Alzheimer's & Dementia

INTRODUCTIONAlzheimers disease (AD) and frontotemporal dementia (FTD) have considerable clinical and pathological overlap. While plasma proteomics has advanced in AD, deep comparative analyses with FTD-particularly in diverse, biomarker-confirmed Asian cohorts-remain limited. METHODSPlasma from 101 individuals with known pTau217 status was profiled using Olink Explore-HT. Differential expression-pathway enrichment, penalized regression-GLMNET, single-cell transcriptomic integration, associations with cognitive measures and, cross-platform validation were performed. RESULTSAmong 5,400-proteins, 1,168 were differentially expressed in AD and 370 in FTD (FDR<0.05). Distinct and overlapping proteomic signatures were identified in AD and FTD, reflecting gliosis, synaptic dysfunction, immune activation, and metabolic pathways. Prioritized proteins correlated with cognitive performance and plasma phosphorylated tau, A{beta}42, and neurofilament light chain, linking circulating proteins to disease severity. Cross platform validation revealed strong concordance with large independent datasets. CONCLUSIONComprehensive plasma proteomics in Asian cohort supports scalable framework for blood-based biologically informed targets for precision diagnosis and therapeutic stratification.

INTRODUCTIONHerpes simplex virus-1 (HSV-1) has been implicated in Alzheimer disease (AD). METHODSReads from Alzheimers Disease Sequencing Project whole-genome sequencing data collected from brain (2,203 AD; 616 controls) and blood (8,908 AD; 15,768 controls) were aligned to viral genomes. Generalized linear mixed-models tested for the effect of HSV-1 DNA on AD, and we performed GWAS on HSV-1 presence and SNPxHSV-1 interaction effects on AD, adjusting for age, sex, tissue, library preparation, relatedness, and ancestry principal components. RESULTSAcross ancestry groups, HSV-1 DNA was consistently less frequent in AD cases; reads predominantly mapped to regions containing the latency-associated transcript region. DNA prevalence was lower in APOE-{varepsilon}4 carriers; HSV-1 was associated with reduced AD risk in {varepsilon}4 non-carriers but increased risk in carriers. GWAS identified host genetic influences on HSV-1 detection and interaction loci affecting AD risk. DISCUSSIONHSV-1 DNA showed an inverse association with AD and is affected by genetics.

Importance: APOE e4 is the strongest genetic risk factor for Alzheimer's disease (AD), yet its effect varies across ancestral populations. As blood-based biomarkers increasingly inform AD diagnosis, failure to account for both APOE genotype and ancestry could lead to misinterpretation of biomarker profiles and inaccurate diagnostic classification. Understanding how ancestry modulates APOE effects is crucial for ensuring accurate biomarker-based assessments and AD diagnosis. Objective: To determine whether genetic ancestry modulates APOE association with cognitive function, brain morphometry, and plasma biomarkers. Design, Setting, Participants: Cross-sectional analysis of community-dwelling older adults from the Health and Aging Brain Study-Health Disparities (HABS-HD) cohort (N = 2733). Participants spanning the cognitive spectrum underwent cognitive assessment, neuroimaging, plasma biomarker collection, and genome-wide genotyping from 2018 to 2023. Main Outcomes and Measures: Cognitive performance (global cognition, memory, executive function, verbal ability), brain morphometry (cortical thickness, hippocampal volume), and plasma biomarkers (AB42/AB40, pTau181, pTau217, total tau, NfL). Results: In the full cohort, APOE e4+ was associated with worse cognitive performance across all domains, reduced cortical thickness and hippocampal volume, lower AB42/AB40, and elevated pTau181 and pTau217. APOE e2+ was associated with lower pTau217. Ancestry-stratified analyses revealed attenuated e4+ effects on pTau217 and pTau181 in African compared with European participants (~2.5-fold for both), with the pTau217 difference surviving FDR correction. Compositional analysis confirmed that e4+ effects on pTau181 and pTau217 strengthened with increasing European ancestry proportion. Local ancestry analysis showed e4+ effects on pTau217 were significantly attenuated in individuals with African local ancestry at the APOE locus. In contrast, e4+ effects on AB42/AB40, cognition, and neuroimaging were largely consistent across ancestry groups. Meta-analysis with an independent multi-ancestry cohort replicated the attenuated pTau181 findings. Conclusions and Relevance: Genetic ancestry modifies the effect of APOE on AD endophenotypes. In particular, African ancestry attenuates the association between APOE e4+ and pTau181 and pTau217. Accurate AD diagnosis requires consideration of both APOE genotype and ancestry to avoid misclassification in biomarker-based evaluations.

