liss, Roger Clarnette, Kee Hyung Park, Antonio M. Hernandez, Lindsay H. Burns
J Prev Alz Dis 2026;3(13)
Show summaryHide summaryBACKGROUND: Soluble amyloid β1–42 (Aβ42) signals via the α7 nicotinic acetylcholine receptor to hyperphosphorylate tau in Alzheimer's disease (AD). Simufilam disrupts this pathogenic signaling by binding filamin A and disrupts its linkages with inflammatory receptors to reduce neuroinflammation. We assessed simufilam in two Phase 3 clinical trials in mild-to-moderate AD.
METHODS: Participants were age 50–87 with Stage 4 or 5 CE, a mini-mental state exam (MMSE) ≥16 and ≤27 and a Clinical Dementia Rating Global Score (CDR-GS) of 0.5, 1 or 2. The criterion supporting AD pathology was plasma phosphorylated (p)-tau181 or prior amyloid PET. RETHINK randomized participants to simufilam 100 mg or placebo for 52 weeks. REFOCUS evaluated simufilam 50 and 100 mg versus placebo for 76 weeks. Co-primary endpoints were change from baseline on ADAS-Cog12 and ADCS-ADL. Sub-studies assessed exploratory plasma biomarkers and, in REFOCUS only, CSF and imaging biomarkers.
RESULTS: Both trials failed to meet co-primary, secondary or exploratory biomarker endpoints. REFOCUS was terminated early, with 22% of participants still active in the trial. In the predefined mild subgroup in REFOCUS, simufilam was associated with slower cognitive decline than placebo through Week 64 (p = 0.019). This finding disappeared at Week 76 with 45% missing data and did not replicate in RETHINK. Favorable nominal exploratory post-hoc findings amongst participants with the highest half of screening plasma p-tau181 levels occurred in RETHINK but not REFOCUS. The plasma p-tau181 entry criterion did not reliably exclude amyloid PET negativity in the sub-study.
CONCLUSIONS: Simufilam did not meet co-primary or secondary endpoints in these Phase 3 trials. Simufilam was safe and well tolerated. Trials registered at clinicaltrials.gov: NCT04994483 and NCT05026177.
CITATION:
James W. Kupiec ; Anton P. Porsteinsson ; Raymond S. Turner ; Suzanne Hendrix ; Craig Mallinckrodt ; Arifulla Khan ; Ian Cohen ; Jonathan Liss ; Roger Clarnette ; Kee Hyung Park ; Antonio M. Hernandez ; Lindsay H. Burns (2025): Phase 3 randomized clinical trials of simufilam in mild-to-moderate Alzheimer’s disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100469
CLINICAL, IMAGING AND BLOOD BIOMARKER OUTCOMES IN A PHASE 3 CLINICAL TRIAL OF TAU AGGREGATION INHIBITOR HYDROMETHYLTHIONINE MESYLATE IN MILD COGNITIVE IMPAIRMENT AND MILD TO MODERATE DEMENTIA DUE TO ALZHEIMER’S DISEASE
Claude M Wischik, Richard Stefanacci, 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, Lewis K Penny, Mohammad Arastoo, Roger Staff, Anca-Larisa Sandu, Helen Shiells, Serena Lo, Nafeesa Nazlee, Emily Evans, Claire Hull, Bjoern O Schelter
J Prev Alz Dis 2026;3(13)
Show summaryHide summaryBACKGROUND: Hydromethylthionine mesylate (HMTM) targets tau pathology and has tau-independent symptomatic activity.
OBJECTIVES: To evaluate the safety and efficacy of HMTM in participants with mild cognitive impairment (MCI) and mild to moderate dementia due to Alzheimer’s disease (AD).
SETTING: 82 centres in Canada, European Union, United Kingdom and United States of America.
PARTICIPANTS: A total of 598 amyloid β-PET positive participants were included; 44% (263) met clinical criteria for MCI due to Alzheimer’s disease and 56% (335) were diagnosed with mild to moderate dementia due to AD. Intervention: HMTM 16 mg/day and 8 mg/day were compared with methylthioninium chloride (MTC) 4 mg twice weekly, intended as an inactive urinary colourant to preserve blinding with respect to possible urinary discolouration caused by HMTM.
MEASUREMENTS: HMTM and MTC were compared on cognitive and functional endpoints for the first 52 weeks followed by all receiving HMTM 16 mg/day to 104 weeks in a modified delayed-start trial design. Biomarker outcomes included change in plasma levels of neurofilament light chain (NfL), pTau217 and MRI measures of grey matter atrophy.
RESULTS: It was not possible to demonstrate significant differences on the co-primary clinical endpoints (ADAS-cog11 and ADCS-ADL23) at 52 weeks due to symptomatic activity in the control arm. In participants with MCI, statistically significant differences in cognitive decline (ADAS-cog13) emerged at 78 weeks (p = 0·0291) and 104 weeks (p = 0·0308) between early- and delayed-start HMTM 16 mg/day in analyses specified prior to the 24-month database lock. Statistically significant cognitive improvement over baseline score was sustained for 78 weeks in the early start MCI group, with no significant cognitive or functional decline to 104 weeks. There was a significant reduction in progression of neurodegeneration measured by NfL change (p = 0·0291) at 52 weeks in the whole population, consistent with significant reductions in progression of grey matter atrophy at 52 and 104 weeks, and a reduction in progression of tau pathology (pTau217, p = 0·0165) in MCI. Headache (1·5%) and diarrhoea (1·2%) were the most frequent adverse effects.
CONCLUSIONS: Although HMTM 16 mg/day arrested progression of neurodegeneration and reduced grey matter atrophy at 52 weeks, symptomatic activity in the control arm precluded separation of treatment arms at 52 weeks on primary clinical endpoints. In participants with MCI, significant clinical separation was seen only at 78 and 104 weeks. This effect has been confirmed in a further study. HMTM was well tolerated and has the potential to offer an accessible oral treatment option with a benign safety profile which could be delivered with minimal patient/physician burden.
