Journals
2025 EN
Ashton Nicholas J. · Keshavan Ashvini · Brum Wagner S.
+41 more
Abstract INTRODUCTION The Alzheimer's Association Global Biomarker Standardization Consortium conducted a blinded case–control study to learn which phosphorylated tau (p‐tau) assays provide the largest fold‐changes in Alzheimer's disease (AD) versus non‐AD and show commutability in measuring patient samples and candidate certified reference materials (CRMs). METHODS Thirty‐three different p‐tau assays measured paired plasma and cerebrospinal fluid (CSF) from 40 participants (25 with “AD pathology” and 15 with “non‐AD pathology” by CSF amyloid beta [Aβ]42/Aβ40 and p‐tau181 criteria). Four CRMs were assessed. RESULTS Plasma p‐tau217 demonstrated higher fold‐changes between AD and non‐AD than other p‐tau epitopes. Fujirebio LUMIPULSE G, UGOT IPMS, and Lilly MSD p‐tau217 provided the highest fold‐changes. Plasma p‐tau217 showed the strongest correlations between plasma assays (rho = 0.81–0.97). The CRMs were not commutable across assays. DISCUSSION Plasma p‐tau217 showed larger fold‐changes and better accuracy for detecting AD pathology in symptomatic individuals, with greater cross‐platform agreement than other p‐tau variants. Further work is needed to develop suitable CRMs facilitating cross‐assay standardization. Highlights Paired plasma and cerebrospinal fluid (CSF) samples from twenty‐five Alzheimer's disease (AD) and 15 non‐AD patients were measured blind. Thirty‐three plasma assays were compared, for phosphorylated tau‐181 (p‐tau181), 205, 212, 217 and 231. Plasma p‐tau217 consistently had the highest fold‐change and was best correlated between assays. Plasma‐CSF correlations were weak to moderate. There was lack of commutability for four candidate reference materials.
Journals
2025 EN
Ferguson Erin L. · Zimmerman Scott C. · Jiang Chen
+11 more
Abstract INTRODUCTION We evaluated the independent associations between high‐density lipoprotein cholesterol (HDL‐C) and triglyceride (TG) levels with Alzheimer's disease and related dementias (ADRD). METHODS Among 177,680 members of Kaiser Permanente Northern California who completed a survey on health risks, we residualized TGs and HDL‐C conditional on age, sex, and body mass index. We included these residuals individually and concurrently in Cox models predicting ADRD incidence. RESULTS Low (hazard ratio [HR] 1.06, 95% confidence interval [CI] 1.02–1.10) and high quintiles (HR 1.07, 95% CI 1.03–1.12) of HDL‐C residuals were associated with an increased risk of ADRD compared to the middle quintile. Additional adjustment for TGs attenuated the association with high HDL‐C (HR 1.03, 95% CI 0.99–1.08). Low TG residuals were associated with an increased ADRD risk (HR 1.10, 95% CI 1.06–1.15); high TG residuals were protective (HR 0.92, 95% CI 0.88–0.96). These estimates were unaffected by HDL‐C adjustment. DISCUSSION Low HDL‐C and TG levels are independently associated with increased ADRD risk. The correlation with low TG level explains the association of high HDL‐C with ADRD. Highlights Strong correlations between lipid levels are important considerations when investigating lipids as late‐life risk factors for Alzheimer's disease and related dementias (ADRD). Low levels of high‐density lipoprotein cholesterol (HDL‐C) and triglycerides (TGs) were independently associated with an increased risk of ADRD. We found no evidence for an association between high HDL‐C and increased ADRD risk after adjustment for TGs. High levels of TGs were consistently associated with a decreased risk of ADRD. There may be interaction between TG and HDL‐C levels, where both low HDL‐C and TG levels increase the risk of ADRD compared to average levels of both.