Structured AbstractO_ST_ABSBackgroundC_ST_ABSSubjective cognitive decline (SCD) is associated with increased cognitive impairment and dementia. However, limited research has explored how amyloid (A) pathology contributes to these cognitive changes over time and whether these changes differ by sex. Methods1185 cognitively normal older adults (955 A-, 230 A+; 959 SCD-, 226 SCD+) from the National Alzheimers Coordinating Center dataset were included. Linear mixed effects examined the interactions between SCD, sex, and amyloid positivity in predicting cognitive decline. ResultsSCD+ and A+ individuals exhibited increased global cognition declines (p<.05), and A+SCD+ individuals showed the steepest decline in global cognition and function status (p<.05). A+ males exhibited increased functional deficits (p<.05), while A+SCD+ females exhibited increased language deficits (p<.05). DiscussionOur findings suggest that SCD and amyloid-positivity differentially impact global cognition, functional status, and language in males versus females, with important implications for clinical trials and therapeutic interventions. Highlights- Few studies have explored the independent and joint effects of amyloid and sex in SCD - SCD is associated with increased rates of global cognitive decline - Amyloid positive females with SCD exhibit increased language declines - Amyloid positive males exhibit increased functional status declines Research in ContextO_ST_ABSSystematic reviewC_ST_ABSWe reviewed the literature using traditional sources (e.g., PsycInfo, PubMed) and found that there are limited findings exploring longitudinal cognitive trajectories in people who are amyloid positive with SCD and whether these trajectories differ by sex. InterpretationOur findings suggest that SCD and amyloid positivity jointly interact to influence global cognitive and functional declines. Females experience language deficits when they have both SCD and amyloid positivity whereas males with amyloid positivity exhibit increased functional deficits. Together these findings suggest that SCD status and amyloid positivity differentially impact females and males. Future directionsMore research is needed using grouping amyloid, tau, neurodegeneration, and vascular pathologies together to explore the joint impact on cognitive change and conversion in people with SCD.

Structured AbstractO_ST_ABSINTRODUCTIONC_ST_ABSAPOE-{varepsilon}4 is the strongest common genetic risk factor for Alzheimers disease (AD), yet many carriers remain cognitively unimpaired into late life. We tested whether a protected-{varepsilon}4-first proteomic approach could identify plasma proteins associated with delayed clinical onset among {varepsilon}4 carriers. METHODSWe analyzed harmonized plasma proteomics from the Global Neurodegeneration Proteomics Consortium. Protected {varepsilon}4 carriers ({varepsilon}3/{varepsilon}4 aged [&ge;]75 years; {varepsilon}4/{varepsilon}4 aged [&ge;]65 years; CDR=0; n=456) were compared with {varepsilon}4 carriers with AD (n=1,096). Protein-wise linear models adjusted for age, sex, {varepsilon}4 dosage, and plasma proteomic principal components. Top signals were integrated with high-confidence loss-of-function burden testing and plasma/CSF Mendelian randomization. RESULTS{varepsilon}4 protected was associated with 721 protein levels. Integrated analyses prioritized proteins linked to {varepsilon}4-modified disease biology, including LILRA5, DBI, BPNT1, PTEN, EPHA1, and PCDH10, and proteins aligned with broader AD-related change, including OMG, SELENOW, VAT1, and TPPP3. TREM2 and ACE were also identified, providing internal biological validation of the approach. DISCUSSIONA protected-{varepsilon}4-first plasma proteomic strategy highlights immune, synaptic, metabolic-stress, and myelin/axonal pathways that may delay AD onset and helps prioritize candidate {varepsilon}4-specific modifiers for prevention-focused therapeutics.