CITATION:
Claude M Wischik ; Richard Stefanacci ; 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 ; Lewis K Penny ; Mohammad Arastoo ; Roger Staff ; Anca-Larisa Sandu ; Helen Shiells ; Serena Lo ; Nafeesa Nazlee ; Emily Evans ; Claire Hull ; Bjoern O Schelter (2026): Clinical, imaging and blood biomarker outcomes in a Phase 3 clinical trial of tau aggregation inhibitor hydromethylthionine mesylate in mild cognitive impairment and mild to moderate dementia due to Alzheimer’s disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100480
SAFETY PROFILES OF LECANEMAB: A SYSTEMATIC REVIEW AND META-ANALYSIS OF RANDOMIZED CONTROLLED TRIALS AND REAL-WORLD EVIDENCE
Lin Qi, Fangxue Zheng, Mengjiao Tu, Reema Abdullah, Yilei Zhao, Xinhui Su, Dan Zhou, Guoping Peng
J Prev Alz Dis 2026;3(13)
Show summaryHide summaryBACKGROUND: Safety profiles of lecanemab, an anti-amyloid-β antibody for the treatment of early Alzheimer’s disease (AD), remain uncertain and may vary between randomized controlled trials (RCTs) and real-world evidence (RWE) studies.
OBJECTIVES: This systematic review and meta-analysis aimed to evaluate the safety, tolerability, and acceptability of lecanemab based on findings from both RCTs and emerging RWE studies.
METHODS: We systematically searched major databases and clinical trial registries from their inception to June 2025. Random-effects meta-analyses were performed to estimate the pooled incidence of key safety outcomes, including amyloid-related imaging abnormalities (ARIA), infusion-related reactions (IRRs), and treatment discontinuation (due to ARIA, adverse events [AEs], or any cause). The risk of ARIA according to the ApoE4 genotype was assessed via relative risk (RR). This study was registered with PROSPERO (No. CRD420251110679).
RESULTS: A total of two RCTs and five RWE studies encompassing 1576 patients were included. The pooled ARIA incidence was 19% (95% CI: 16%-23%), which was significantly modulated by ApoE4 status (RR 1.45 for heterozygotes, 3.54 for homozygotes vs noncarriers) and the pooled symptomatic ARIA incidence was 3% (95% CI: 2%-4%). IRRs occurred in 26% (95% CI: 19%–34%), with heterogeneity reduced in patients receiving specific pre-infusion prophylaxis. The pooled rate of discontinuation due to AEs was 8% (95% CI: 5%-11%), with discontinuation due to ARIA occurring in 5% (95% CI: 3%-7%) of patients in RWE studies.
CONCLUSIONS: Lecanemab-related ARIA demonstrates a clear ApoE4 gene-dose effect, supporting routine ApoE4 genotyping before treatment. Standardizing pre-infusion prophylaxis may reduce variability in IRRs incidence, while prompt recognition and management of ARIA are critical for improving treatment tolerability. These findings provide important evidence to support the safe clinical use of lecanemab.
CITATION:
Lin Qi ; Fangxue Zheng ; Mengjiao Tu ; Reema Abdullah ; Yilei Zhao ; Xinhui Su ; Dan Zhou ; Guoping Peng (2025): Safety profiles of lecanemab: A systematic review and meta-analysis of randomized controlled trials and real-world evidence. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100473
A REGIONAL FRAMEWORK FOR THE DETECTION AND MANAGEMENT OF ARIA WITH ANTI-AMYLOID THERAPIES IN EARLY ALZHEIMER’S DISEASE IN ASIA
So Young Moon, Ta-Fu Chen, Bo-Ching Lee, Won Jin Moon, Nagaendran Kandiah, Sumeet Kumar, Young Ho Park, Kaori Inaba, Amitabh Dash
J Prev Alz Dis 2026;3(13)
Show summaryHide summaryAlzheimer’s disease (AD) is a growing public health concern in Asia, with an increasing prevalence driven by demographic shifts and rising life expectancy. The introduction of anti-amyloid monoclonal antibodies such as lecanemab and donanemab marks a pivotal transition from symptomatic management of AD to disease-modifying approaches, but their clinical use requires careful monitoring for amyloid-related imaging abnormalities (ARIA), a key safety consideration that presents either as vasogenic edema or as microhemorrhages and superficial siderosis. ARIA has been observed in varying frequencies across global and Asian clinical trial populations, underscoring the need for region-specific guidance. With our early clinical experiences in South Korea, Taiwan and Singapore serving as archetypes in Asia, we outline a framework for the detection and management of ARIA in Asian healthcare settings, accounting for disparities in imaging infrastructure, genetic factors, and clinician experience. Pre-treatment risk stratification, standardized imaging protocols, and severity-based treatment modifications are central to the framework, highlighting the critical role of multidisciplinary collaboration involving neurologists, geriatricians, psychiatrists, and radiologists in ensuring accurate detection and management of ARIA. Additionally, the paper highlights the role of pharmacovigilance, real-world evidence generation, physician education, and healthcare system preparedness in optimizing the safety and efficacy of anti-amyloid therapies in Asia. The proposed framework aims to ensure safe and effective use of anti-amyloid therapies while mitigating ARIA-related risks, thereby optimizing therapeutic outcomes for early AD in diverse healthcare settings across Asia.
CITATION:
So Young Moon ; Ta-Fu Chen ; Bo-Ching Lee ; Won Jin Moon ; Nagaendran Kandiah ; Sumeet Kumar ; Young Ho Park ; Kaori Inaba ; Amitabh Dash (2026): A regional framework for the detection and management of ARIA with anti-amyloid therapies in early Alzheimer’s disease in Asia. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100477
THE INFLUENCE OF BAPINEUZUMAB AND SEMAGACESTAT ON RAPID PROGRESSORS: A RETROSPECTIVE COHORT STUDY
Kristofer Harris, Madison Shyer, Dulin Wang, Elizabeth He, Matias Cattani, Catherine Zhang, Christine M. Farrell, Xiaoqian Jiang, Yejin Kim, Paul E. Schulz
J Prev Alz Dis 2026;3(13)
Show summaryHide summaryBACKGROUND: A subset of Alzheimer's disease patients progresses much more rapidly than average. These rapid progressors exhibit accelerated cognitive and functional decline. Potential differences in Alzheimer’s biomarkers for rapid progressors and their responses to disease-modifying treatments remain poorly understood, with previous clinical trials and studies producing limited biomarker data and inconsistent results.