Journals
2025 EN
Choi Minhyuk · Zimmerman Scott C. · Jiang Chen
+13 more
Abstract INTRODUCTION Mixed evidence on how statin use affects risk of Alzheimer's disease and related dementias (ADRD) may reflect heterogeneity across sociodemographic factors. Few studies have sufficient power to evaluate effect modifiers. METHODS Kaiser Permanente Northern California (KPNC) members ( n = 705,061; n = 202,937 with sociodemographic surveys) who initiated statins from 2001 to 2010 were matched on age and low‐density lipoprotein cholesterol (LDL‐C) with non‐initiators and followed through 2020 for incident ADRD. Inverse probability‐weighted Cox proportional hazards models were used to evaluate effect modification by age, gender, race/ethnicity, education, marital status, income, and immigrant generation. RESULTS Statin initiation (vs non‐initiation) was not associated with ADRD incidence in any of the 32 subgroups ( p > .05). Hazard ratios ranged from 0.964 (95% CI: 0.923 to 1.006) among Asian‐identified participants to 1.122 (95% CI: 0.995 to 1.265) in the highest income category. DISCUSSION Sociodemographic heterogeneity appears to have little to no influence on the relationship between statin initiation and dementia. Highlights The study includes a large and diverse cohort from Kaiser Permanente ( N = 705,061). An emulated trial design of statin initiation on dementia incidence was used. Effect modification by sociodemographic factors was assessed. There were no significant Alzheimer's disease and related dementias (ADRD) risk differences in 32 sociodemographic subgroups ( p > 0.05).
Journals
2025 EN
D'Aoust Tim · ClocchiattiTuozzo Santiago · Rivier Cyprien A.
+23 more
Abstract INTRODUCTION An integrative polygenic risk score (iPRS) capturing the neurodegenerative and vascular contribution to dementia could identify high‐risk individuals and improve risk prediction. METHODS We developed an iPRS for dementia (iPRS‐DEM) in Europeans (aged 65+), comprising genetic risk for Alzheimer's disease (AD) and 23 vascular or neurodegenerative traits (excluding apolipoprotein E [ APOE ]). iPRS‐DEM was evaluated across cohorts comprising older community‐dwelling people ( N = 3702), a multi‐ancestry biobank ( N = 130,797 Europeans; 105,404 non‐Europeans), and dementia‐free memory clinic participants ( N = 2032). RESULTS iPRS‐DEM was associated with dementia risk independently of APOE in the elderly (subdistribution hazard ratio [sHR] per1SD = 1.15, 95% confidence interval [CI]: 1.03 to 1.28), which generalized to Europeans (EUR‐sHR per1SD = 1.28, 95% CI: 1.09 to 1.51]), East‐Asians (EAS‐sHR per1SD = 5.29, 95% CI: 1.43 to 34.36), and memory‐clinic participants (sHR per1SD = 1.25, 95% CI: 1.11 to 1.42). Prediction was comparable to clinical risk factors in older community‐dwelling people, with improved performance among memory‐clinic patients. Risk stratification was enhanced by defining four genetic risk groups with iPRS‐DEM and APOE ε4, reaching five‐fold increased risk in APOE ε4+/iPRS‐DEM+ memory‐clinic participants. DISCUSSION Alongside APOE ε4, iPRS‐DEM may refine risk stratification for the enrichment of dementia clinical trials and prevention programs. Highlights iPRS‐DEM reflects neurodegenerative and vascular contribution to dementia. We show iPRS‐DEM captures additional dementia genetic risk beyond APOE and AD‐PRS. iPRS‐DEM, in combination with APOE ε4, shows promise for dementia risk stratification. Our results generalize across both population‐based and memory‐clinic settings. We show transportability of iPRS‐DEM to East Asian ancestry.
Journals
2025 EN
Frost Bess · Rowe James B. · Akinyemi Rufus O.