Background and Objectives: In Lewy body disease (LBD), co-occurring Alzheimer's disease (AD) neuropathologic change (ADNC) is associated with worse clinical outcomes. While plasma pTau217 detects ADNC in LBD, its prognostic, monitoring, and risk-stratification utility remains unclear. We evaluated whether plasma pTau217 predicted cognitive and functional decline and risk for progression to MCI or dementia in LBD. Methods: We included 501 participants enrolled in the Stanford Alzheimer's Disease Research Center with plasma pTau217 data who were clinically diagnosed as LBD spectrum (n = 131), AD spectrum (n = 133), or healthy controls (HC; n = 237). To assess prognostic and monitoring utility in LBD, linear mixed-effect models tested continuous baseline and longitudinal (2-5 years) plasma pTau217 as predictors of change in 2-8-year clinical outcome trajectories including: daily functioning (CDR-SB), global cognition (MoCA), and five domain-specific cognitive indices. For risk-stratification in LBD, baseline plasma pTau217 was dichotomized using an amyloid PET-derived, LBD-specific cut-point to examine effects of abnormal versus normal levels on clinical outcomes in separate mixed-effects and survival models. Results: In LBD, higher continuous baseline plasma pTau217 predicted accelerated CDR-SB increase ({beta} = 0.29, p < 0.001), MoCA decline ({beta} = -0.37, p = 0.014), and cognitive index decline (memory, executive function, visuospatial function, processing speed; {beta}s = -2.24 to -0.06, ps [&le;] 0.01). Faster longitudinal pTau217 increase predicted accelerated CDR-SB increase ({beta} = 0.24, p = 0.001). In AD, higher continuous baseline pTau217 predicted accelerated CDR-SB increase and MoCA decline, whereas faster longitudinal increase predicted accelerated cognitive index decline (ps [&le;] 0.04). In HC, higher continuous baseline pTau217 predicted accelerated memory index decline (p = 0.008). In LBD, abnormal baseline pTau217 predicted a 0.87 points/year (95% CI: -1.62, -0.58) faster MoCA decline, 0.85 points/year (95% CI: 0.56, 1.14) faster CDR-SB increase, accelerated decline on cognitive indices, and a three-fold higher risk of progressing to MCI or dementia (HR = 3.41, 95% CI 1.60, 7.28, p = 0.002) compared to normal pTau217. Discussion: Plasma pTau217 is a promising prognostic, monitoring, and risk stratification biomarker of clinical progression in LBD, underscoring its utility in mixed pathology groups for clinical practice and trials.

Multiple plasma phosphorylated tau assays are now commercially available for detection of Alzheimers disease (AD) pathology, yet clinical laboratories lack a comprehensive comparative evaluation to guide implementation decisions. Diagnostic accuracy and analytical performance were assessed in a cohort of 273 participants with paired EDTA plasma and CSF specimens. CSF AD core biomarkers were used as the reference standard, and index tests included three plasma pTau217 assays by Roche, Fujirebio, and Meso Scale Discovery [MSD], and a pTau181 assay by Roche. Participants had a median age of 70 [IQR: 64-76] years, 42% were female and 60% were AD-positive. Diagnostic performance was statistically similar across all pTau217 assays (range: 0.88-0.89 area under the receiver operating characteristic curve [AUC]) with the pTau181 assay having lower accuracy (AUC = 0.85). All assays were resistant to hemolysis, icterus, and lipemia. Automated assays (Roche, Fujirebio) showed superior analytical precision and freeze/thaw stability ([&ge;]6 cycles) compared to the manual MSD assay (2 cycles). Given that plasma pTau217 assays demonstrated high and comparable accuracy in this head-to-head comparison, their differences in analytical performance characteristics and general clinical laboratory suitability became the differentiating factors for clinical implementation.