OBJECTIVES: Examine differences in rapid progressor versus non-rapid progressor outcomes in two AD treatment trials (bapineuzumab and semagacestat) and investigate cognitive and biomarker progression in the placebo groups.
DESIGN: Retrospective cohort study.
SETTING: Four randomized, double-blind, phase 3 clinical trials from the Center for Global Clinical Research Data (Semagacestat) and the Yale University Open Data Access Project (Bapineuzumab).
PARTICIPANTS: 4,902 patients (2,355 in bapineuzumab trials, 2,647 in semagacestat trials). Rapid progressors were operationally defined as the 10% of patients with the largest changes in cognitive scores from baseline to trial end.
INTERVENTION: Bapineuzumab (monoclonal antibody) and Semagacestat (γ-secretase inhibitor).
MEASUREMENTS: Cognitive assessments (CDR-SB, MMSE, ADAS-Cog, ADCS-ADL) and biological markers (CSF and plasma levels, MRI, FDG PET Scan, and Amyloid PET Scan) at baseline and endpoint.
RESULTS: Rapid progressors showed distinct baseline characteristics in both the bapineuzumab and semagacestat trials: younger age (61.27 vs 63.14 years, p=0.008; and, 72.64 v. 73.64 years, p=0.046), a higher proportion of APOE4 carriers (87.6% vs 41.4%, p<0.001; and, 85.2% vs 49.3%, p = 0.022), and greater cognitive impairment across all measures (p<0.001). Both progression groups demonstrated improvement in specific biomarkers with treatment, though with different patterns. With bapineuzumab according to Conditional Average Treatment Effect analysis, rapid progressors showed biomarker improvement in amyloid CSF, p-Tau CSF, and amyloid PET scan, while non-rapid progressors demonstrated biomarker improvements in p-Tau CSF, amyloid PET, and MRI. With semagacestat, rapid progressors showed improvements in amyloid CSF and plasma while non-rapid progressors showed improvements in amyloid CSF, FDG PET, and MRI.
CONCLUSIONS: This study provides crucial insights for clinical practice and trial design. The distinct response patterns between progression groups suggest that early identification and balancing of RPs between groups could improve clinical trial efficiency. The findings support the development of personalized treatment approaches for rapid progressors, who have aggressive disease progression. These results may significantly modify clinical trial design and patient care in Alzheimer’s disease.
CITATION:
Kristofer Harris ; Madison Shyer ; Dulin Wang ; Elizabeth He ; Matias Cattani ; Catherine Zhang ; Christine M. Farrell ; Xiaoqian Jiang ; Yejin Kim ; Paul E. Schulz (2026): The influence of bapineuzumab and semagacestat on rapid progressors: A retrospective cohort study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100483
LECANEMAB OVER A TWO-YEAR DURATION: KEY INSIGHTS FROM A REGIONAL SPECIALTY MEDICAL CENTER
Lisa B.E. Shields, Hust Hannah, Gregory E. Cooper, Theresa Kluthe, Rachel N. Hart, Andrew P. Thaliath, Brandon C. Dennis, Stephanie W. Freeman, Jessica F. Cain, Whoy Y. Shang, Kendall M. Wasz, Adam T. Orr, Christopher B. Shields, Shirish S. Barve, Kenneth G. Pugh
J Prev Alz Dis 2026;3(13)
Show summaryHide summaryBACKGROUND AND OBJECTIVES: The anti-amyloid monoclonal antibody lecanemab (Leqembi®) treats patients with mild cognitive impairment (MCI) or mild dementia due to Alzheimer’s disease (AD). We sought to evaluate the incidence of amyloid-related imaging abnormalities) ARIA and other adverse events associated with lecanemab.
DESIGN, SETTING, AND PARTICIPANTS: This retrospective and observational study features 187 patients who received at least one lecanemab infusion at our multidisciplinary Norton Neuroscience Institute Memory Center over a two-year duration (August 25, 2023-August 24, 2025).
RESULTS: A total of 109 (58.3 %) patients were diagnosed with MCI, and 78 (41.7 %) had mild dementia prior to starting lecanemab. The mean age at the initial infusion was 73 years (Range: 49-90 years). Most (127 [67.9 %]) patients were female, and the majority (181 [96.8 %]) were Caucasian. Of the 175 patients who underwent at least one surveillance brain MRI following lecanemab initiation, 39 (22.3 %) had evidence of ARIA (both ARIA-H and ARIA-E: 13 [33.3 %]; solitary ARIA-H: 17 [43.6 %]; and solitary ARIA-E: 9 [23.1 %]). Of these 39 patients, 20 (51.3 %) were ε4 heterozygous, 12 (30.8 %) were ε4 homozygous, and 7 (17.9 %) were ε4 non-carriers. Patients who were ε4 homozygous more frequently had evidence of any ARIA (p-value = 0.002), ARIA-E (p = 0.041), and ARIA-H (p = 0.004). Of the 25 patients who underwent at least one surveillance brain MRI and were ε4 homozygous, 12 (48.0 %) had ARIA detected. Five (12.8 %) patients with ARIA were symptomatic, requiring lecanemab suspension. Three of these symptomatic patients were ε4 homozygous, and two were ε4 heterozygous. The ARIA was most frequently detected on the surveillance brain MRI performed before the 5th infusion (29 [74.4 %] patients). All 39 cases of ARIA occurred before the 14th lecanemab infusion. Patients with more baseline microbleeds more frequently developed any ARIA (ARIA-H and ARIA-E) (p = 0.041) and solitary ARIA-H (p = 0.022). The presence of baseline microbleeds was associated with a higher frequency of solitary ARIA-H, though was only marginally statistically significant (p = 0.051). Sixty (32.1 %) patients experienced infusion-related adverse effects, with 54 (90.0 %) occurring after the first lecanemab infusion. Mild and transient headaches were most common, affecting 26 (48.1 %) of these patients after the first infusion. After initiating a pre-infusion oral cocktail of acetaminophen 650 mg, loratadine 10 mg, and famotidine 20 mg, the number of patients who experienced an infusion-related adverse event decreased from 45.2 % to 28.3 %. Thirty-two (17.1 %) patients discontinued lecanemab, primarily due to cognitive decline associated with progressive AD (10 [31.2 %]) and ARIA progression (9 [28.1 %]). Of the 73 patients who had MMSE scores performed at baseline and after 1 year post-lecanemab, 13 (17.8 %) had increased scores, 51 (69.9 %) had decreased scores, and the scores remained the same in 9 (12.3 %) patients.