+40 more
Abstract Recent years have seen major advances in tau‐associated brain disorders through interdisciplinary research spanning molecular biology, neuroimaging, clinical trials, and therapeutic development. The Tau2024 Global Conference, hosted by the Alzheimer's Association, CurePSP, and Rainwater Charitable Foundation, showcased these efforts by bringing together researchers and experts worldwide to discuss the latest advancements in tau research. The conference aimed to attract talent and funding to study tauopathies, particularly among early‐career researchers, and to foster interdisciplinary alignment and collaboration around challenges in tau research. In this manuscript, we summarize proceedings of the Tau2024 Global Conference, covering a wide range of topics, including lived experiences of individuals with genetic forms of tauopathies, global perspectives on tauopathies, and molecular mechanisms, brain microenvironments, biomarker developments, clinical trials, and therapeutic approaches to tauopathies. Through international, collaborative efforts, innovative research, and a commitment to inclusivity, researchers worldwide have demonstrated transformative breakthroughs toward diagnosing, treating, and, ultimately, preventing tau‐related diseases. Highlights The Tau2024 Global Conference presented updates and advances in tau research. Blood‐based biomarkers offer specificity and longitudinal monitoring capabilities. There are a range of targetable mechanisms in the cascade of pathogenesis. International collaboration is vital to address disparities in tauopathies.
Journals
2025 EN
Grasset Leslie · Bis Joshua C. · Frenzel Stefan
+31 more
Abstract INTRODUCTION To investigate the associations of education level, marital status, and physical activity with dementia risk and brain MRI markers. METHODS Data from six community‐based samples from the Cross‐Cohort Collaboration Consortium were analyzed. Self‐reported education level, marital status, and physical activity at age 60 to 75 years were harmonized. Subsamples of participants with brain MRI markers at time of exposure were selected. Associations with dementia risk and cross‐sectional MRI markers were meta‐analyzed. RESULTS Higher education level was associated with lower dementia risk (hazard ratio [HR] = 0.65, 95% confidence interval [CI] = 0.59; 0.72 vs low level) but not significantly with brain MRI markers. Compared with being unmarried, being married was only associated with higher total brain and hippocampal volumes. Being physically active was associated with lower dementia risk (HR = 0.73, 95% CI = 0.52; 1.04), as well as larger total brain volume and smaller white matter hyperintensity volume. DISCUSSION This study provides further evidence regarding the contribution of education level and physical activity to dementia resilience. Highlights Education level, marital status, and physical activity are thought to contribute to resilience against ADRD. We used random‐effects meta‐analysis to summarize results from six community‐based samples from the CCC. In this cross‐cohort meta‐analysis, higher education level and being physically active were associated with lower risk of dementia. In cross‐sectional analyses, being married was associated with larger TBV and HV, while being physically active was associated with larger TBV and lower WMHV.
Journals
2025 EN
Boyle Rory · Koops Elouise A. · Ances Beau
+42 more
Abstract Due to the high prevalence of Alzheimer's disease (AD) in adults with Down syndrome (DS), trisomy 21 is now considered a genetic form of AD (DSAD). A better understanding of factors that can prevent or delay AD is vital to improve outcomes for adults with DS. In this narrative review, we apply AD and cognitive aging research frameworks to study resistance and resilience in DSAD. Given the variability in the timing of pathology and symptoms, we discuss the evidence supporting the role of genetic, biological, socio‐behavioral, lifestyle, and environmental factors in resistance and resilience to DSAD. We also consider how co‐occurring health conditions in DS may influence resistance and resilience, and how methods from AD research can be applied to DSAD. Ultimately, this framework aims to guide future research and translate findings into clinical interventions to improve outcomes in DSAD. Highlights Definitions of resistance and resilience in the genetic form of Alzheimer's disease (DSAD) are proposed for guiding the field. Variability in the timing of AD pathology and symptoms suggests the potential for resistance and resilience mechanisms in DSAD. Genetic, biological, socio‐behavioral, lifestyle, and environmental factors have the potential to build resistance or resilience in DSAD. Future research will require longitudinal and experimental designs, life course approaches, and large cohort studies.