Background: Cognitive assessments are sparsely documented in electronic health records (EHRs), limiting scalable detection of cognitive worsening in real-world clinical settings. Methods: We applied a deep neural network optimized for identifying clinical event timing from sparsely labeled gold-standard data (label-efficient incident phenotyping from longitudinal EHR, LATTE) to predict time-to-first sustained cognitive worsening in AD patients from a large healthcare system (2011-2022) with linkage to an AD Research Center registry in a subset. Sustained cognitive worsening was defined as cognitive decline persisting over [&ge;]2 consecutive visits within 3 years. Separate LATTE models were trained with worsening labels from Clinical Dementia Rating (CDR), Mini-Mental Status Examination (MMSE), and Montreal Cognitive Assessment (MoCA) scores; semi-supervised learning scaled predictions to larger imputation cohorts lacking sufficient longitudinal scores. We evaluated model performance using average time-specific area under the receiver operating characteristic curve (AUC), area between curves (ABC), and Brier scores. To demonstrate clinical utility, we examined whether predicted time-to-worsening differentiated clinically meaningful patient subgroups using competing-risk Cox proportional hazards models accounting for death. Findings: The cohort comprised 27,614 AD patients (65% women, 91% non-Hispanic White, mean [SD] age at start of follow-up 78.76 [9.53] years). In gold-standard cohorts (n: CDR=632, MMSE=710, MoCA=752; remaining patients formed imputation cohorts), LATTE demonstrated robust predictive performance (average time-AUC: CDR 0.816, MMSE 0.694, MoCA 0.710; ABC: CDR 0.067, MMSE 0.293, MoCA 0.078; Brier score: CDR 0.252, MMSE 0.437, MoCA 0.295). APOE-{varepsilon}4 carriers had shorter predicted time-to-worsening compared to non-carriers across all assessments in the imputation cohorts (HRs 1.241-1.376, all p<0.025), and k-means derived patient clusters showed differential time-to-worsening in the overall and imputation cohorts (HRs 0.777-0.908, all p<.001). Interpretation: LATTE enables scalable prediction of sustained cognitive worsening timing, differentiating clinically meaningful patient subgroups. This approach could improve AD clinical monitoring and decision-making in routine care and support targeted clinical trial enrichment.

Background: The Alzheimer's Disease Sequencing Project Gene Verification Committee developed a systematic framework to adjudicate genetic evidence for AD and related dementias, addressing wide variation in association quality. Methods: Phase 1 established tiered criteria by evaluating 23 nominated loci across study designs. Phase 2 applied this framework to 29 large-scale genome-wide studies published since 2015, tiering 163 unique loci. Results: Phase 1 yielded 17 high-confidence loci (12 linked to specific genes), and Phase 2 identified 111 high-confidence loci/genes with replicated associations across ancestries and convergent single-variant/variant-set evidence. Prioritized loci highlight APP processing, microglial immunity, and lipid metabolism pathways, including genes not captured by existing resources like Agora or Open Targets. Summarized results can be viewed at https://topgenes.niagads.org/. Conclusion: This rigorously adjudicated catalog represents the most comprehensive AD/ADRD genetics resource to date, providing a foundation for functional validation and therapeutic discovery with broad applicability to complex diseases.

Introduction: Alzheimers disease and related dementias (AD/ADRD) pathology begin decades before diagnosis, yet scalable risk detection infrastructures for midlife adults remain limited. The Biomarker Evaluation of Young Onset Dementia from Diverse Populations (BEYONDD; R56AG075744) pilot study was designed to address this gap through a decentralized, community-engaged research (CER) model for neurodegenerative risk detection in midlife adults with subjective cognitive or behavioral complaints (sCBC). Methods: This cross-sectional pilot assessed the feasibility of CER-based digital recruitment and participant completion of remotely-acquired screening, cognitive, clinical, and phlebotomy assessments with support of Community Research Navigators (CRNs). Feasibility was evaluated using digital recruitment metrics, yield, retention, and geographic reach. Results: Our approach generated 1.8+ million advertisement impressions,161,100 clicks, and 4,089 web-registrants. 2,117 individuals completed the online screener, exceeding the prespecified screening goal by 141%. We enrolled a multi-ethnic, midlife cohort of 579 participants (Mage=51.6[6.5]; 75% female; 44% Latinx, 31% non-Latinx Black-American, and 26% all other race/ethnicities), exceeding the enrollment goal by 290%, and 476 participants completed the remote protocol (82% retention). Participants were recruited from 49 U.S. states, Puerto Rico, Australia, and Canada. CRN engagement was concentrated during study stage transitions. Discussion: BEYONDDs decentralized, CER-based screening infrastructure demonstrated wide geographic reach, strong early-stage engagement, and efficient recruitment among diverse midlife adults. These findings support the feasibility of scalable CER-based digital recruitment for decentralized early detection initiatives and AD/ADRD trials.