CONCLUSIONS: Our findings suggest that ARIA is a significant concern especially in patients who are ε4 homozygous. Close monitoring of patients who are ε4 carriers is recommended to recognize any complications that may ensue.
CITATION:
Lisa B.E. Shields ; Hust Hannah ; Gregory E. Cooper ; Theresa Kluthe ; Rachel N. Hart ; Andrew P. Thaliath ; Brandon C. Dennis ; Stephanie W. Freeman ; Jessica F. Cain ; Whoy Y. Shang ; Kendall M. Wasz ; Adam T. Orr ; Christopher B. Shields ; Shirish S. Barve ; Kenneth G. Pugh (2026): Lecanemab over a two-year duration: Key insights from a regional specialty medical center. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100489
PLASMA AΒ42/AΒ40 DETERMINED BY MASS SPECTROMETRY IS ASSOCIATED WITH LONGITUDINAL CHANGES IN AMYLOID ACCUMULATION, BRAIN ATROPHY, AND CONVERSION TO MILD COGNITIVE IMPAIRMENT DUE TO ALZHEIMER’S DISEASE IN INDIVIDUALS WITH SUBJECTIVE COGNITIVE DECLINE: 5-YEAR FOLLOW-UP OF THE FACEHBI COHORT
Noelia Fandos, María Pascual-Lucas, Leticia Sarasa, Jose Terencio, Mª Eugenia Sáez, Juan Pablo Tartari, Ángela Sanabria, Oscar Sotolongo-Grau, Amanda Cano, Lluís Tárraga, Miren Jone Gurruchaga, Agustín Ruíz, Xavier Montalban, Mercè Boada, Montserrat Alegret, Marta Marquié, José Antonio Allué, on behalf of the FACEHBI study group, on behalf of the AMYPAD consortium
J Prev Alz Dis 2026;3(13)
Show summaryHide summaryBACKGROUND: The accurate identification of individuals at risk of Alzheimer’s disease (AD) through blood-based biomarkers remains challenging.
OBJECTIVES: To evaluate the association between plasma amyloid-beta (Aβ)42/Aβ40 ratio and longitudinal amyloid deposition, clinical progression, brain atrophy and cognitive decline.
DESIGN, SETTING AND PARTICIPANTS: This study extends the Fundació ACE Healthy Brain Initiative (FACEHBI) study (Barcelona, Spain), comprising 200 individuals with subjective cognitive decline (SCD) followed over five years.
MEASUREMENTS: Aβ42/Aβ40 ratio was quantified using ABtest-MS, an antibody-free mass-spectrometry (MS) method. Survival analyses compared conversion risks to amyloid-PET positivity and mild cognitive impairment (MCI), in participants classified as low or high Aβ42/Aβ40, based on a cutoff of ≤ 0.241. Linear mixed-effect models evaluated associations of this biomarker with longitudinal changes in amyloid deposition, brain volume, and cognition.
RESULTS: Low baseline Aβ42/Aβ40 was significantly associated with increased amyloid accumulation (β = 0.257, 95% confidence interval (CI) 0.177–0.336, P < 0.001), and with higher risk of conversion to Aβ-PET positivity (Hazard ratio (HR) = 2.84, 95% CI 1.14–7.04, P = 0.025) and to MCI due to AD (HR = 3.25, 95% CI 1.17–9.01, P = 0.024). It was also linked to decreased hippocampal (β = -1.183, 95% CI -2.154 to -0.211, P = 0.017) and cortical (β = -75.921, 95% CI -151.728 to -0.113, P = 0.050) volumes, and increased ventricular volume (β = 35.175, 95% CI 18.559–51.790, P < 0.001). Moreover, lower baseline levels of Aβ42/Aβ40 were weakly associated with greater worsening in Mini-Mental State Examination and complex associative memory.
CONCLUSIONS: Our findings suggest that the plasma Aβ42/Aβ40 ratio is associated with future amyloid accumulation, brain atrophy, and conversion to prodromal AD in individuals with SCD. This biomarker may help characterize individuals with a higher likelihood of progression and could support earlier and more personalized strategies.
CITATION:
Noelia Fandos ; María Pascual-Lucas ; Leticia Sarasa ; Jose Terencio ; Mª Eugenia Sáez ; Juan Pablo Tartari ; Ángela Sanabria ; Oscar Sotolongo-Grau ; Amanda Cano ; Lluís Tárraga ; Miren Jone Gurruchaga ; Agustín Ruíz ; Xavier Montalban ; Mercè Boada ; Montserrat Alegret ; Marta Marquié ; José Antonio Allué ; on behalf of the FACEHBI study group (2025): Plasma Aβ42/Aβ40 determined by mass spectrometry is associated with longitudinal changes in amyloid accumulation, brain atrophy, and conversion to mild cognitive impairment due to Alzheimer’s disease in individuals with subjective cognitive decline: 5-year follow-up of the FACEHBI cohort. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100465
COST-EFFECTIVENESS ANALYSIS OF BLOOD-BASED BIOMARKER TESTING IN THE DIAGNOSIS OF ALZHEIMER’S DISEASE PATHOLOGY
Yonghong Li, Robert J. Lagier, Michael K. Racke, Yuri A. Fesko
J Prev Alz Dis 2026;3(13)
Show summaryHide summaryOBJECTIVES: We aimed to evaluate the cost-effectiveness of blood-based biomarker (BBM) testing vs amyloid positron emission tomography (PET) in patients with signs and symptoms of cognitive decline in a neurologist/specialist care setting.