Journals
2025 EN
Jonaitis Erin M. · MacLeod Karen · Lamoureux Jennifer
+18 more
Abstract INTRODUCTION Multi‐etiology dementia necessitates in vivo markers of copathologies including misfolded α alpha}}$ ‐synuclein (syn). We measured misfolded syn aggregates (syn‐seeds) via qualitative seed amplification assays (synSAA) and examined relationships with markers of Alzheimer's disease (AD). METHODS Cerebrospinal fluid (CSF) was obtained from 420 participants in two AD risk cohorts (35% male; 91% cognitively unimpaired; mean [standard deviation] age, 65.42 [7.78] years; education, 16.17 [2.23]) years). synSAA results were compared to phosphorylated tau (T), amyloid beta (A), and clinical outcomes. Longitudinal cognition was modeled with mixed effects. RESULTS Syn positivity (synSAA+) co‐occurred with T (in synSAA+ vs. synSAA−, 36% vs. 20% T+; P p = 0.011) and with cognitive impairment (10% vs. 7% mild cognitive impairment; 10% vs. 0% dementia; p = 0.00050). synSAA+ participants’ cognitive performance declined ≈ 40% faster than synSAA– for Digit Symbol Substitution, but not other tests. DISCUSSION Findings support prevalent syn copathology in a mostly unimpaired AD risk cohort. Relationships with progression should be evaluated once more have declined. Highlights In a middle‐aged sample, misfolded α alpha}}$ ‐synuclein (syn) co‐occurred with phosphorylated tau181 (T). syn+/T+ status was linked with higher levels of other cerebrospinal fluid biomarkers. syn+ individuals were more likely than syn– to be cognitively impaired. syn+ status was linked to faster decline on an executive function task.
Journals
2025 EN
Cummings Jeffrey · Cohen Sharon · Murphy Jennifer
+14 more
Abstract INTRODUCTION In EMERGE (NCT02484547), participants receiving aducanumab had significantly less progression versus placebo on all prespecified clinical endpoints at week 78. Here, we explicate the clinical meaningfulness of these treatment effects by analyzing item‐level data and the persistence of treatment benefit. METHODS Participants with early Alzheimer's disease (AD) were stratified by apolipoprotein E ( APOE ) ε4 status and randomized (1:1:1) to receive low‐ or high‐dose aducanumab, or placebo. Prespecified principal component analyses (PCAs) per the Statistical Analysis Plan were followed by post hoc examination of individual domains/items across all five clinical endpoints. Progression analysis assessed reduction in clinical decline. RESULTS High‐dose aducanumab demonstrated clinically meaningful slowing of progression across clinical endpoints measuring cognition, daily function, and behavioral symptoms. Delay of progression over 18 months was consistent across measures; treatment effects increased over time. DISCUSSION Across multiple analyses aducanumab slowed cognitive decline, prolonged functional independence, and attenuated behavioral symptoms in participants with early AD. These outcomes comprise the elements of a clinically meaningful response to treatment. Highlights Endpoints in EMERGE assessed different aspects of cognition, daily function, and behavioral symptoms. Treatment benefits were observed across subdomains on all five clinical endpoints. Aducanumab meaningfully slowed disease progression in participants with early AD.
Journals
2025 EN
Clark Daniel O. · Xu Huiping · Tangney Christy C.
+11 more
Abstract INTRODUCTION We report the feasibility and cognitive outcomes of a stage 1b randomized trial testing 3 months of home‐delivered high polyphenol snacks (e.g., nuts, berries) and online speed of processing training among older adults with 12 or fewer years of education. METHODS One hundred eighty participants were randomized to polyphenol‐rich snacks and online cognitive training, polyphenol snacks and online control games, control snacks and cognitive training, or control snacks and control games. The outcomes were feasibility of recruitment, retention, and adherence (RRA) and change in a cognitive composite score. RESULTS Feasibility goals for RRA were met. Improvements in the cognitive score were evident in all groups (effect sizes ranged from 0.15–0.35) but improvements did not differ significantly between arms. DISCUSSION Dementia prevention trials with longer intervention and follow‐up focused on adults with limited formal education should be considered given the observed cognitive gains in those with elevated risk. Clinical Trial Registration: ClinicalTrials.gov (NCT03419052). Highlights The study focused on adults with low education; a group with a high risk for cognitive decline. Two interventions were tested in a randomized trial design that included two controls. Nutrition intervention was designed with input from adults with limited education. Primary outcome: A cognitive composite score was formed from five established cognitive tests. The study establishes the feasibility of dementia prevention targeting adults with low education.