INTRODUCTION: Synaptic markers are altered in the CSF of Alzheimer's disease (AD) patients, but their quantification in plasma remains challenging. We evaluated plasma synaptic markers in MCI and mild AD using the nucleic acid linked immunosandwich assay (NULISA) and their correlation with APOE genotype. METHODS: 272 participants (154 CSF confirmed AD, 118 controls) underwent plasma assessment with the NULISA CNS panel. A subset (n=48) also had CSF measurements. Analyses were adjusted for age, sex, comorbidity, and renal function. RESULTS: NULISA revealed plasma alterations in NPTX2, NPTXR, SNAP25, and VSNL1 in AD, with SNAP25 and NPTXR already altered at MCI stage. APOE e4/e4 carriers showed higher plasma SNAP25. Plasma SNAP25 and NPTXR correlated positively with pTau217. No plasma/CSF concordance was observed. DISCUSSION: NULISA identifies plasma synaptic biomarker alterations in early AD, with APOE e4 influencing SNAP25 levels. Associations with pTau217 suggest a link between synaptic damage and tau phosphorylation. Longitudinal studies are warranted.

Large-scale plasma proteomics can capture molecular changes across the Alzheimers disease (AD) continuum and provide insight into biological mechanisms associated with AD pathology. We analysed the Bio-Hermes cohort (n = 961), with participants enrolled across 17 sites in the United States from April 2021 to November 2022. Participants were stratified by clinical status and amyloid PET scan-based Core1 biomarker status (CN Core1-, CN Core1+, MCI Core1+, and AD dementia Core1+). We performed differential abundance analyses across biologically defined contrasts, clustered proteins into co-expression networks, and evaluated protein panels to distinguish participants with biologically defined AD from amyloid-negative cognitively normal controls. We also used Mendelian randomization (MR) to assess genetic evidence for potential causal relationships with AD risk. The biologically defined contrast, Core1+ vs. CN Core1-, identified 69 differentially abundant proteins. Across AD stages, eight core proteins were consistently dysregulated from preclinical through prodromal and dementia phases, and three additional proteins emerged at MCI Core1+ and remained altered in AD dementia Core1+. We identified 29 co-expression modules, six of which varied significantly across the AD continuum. Among differential abundance proteins, ACHE ranked highest for distinguishing biologically defined AD from CN Core1-. Stage-specific protein panels improved the discriminatory performance for MCI Core1+ (AUC = 0.850) and AD dementia Core1+ (AUC = 0.856). MR provided genetic evidence consistent with an association between plasma ACHE abundance and AD risk. Plasma proteomics delineated a stage-spanning core signature across the AD continuum. These findings nominate co-expression modules and candidate proteins for further validation in early detection and AD screening.

BackgroundDetection of cerebral amyloid pathology currently requires amyloid PET imaging ($5,000-$8,000) or cerebrospinal fluid analysis via lumbar puncture, procedures that are inaccessible for population-level screening. The FDA-cleared Lumipulse G pTau217/A{beta}1-42 plasma ratio test (May 2025) represents the first approved blood-based alternative; however, single-ratio approaches cannot distinguish Alzheimers disease (AD) from non-AD neurodegeneration or provide multi-dimensional disease characterization. MethodsWe developed Virtual Spectral Decomposition (VSD), a framework that decomposes plasma biomarker profiles into biologically interpretable diagnostic channels. Four plasma biomarkers--phosphorylated tau-217 (pTau217), amyloid-{beta}42/40 ratio, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP)--were measured in 1,139 Alzheimers Disease Neuroimaging Initiative (ADNI) participants. Each biomarker was mapped to a VSD channel representing a distinct pathophysiological axis: tau/amyloid phosphorylation, amyloid clearance, neurodegeneration, and astrocytic activation. Channel weights were calibrated via logistic regression, and performance was evaluated against amyloid PET (UC Berkeley) using 10x5-fold repeated cross-validation. ResultsVSD 4-channel fusion achieved AUC = 0.900 ({+/-}0.018), exceeding pTau217 alone (0.888{+/-}0.022). Optimal sensitivity was 89.7% with 78.1% specificity (NPV = 90.8%). The NfL channel received a negative weight ({beta} = -1.1), functioning as a disease-exclusion signal: elevated neurodegeneration without amyloid-tau coupling actively reduces the AD probability, distinguishing AD from non-AD neurodegeneration. Complementary CSF proteomics analysis (7,008 proteins, 533 participants) identified 17 amyloid-specific proteins (0.24% of the proteome), revealing a 49:1 tau-to-amyloid asymmetry that explains why blood-based tau markers outperform amyloid markers. ConclusionsBlood-based VSD provides an interpretable, multi-channel framework for amyloid detection that incorporates explicit disease-exclusion logic unavailable to single-biomarker approaches. The architecture extends to multi-disease screening, where the same blood specimen could be routed through disease-specific modules for AD, Parkinsons disease, and cancer.