METHODS: We constructed a decision-tree model to compare diagnostic outcomes and costs of two testing strategies: BBM testing with confirmatory PET scan vs PET scan alone. Their cost-effectiveness was evaluated from a payer perspective with test performance taken from a clinical study and costs including testing/imaging and physician fees.
RESULTS: When access to PET scans is unlimited, BBM triage testing would identify 98.2 % of PET+ patients with a lower average cost per diagnosis compared with PET scan alone ($8868 vs 10,345 per PET+ diagnosis). In terms of incremental cost-effectiveness, BBM triage testing would save $93,984 for each loss of PET+ diagnosis (9.1 times the average cost per PET+ diagnosis by PET scan). Under limited capacity of PET scans, more test-positive patients could be identified using BBM testing than PET scan alone. When access to PET scans is limited to 50 % of the patients, BBM testing would identify 90.6 % more test-positive patients (at 93 % sensitivity) at an incremental cost-effectiveness ratio of $3484 per gain of positive diagnosis, lower than the average cost of a PET+ diagnosis by PET scan ($10,938).
CONCLUSION: BBM testing, compared with PET scan alone, is more efficient in the utilization of available amyloid PET scans and is cost-effective for assessment of Alzheimer’s disease pathology in patients with signs and symptoms of cognitive decline.
CITATION:
Yonghong Li ; Robert J. Lagier ; Michael K. Racke ; Yuri A. Fesko (2025): Cost-effectiveness analysis of blood-based biomarker testing in the diagnosis of Alzheimer’s disease pathology. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100474
HEAD INJURY/TRAUMATIC BRAIN INJURY AND THE RISK OF DEMENTIA: AN OBSERVATIONAL AND MENDELIAN RANDOMIZATION STUDY
Ziyu Ouyang, Bin Jiao, Xuewen Xiao, Qijie Yang, Yuan Zhu, Lu Shen, Nan Li
J Prev Alz Dis 2026;3(13)
Show summaryHide summaryBACKGROUND: This study aimed to investigate the link between head injury (HI)/traumatic brain injury (TBI) and dementia risk, as it remains unclear.
METHODS: We examined the associations between HI/TBI-related factors, including the frequency of HIs and the severity of TBI, and the risk of dementia (n = 397,581), as well as neuroimaging outcomes (n = 42,380) using prospective data (50 years at baseline) from the UK Biobank. In the observational analyses, Cox proportional-hazards modeling and logistic regression were used to estimate the associations between factors. Mendelian randomization (MR) was conducted to investigate the underlying causality between TBI (n = 392,423, ncases=19,842) and Alzheimer's disease (AD) (n = 41,944, ncases=21,982).
RESULTS: During the 12.5-year follow-up period, 7524 participants developed dementia. HI and TBI conferred an increased dementia risk (hazard ratio (HR)=1.72, 95 % confidence interval (CI): 1.50–1.97; HR=1.86, 95 % CI: 1.46–2.38, respectively). The risk increased in relation to recurrent HIs (HR=4.05, 95 % CI: 2.24–7.32) or severe TBI (HR=4.50, 95 % CI: 3.18–6.37). Dementia risk was highest during the first 30 months following HI occurrence (HR=2.20, 95 % CI: 1.66–2.92), whereas there was no association after 40 years post-HI. Patients with recurrent HIs also exhibited reduced hippocampal volumes and increased white matter hyperintensity. HI was additionally associated with poorer reasoning ability and longer reaction time. Besides, the MR analysis supported a causal association between TBI and AD (odds ratio (OR)=1.17, 95 % CI: 1.01–1.37).
CONCLUSION: These results imply that HI/TBI is associated with increased dementia risk. Strategies are needed to mitigate the impact of subsequent dementia.
CITATION:
Ziyu Ouyang ; Bin Jiao ; Xuewen Xiao ; Qijie Yang ; Yuan Zhu ; Lu Shen ; Nan Li (2025): Head injury/traumatic brain injury and the risk of dementia: An observational and Mendelian randomization study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100468
PREECLAMPSIA AS A REVERSIBLE RISK FACTOR FOR ALZHEIMER’S DISEASE: A PROSPECTIVE MRI STUDY ON MORPHOLOGICAL CHANGES OF THE CEREBRAL CORTEX AND IMPAIRMENT OF COGNITIVE FUNCTIONS
Yuanyuan Wang, Meng Li, Tao Chen, Yanli Li, Qingqing Wang, Xinyue Zhang, Na Wang, Linfeng Yang, Lingfei Guo, Wenying Nie
J Prev Alz Dis 2026;3(13)
Show summaryHide summaryPURPOSE: To investigate the cross-sectional and longitudinal alterations in cortical thickness and surface area and Cognitive Impairment among patients with preeclampsia.
METHODS: The thickness and surface area of the cerebral cortex were systematically segmented from MRI using the automated cortical segmentation software FreeSurfer, and the corresponding values for each brain region were accurately quantified. Data collection includes the clinical characteristics, serological markers of proteins associated with cognitive function, and cognitive assessments.
RESULTS: Compared with healthy pregnancies, the cortical thicknesses of the right caudal anterior cingulate (R-CACg), right posterior cingulate (R-PoCg), right rostral anterior cingulate (R-RoACg), and right superior frontal (R-SF) in the preeclampsia group exhibited significant alterations. Notably, the change in the R-SF was specific to preeclampsia and was not associated with normal physiological pregnancies. Mediation analysis further confirmed that elevated prepregnancy BMI was directly associated with reduced Symbol Digit Modalities Test scores and indirectly contributed to cognitive decline through an increase in MAP. The cortical thickness of left pars opercularis was identified as a key component in this underlying mechanism. No statistically significant changes in cortical surface area were observed in patients with preeclampsia. Follow-up studies have indicated that cortical thickness alterations in brain regions associated with preeclampsia demonstrate signs of recovery. Among cognitive-related test indicators, only the Auditory Word Learning Test exhibited a statistically significant improvement.
CONCLUSION: The cortical thickness alterations in the R-CACg, R-PoCg, R-RoACg, and R-SF of patients with preeclampsia may represent the structural basis for cognitive impairment. Longitudinal studies have confirmed the neuroplasticity of cortical thickness changes and the potential for recovery from preeclampsia-related memory deficits.
CITATION:
Yuanyuan Wang ; Meng Li ; Tao Chen ; Yanli Li ; Qingqing Wang ; Xinyue Zhang ; Na Wang ; Linfeng Yang ; Lingfei Guo ; Wenying Nie (2025): Preeclampsia as a reversible risk factor for Alzheimer’s disease: A prospective MRI study on morphological changes of the cerebral cortex and impairment of cognitive functions. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100475
THE LIVER AS A METABOLIC AND IMMUNE HUB IN ALZHEIMER’S DISEASE: FROM MECHANISMS TO THERAPEUTIC OPPORTUNITIES
Jiajie Chen, Luyao Wang, Yingying Zhou, Shuoyan Zhao, Qin Chen, Kai Zheng
J Prev Alz Dis 2026;3(13)
Show summaryHide summaryResearch on Alzheimer’s disease (AD) has traditionally focused on the brain. However, emerging evidence indicates that the liver acts as a silent partner in neurodegeneration. As a core hub for metabolic and immune regulation, the liver communicates bidirectionally with the brain via the liver–brain axis, participating in the regulation of various neurophysiological processes, including neurotransmitter regulation, feeding behavior, and cognition. This review summarizes how liver-derived hepatokines, inflammatory mediators, and metabolic products modulate brain function. We highlight that liver dysfunction disrupts the expression of critical molecules—including fibroblast growth factor 21, insulin-like growth factor 1, lipopolysaccharide, and lipocalin-2—thereby driving AD progression by impairing pathological protein clearance, activating neuroinflammation, exacerbating insulin resistance and oxidative stress, and disrupting lipid metabolism. We also discuss the therapeutic potential of targeting the liver–brain axis through lifestyle interventions (e.g., exercise and diet) and pharmacological approaches, to identify novel strategies to delay AD progression. In summary, we underscore the pivotal role of the liver–brain axis in AD pathogenesis and propose it as a promising target for early diagnosis and innovative therapies.
CITATION:
Jiajie Chen ; Luyao Wang ; Yingying Zhou ; Shuoyan Zhao ; Qin Chen ; Kai Zheng (2026): The liver as a metabolic and immune hub in Alzheimer’s disease: From mechanisms to therapeutic opportunities. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100478
CEREBRAL HAEMODYNAMICS AND WHITE MATTER HYPERINTENSITIES: FINDINGS USING NON-INVASIVE BRAIN IMAGING
Ashwati Vipin, James Xiao Yuan Chen, Mervin Tee, Saima Hilal, Yi Jin Leow, Simon Konstandin, Klaus Eickel, Matthias Günther, Jan Petr, Henk JMM Mutsaerts, Nagaendran Kandiah
J Prev Alz Dis 2026;3(13)
Show summaryHide summaryBACKGROUND: Utilizing non-invasive neuroimaging for characterization of blood brain barrier (BBB) changes and perfusion deficits underlying small vessel disease pathobiology including white matter hyperintensities (WMH) remains largely unexplored.
OBJECTIVES: We examined the underlying haemodynamics of WMH by assessing complex relationships between cerebral blood flow, BBB permeability and WMH burden.
DESIGN, SETTING, PARTICIPANTS: Cross-sectional data from study participants belonging to the community-based Biomarker and Cognition Cohort Study, Singapore was obtained.
MEASUREMENTS: Brain structural and novel non-invasive multi-echo Arterial Spin Labeling data was obtained from 128 participants to derive cerebral blood flow (CBF), arterial transit time (ATT) and BBB time of exchange (Tex).
RESULTS: Neurovascular measures from BBB imaging comprising lower CBF (β=-0.005; p = 0.0139), longer ATT (β=0.644; p = 0.0132) and shorter BBB Tex (β=-0.002; p = 0.0023) were independently associated with higher WMH and higher age-at-visit. Model fit statistics indicated good fit for the structural equation model with a comparative fit index of 0.975 and Standardized Root Mean Square Residual of 0.074. Structural equation modelling revealed CBF (β=0.533; p < 0.001) and ATT (β=-0.254; p = 0.001) as predictors of BBB permeability. Subsequently higher BBB permeability predicted higher WMH burden (β=-0.387; p < 0.001). Additionally, vascular risk factors comprising higher blood pressure and haemoglobinA1C related to lower CBF and shorter BBB Tex.
CONCLUSIONS: Our study highlights that CBF and ATT contribute to BBB permeability, which in turn impacts WMH burden. Vascular risk factors also impact neurovascular measures. These findings add to the growing evidence on the potential role of BBB and perfusion deficits underlying small vessel disease burden.