BackgroundAlzheimers disease (AD) exhibits marked sex differences. While sex hormone levels across the lifespan likely contribute to this, little remains known about their causal impact and their relation to sex-biased genetic risk for AD. We therefore sought to identify potential shared genetic architectures, as well as causal genes and relationships, between sex hormone-related traits and AD risk. MethodsLarge-scale AD sex-stratified genome-wide association study (GWAS) results were available from case-control, proxy-based, and population-based cohorts, including the Alzheimers Disease Genetics Consortium, Alzheimers Disease Sequencing Project, UK Biobank, and FinnGen. Sex hormone-related trait GWAS were available for age at menarche, menopause, and voice breaking, as well as testosterone, sex hormone-binding globulin (SHBG), progesterone, follicle stimulating hormone, luteinizing hormone, and estradiol levels. Cross-trait conjunctional analyses were conducted to identify pleiotropic overlap between sex-hormone traits and AD, followed by prioritization of candidate causal sex-biased AD genes through quantitative trait locus genetic colocalization analyses. The potential regulatory impact of sex hormones on these genes was assessed through transcription factor motif analyses. Finally, sex-stratified mendelian randomization analyses were used to infer causal effects of sex hormones on AD risk. ResultsGenome-wide pleiotropy analyses demonstrated enrichment of AD with testosterone, SHBG, and age-at-menarche traits in women. We identified 12 high-confidence pleiotropic loci, 9 of which showed stronger AD effect sizes in women (3 in men) and 8 that were novel. Genes at these loci were often causally implicated in brain tissues and enriched for promoter-associated androgen receptor transcription factor binding motifs. Mendelian randomization indicated higher bioavailable testosterone in women (OR:0.88; 95%-CI:0.82-0.96) and higher SHBG levels in men (OR:0.86; 95%-CI:0.77-0.96) were associated with lower AD risk. ConclusionsOur findings reveal sex-specific shared genetic architectures between AD and sex hormone-related traits and nominate related genes that may drive sex-biases in AD risk. Several of the implicated female-biased genes are relevant to phosphatidylinositol and lipid metabolism, including Fatty Acid Desaturase 2 (FADS2). While we observed no causal effect of estradiol-related traits on AD risk, the protective effects of bioavailable testosterone in women and SHBG in men provide targets for sex-informed AD risk stratification and prevention strategies.

BackgroundThe apolipoprotein E (APOE) locus is the strongest genetic risk factor for late-onset Alzheimers disease (AD). Variation in APOE isoforms is known to have diverse pleiotropic effects on circulating lipids and other metabolites, but effects on the circulating proteome across the life course are not well characterised. We investigated the specific effects of APOE {varepsilon}4 and APOE {varepsilon}2 carriage on the circulating proteome in middle-age and later life. MethodsIn primary modelling, we analysed associations of APOE {varepsilon}4 and {varepsilon}2 carriage (reference {varepsilon}3/{varepsilon}3) with circulating proteins in UK Biobank participants (N = 42,642; age = 39.1 to 70.9 years). Using multivariable linear regression, we conducted ancestry-specific analyses of 2,922 assayed plasma proteins across individuals of European (EUR), African (AFR), and South Asian (SAS) ancestry. To identify age-dependent effects, stratified analyses were performed with the sample split into age groups. We then performed replication analyses of APOE-associated proteins in age-matched groups, using data from two independent UK-based cohorts. ResultsWe identified 351 proteins associated with {varepsilon}2 carriage and 480 with {varepsilon}4 carriage among individuals of European ancestry (n = 40,092); 130 of these were associated with both {varepsilon}2 and {varepsilon}4 carriage (with either consistent or inverse association directions). These included established biomarkers of neurodegeneration (GFAP and NEFL) and other proteins implicated by AD genetic risk loci (e.g., TREM2, CTSB, IDUA, SORT1, GRN). Many of these proteins are linked to other neurodegenerative diseases besides AD. In multiple age groups, {varepsilon}4 carriage was strongly associated with consistent differences in circulating APOE, MENT, and PLA2G7 levels across ancestries and cohorts. ConclusionAPOE {varepsilon}4 and {varepsilon}2 exert broad, often age-dependent effects on the plasma proteome, detectable decades before typical ages of AD diagnoses, highlighting a potential early window for monitoring and intervention.