CITATION:
Ashwati Vipin ; James Xiao Yuan Chen ; Mervin Tee ; Saima Hilal ; Yi Jin Leow ; Simon Konstandin ; Klaus Eickel ; Matthias Günther ; Jan Petr ; Henk JMM Mutsaerts ; Nagaendran Kandiah (2026): Cerebral haemodynamics and white matter hyperintensities: findings using non-invasive brain imaging. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100479
POTENTIAL ROLE OF MRI TO OPTIMIZE CLINICAL TRIAL DESIGN FOR PROGRESSIVE SUPRANUCLEAR PALSY AND CORTICOBASAL DEGENERATION
Jesús García-Castro, Lawren VandeVrede, Michael C. Donohue, Lídia Vaqué-Alcázar, Sara Rubio-Guerra, Judit Selma-González, Hilary W. Heuer, Alejandra O. Morcillo-Nieto, María Franquesa, Oriol Dols-Icardo, Alexandre Bejanin, Olivia Belbin, Juan Fortea, Daniel Alcolea, Maria Carmona-Iragui, Carla Abdelnour, Isabel Barroeta, Miguel Santos-Santos, María Belen Sánchez Saudinós, Isabel Sala, Alberto Lleó, Maria Luisa Gorno-Tempini, Maria Luisa Mandelli, Rema Raman, Anne-Marie A Wills, Eden Barragan, Irene Litvan, Brad Boeve, Brad Dickerson, Murray Grossman, Edward D. Huey, David J. Irwin, Alex Pantelyat, Carmela Tartaglia, Julio C. Rojas, Adam L. Boxer, Ignacio Illán-Gala, on behalf of theFour Repeat Tau Neuroimaging Initiative (4RTNI) and the AL108-231 Investigators
J Prev Alz Dis 2026;3(13)
Show summaryHide summaryBACKGROUND: Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are 4–repeat tauopathies (4RT) presenting with overlapping syndromes. Imperfect clinicopathological associations increase sample-size demands in clinical trials. We test whether MRI can enrich trials for PSP/CBD and provide sensitive MRI-based outcome measures.
METHODS: Longitudinal cohort analysis including participants from the 4 Repeat Tauopathy Neuroimaging Initiative (4RTNI) and phase 2/3 Davunetide trial (DAV). An MRI model trained on autopsy-confirmed cases predicted PSP (MRI-PSP) or CBD (MRI-CBD); corticobasal syndrome (CBS) with positive Alzheimer’s biomarkers was reclassified. Clinical scales and MRI-derived thickness/volume were analyzed with linear mixed-effects models. We derived data-driven MRI-signatures (optimal regional combinations) to minimize required trial sample sizes.
RESULTS: 206 participants from 4RTNI (n = 106 with Richardson’s syndrome [RS], CBS, or nonfluent/agrammatic primary progressive aphasia [nfvPPA]) and DAV (n = 100 with RS). In 4RTNI, 49 participants were predicted MRI-PSP and 43 MRI-CBD. 76% of MRI-PSP had RS, 24% had CBS/nfvPPA; 66% of MRI-CBD had CBS. PSP and CBD signatures shared midbrain/pontine atrophy but differed in cortical involvement. PSP signature correlated strongly with 12-month change on the PSP Rating Scale (β = –0.59, p < 0.001). MRI-based signatures reduced the estimated sample sizes required to detect 30% reduction in progression over 12-months by 50% for MRI-PSP and 87% for MRI-CBD, compared with clinical outcomes. In DAV, feasibility was replicated.
CONCLUSION: MRI-derived models can identify PSP or CBD with high accuracy, and MRI-based signatures track progression more sensitively than established clinical outcomes. Incorporating these tools into therapeutic trial design could reduce sample sizes and enable more inclusive disease-modifying trials for 4RT.
CITATION:
Jesús García-Castro ; Lawren VandeVrede ; Michael C. Donohue ; Lídia Vaqué-Alcázar ; Sara Rubio-Guerra ; Judit Selma-González ; Hilary W. Heuer ; Alejandra O. Morcillo-Nieto ; María Franquesa ; Oriol Dols-Icardo ; Alexandre Bejanin ; Olivia Belbin ; Juan Fortea ; Daniel Alcolea ; Maria Carmona-Iragui ; Carla Abdelnour ; Isabel Barroeta ; Miguel Santos-Santos ; María Belen Sánchez Saudinós ; Isabel Sala ; Alberto Lleó ; Maria Luisa Gorno-Tempini ; Maria Luisa Mandelli ; Rema Raman ; Anne-Marie A Wills ; Eden Barragan ; Irene Litvan ; Brad Boeve ; Brad Dickerson ; Murray Grossman ; Edward D. Huey ; David J. Irwin ; Alex Pantelyat ; Carmela Tartaglia ; Julio C. Rojas ; Adam L. Boxer ; Ignacio Illán-Gala ; on behalf of theFour Repeat Tau Neuroimaging Initiative (4RTNI) and the AL108-231 Investigators (2026): Potential role of MRI to optimize clinical trial design for progressive supranuclear palsy and corticobasal degeneration. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100486
ASSOCIATION OF PLASMA P-TAU AND P-TAU/AΒ RATIO WITH ALZHEIMER\'S PATHOLOGY
Xuhui Chen, Mingxing Jiang, Laihong Zhang, Jiayi Zhu, Anqi Li, Zhengbo He, Xin Zhou, Yalin Zhu, Chen Zhang, Cong Wang, Mingxu Li, Yiying Wang, Xinyue Ma, Binhui Liu, Rong Ma, Yipeng Jin, Xiang Fan, Zhen Liu, Tengfei Guo, Yong-An Sun, Guoyu Lan
J Prev Alz Dis 2026;3(13)
Show summaryHide summaryBACKGROUND: Plasma phosphorylated tau (p-tau) and β-amyloid (Aβ) are promising biomarkers for Alzheimer’s disease (AD). However, it remains unclear whether combining p-tau with Aβ provides better predictive performance than using p-tau alone.
OBJECTIVES: To evaluate the predictive utility of plasma p-tau and Aβ combinations for AD-related pathology, brain atrophy, and cognitive decline.
DESIGN, SETTING, AND PARTICIPANTS: This study included 352 participants from the Greater-Bay Area Healthy Aging Brain Study (GHABS) cohort in China, classified into 227 Aβ-negative and 125 Aβ-positive individuals.
MEASUREMENTS: Participants underwent Aβ positron emission tomography (PET) and plasma biomarker assessments. Plasma concentrations of p-tau181, p-tau217, p-tau231, Aβ42, and Aβ40 were quantified on the Quanterix HD-X and Lumipulse G1200 platform.
RESULTS: Among the individual plasma p-tau variants, p-tau217 consistently outperformed p-tau181 and p-tau231. The combination of p-tau biomarkers (p-tau181, p-tau217, and p-tau231) with Aβ42 or the Aβ42/40 ratio further improved discrimination between Aβ+/CU (cognitively unimpaired) and Aβ-/CU individuals. Both p-tau/Aβ42 and p-tau/(Aβ42/40) exhibited slightly stronger or comparable associations with Aβ PET burden, baseline and longitudinal measures of hippocampal atrophy, AD-typical cortical thinning, and cognitive decline, relative to p-tau alone.
CONCLUSIONS: The head-to-head comparisons indicate that p-tau217 is the most robust biomarker among the variants tested, and p-tau/Aβ ratios perform comparably or slightly better than p-tau alone in reflecting AD pathology, potentially providing complementary information for early detection and monitoring of disease progression.
CITATION:
Xuhui Chen ; Mingxing Jiang ; Laihong Zhang ; Jiayi Zhu ; Anqi Li ; Zhengbo He ; Xin Zhou ; Yalin Zhu ; Chen Zhang ; Cong Wang ; Mingxu Li ; Yiying Wang ; Xinyue Ma ; Binhui Liu ; Rong Ma ; Yipeng Jin ; Xiang Fan ; Zhen Liu ; Tengfei Guo ; Yong-An Sun ; Guoyu Lan (2026): Association of plasma p-tau and p-tau/Aβ ratio with Alzheimer's pathology. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100472
IDENTIFYING RISK FACTORS OF YOUNG-ONSET DEMENTIA AND EVALUATING EVIDENCE HIERARCHY: A META-ANALYSIS AND UMBRELLA REVIEW
Jiayu Zhang, Dandan Yang, Jian Liang, Yin Hu, Liping Rao, Jun Huang, Qijun Wu, Bo Jiang
J Prev Alz Dis 2026;3(13)
Show summaryHide summaryBACKGROUND: Young-onset dementia (YOD) directly affects the working-age population. The premature onset of dementia intensifies peer caregiving responsibilities and diverts medical and nursing resources. While modifiable risk factors for late-onset dementia have been well established, uncertainty remains regarding the applicability of these findings to YOD. We aim to identify modifiable risk factors for YOD and evaluate the strength of evidence.
METHODS: We searched PubMed, Embase, Web of Science, and Ovid Medline from inception to 22 May 2025 for epidemiological studies on non-genetic risk factors for YOD. We used random-effects meta-analyses with the inverse variance method to pool relative risks (RRs) and 95% confidence intervals (CIs). A series of statistical tests were designed to classify the strength of evidence of significant associations as convincing, highly suggestive, suggestive, or weak evidence.
RESULTS: From 25,731 initial and 2289 updated search records, 36 studies examining 31 non-genetic risk factors for YOD were identified. Of the 31 associations examined, 21 were nominally statistically significant at P < 0.05 based on random-effects models. Prior stroke was convincingly associated with an increased risk of YOD. Evidence of association was highly suggestive for alcohol use disorders, diabetes, depression, mood disorders, Parkinson's disease, multiple sclerosis, use of antidepressants/antipsychotics, and asthma.
CONCLUSION: We found that the risk of dementia in young individuals may be closely related to neuropsychiatric symptoms and clinical alcohol disorders. Future research should further validate these findings and explore intervention strategies to reduce dementia risk in younger individuals.
CITATION:
Jiayu Zhang ; Dandan Yang ; Jian Liang ; Yin Hu ; Liping Rao ; Jun Huang ; Qijun Wu ; Bo Jiang (2025): Identifying risk factors of young-onset dementia and evaluating evidence hierarchy: a meta-analysis and umbrella review. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100467
ASSOCIATION BETWEEN PLASMA METAL ELEMENT PROFILES AND COGNITIVE IMPAIRMENT IN OCCUPATIONALLY ALUMINUM-EXPOSED WORKERS AT A LARGE ALUMINUM PLANT IN NORTHERN CHINA
Xin Guo, Fangyu Gao, Mujia Li, Baolong Pan, Feng Gao, Shanshan Wang, Jingsi Zhang, Xiaoting Lu, Jing Song, Linping Wang, Huifang Zhang, Qiao Niu
J Prev Alz Dis 2026;3(13)
Show summaryHide summaryThis study explored the association between plasma levels of multiple metals and cognitive impairment (CI) in 455 aluminum electrolysis workers from a northern Chinese plant, divided into CI (256) and control (199) groups by MoCA scores. Using inductively coupled plasma mass spectrometry, 11 metals were measured, with analyses via conditional logistic regression,generalized linear models (GLM), Bayesian kernel machine regression (BKMR), and age stratification (40 years). Plasma aluminum (Al), lead (Pb), lithium (Li), manganese, cobalt, and copper were significantly higher in the CI group (all P < 0.05), while zinc showed no difference. Single-element analysis found Al, Pb, and Li negatively correlated with MoCA total and subscores (e.g., visuospatial function; P < 0.05), and zinc positively correlated with attention (β = 1.10, P < 0.05). BKMR confirmed metal mixtures above the 25th percentile reduced MoCA scores (β = -0.875, 95 % CI: -1.379 to -0.371), with Al, Pb, and Li as key contributors (PIP > 0.6). Subgroup analysis showed Al primarily affected those <40, while Pb had greater impact in those >40. Findings indicate elevated Al, Pb, and Li associate with higher CI risk, metal mixtures synergistically exacerbate impairment, and age modifies these effects, aiding occupational cognitive impairment prevention.
CITATION:
Xin Guo ; Fangyu Gao ; Mujia Li ; Baolong Pan ; Feng Gao ; Shanshan Wang ; Jingsi Zhang ; Xiaoting Lu ; Jing Song ; Linping Wang ; Huifang Zhang ; Qiao Niu (2025): Association between plasma metal element profiles and cognitive impairment in occupationally aluminum-exposed workers at a large aluminum plant in northern China. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100470