Importance: Broadening access to biomarker-informed risk stratification in mild cognitive impairment (MCI) has become even more critical to early assessment in Alzheimer disease given recent developments in regulatory approvals of disease-modifying therapies and advancements of blood-based biomarkers. This requires accessible approaches that can be deployed at scale to better differentiate the disease biology from the clinical progression risk prediction. While entorhinal tau positron emission tomography (PET) can refine near-term prognostic assessment, the cost and logistic burden of imaging limit broad clinical use. Objective: Evaluate whether a brief informant-reported screen derived from the Functional Activities Questionnaire (FAQ) could better stratify scalable biologically anchored prognostic information for 3-year progression from MCI to Alzheimer disease dementia. The primary study was designed around FAQ-derived screens performance relative to entorhinal tau PET standardized uptake value ratio (SUVR), plasma phosphorylated tau 217 (p-tau217) and Mini-Mental State Examination (MMSE) score. Secondary analyses evaluated the stable FAQ-derived screen selected for clinical risk separation, tau and amyloid PET biological context, additional plasma biomarkers, resource-use scenarios and sensitivity analyses around subgroups, calibration, decision-curve, survival, timing, early-progressor exclusions and endpoint-ascertainment IPW. Design, Setting, and Participants: This retrospective secondary progression risk prediction study analyzed 350 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants with a baseline clinical diagnosis of MCI at the tau PET anchor visit. All studies were conducted in cohorts with 3-year progression status known. The first primary benchmarking included 157 participants (including 32 progressors) for FAQ with entorhinal tau PET SUVR comparisons and 153 participants (including 31 progressors) for FAQ, entorhinal tau PET SUVR and MMSE comparisons. The second primary benchmarking was derived from a smaller UPENN plasma p-tau217 subset of 66 participants (including 13 progressors). Exposures: The FAQ-derived candidate screens were evaluated by leakage-controlled repeated nested cross-validation. The stable 3-item FAQ-derived screen selected was defined as any informant-reported difficulty in at least one of the three activities comprising finances/checkbook, shopping and games/hobbies ("Locked FAQ Trio"). The Locked FAQ Trio was compared against both biological and cognitive comparators: entorhinal tau PET SUVR, plasma p-tau217 and MMSE score. Amyloid PET status and Centiloid burden as well as plasma biomarkers paired per same-file plasma such as A{beta}42/40 ratio, glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL) and a directionally adjusted 4- marker plasma composite were used for biology or exploratory context and not for defining the clinical endpoint. Main Outcomes and Measures: The primary binary endpoint was progression from baseline MCI at the tau PET anchor visit to Alzheimer disease dementia within 3 years. Model performance used the cross-validated area under the receiver operating characteristic curve (AUC), the difference in AUC ({Delta}AUC) was bootstrap 95% confidence intervals (CI) at the participant level with P values adjusted using the Benjamini-Hochberg (BH) procedure. Other measures included Brier scores, calibration summaries, survival discrimination and operating characteristics such as sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and screen-positivity prevalence, while decision-curve analyses and resource-use scenarios remained exploratory. Results: A leakage-controlled nested cross-validation selection repeatedly identified a 3-item screen defined as any difficulty in at least one of the three following activities comprising finances/checkbook, shopping and games/hobbies (Locked FAQ Trio). In an independent 3-year progression benchmark analysis of base-covariate models, the Locked FAQ Trio showed higher numerical, directional but not statistically significant, discrimination than entorhinal tau PET among 157 participants including 32 progressors (AUC, 0.787 vs 0.780; {Delta}AUC, +0.007; 95% CI, -0.099 to 0.113; BH-adjusted P = 0.926) and was statistically significantly higher than MMSE score (AUC, 0.796 vs 0.637; {Delta}AUC, +0.159; 95% CI, 0.045 to 0.276; BH-adjusted P = 0.029). The Locked FAQ Trio was positive in 37.6% of participants and captured 27 of 32 progressors, showing sensitivity of 84.4%, specificity of 74.4%, PPV of 45.8%, and NPV of 94.9%. Progression within 3 years occurred in 45.8% of screen-positive participants versus 5.1% of screen-negative participants and the corresponding adjusted hazard ratio over full follow-up was 7.46. The screen was also associated with higher entorhinal tau burden and remained consistent across survival, timing-sensitive, amyloid and missingness analyses. A different 3-item FAQ-derived companion screen ("Companion FAQ Trio") was evaluated for sensitivity, it was defined as any impairment in at least one of the three activities comprising forms/papers, shopping and remembering appointments/medications/holidays. The Companion FAQ Trio was positive in 54.1% participants and captured 96.9% of progressors, with 36.5% of screen-positive progressing to dementia versus 1.4% of screen-negative. In a second primary benchmark analysis of a smaller matched plasma subset of 66 participants including 13 progressors, plasma p-tau217 showed the highest discrimination (AUC, 0.890) across all single predictors in a base-covariates model, compared with the Locked FAQ Trio (AUC, 0.749) and entorhinal tau PET SUVR (AUC, 0.798). A stratification study of the Locked FAQ Trio combined with p-tau217 showed separation of observed risk, differentiating lower and higher risk of progression per strata. Notably, none (0 of 31) of the participants in the lower risk cohort progressed and 64.3% (9 of 14) of participants in the higher risk cohort progressed. Nevertheless, 37.5% (3 of 8) of participants in the Locked FAQ Trio-negative/p-tau 217-high cohort progressed. This emphasizes that patients should not be excluded from further biomarker testing when clinical concern remains. Conclusion: A brief 3-item stable FAQ-derived screen was identified as a compelling front-end additional layer to prognostic triage in MCI patients. This Locked FAQ Trio screen demonstrated a higher numerical discrimination than entorhinal tau PET SUVR in 3-year base-covariates prediction risk models. Plasma p-tau217 remained the strongest scalable predictor of progression to dementia in a smaller plasma subset. These findings reinforce that adding a brief functional screen to the staged prognosis assessment triage pathway can help prioritize and contextualize biomarker escalation, offering a scalable, deployable, and low burden solution to expand screening to a broader patient population.

IntroductionApoE4 is the strongest genetic risk factor for Alzheimers disease (AD). Emerging evidence suggests that ApoE4 increases AD risk by disrupting microglial metabolism and function. However, whether ApoE lipidation state contributes to microglial dysfunction remains poorly understood. MethodsHuman microglia were treated with lipid-free or lipid-bound ApoE3 or ApoE4. Label-free live-cell holotomography and global proteomics were used to assess isoform- and lipidation-specific effects on lipid droplet dynamics, mitochondrial morphology, and microglial phenotype. ResultsApoE4 treatment resulted in fewer but enlarged lipid droplets and increased mitochondrial fragmentation compared to ApoE3, effects that were enhanced by lipid-bound ApoE4. Proteomic analyses revealed a strong type I interferon response in cells exposed to lipid-free ApoE, which was exacerbated by lipid-free ApoE4. DiscussionThese findings indicate that lipid-bound ApoE4 drives metabolic reprogramming, whereas lipid-free ApoE4 promotes inflammatory signaling, identifying ApoE lipidation as a critical modifier of ApoE4-associated AD risk.

Background Autosomal dominant Alzheimer's disease (ADAD) serves as a model for presymptomatic biomarker discovery. Characterising the temporal profile of plasma biomarker levels in presymptomatic individuals may enhance understanding of disease pathogenesis, inform future clinical trials, and guide clinical interpretation. Methods We evaluated 124 proteins using a NUcleic acid-Linked Immuno-Sandwich Assay (NULISA) panel in 270 plasma samples from a longitudinal cohort study of ADAD, comprising 113 individuals (73 mutation carriers and 40 non-carriers). We determined the plasma proteomic changes that distinguished mutation carriers from non-carriers. We then used predicted age at symptom onset to determine the approximate timing of presymptomatic divergence in biomarker levels in carriers relative to non-carriers. Results Nine proteins (A{beta}42, BACE1, GFAP, pTau181, pTau231, pTau217, MAPT, NfL, and AChE) robustly differed between carriers and non-carriers, cross-sectionally. Longitudinal analyses showed A{beta}42 levels were elevated in carriers at least 26 years before expected symptom onset. Carriers diverged from non-carriers in phosphorylated tau markers at 21-24 years before expected symptoms, total-tau at 19 years, GFAP and BACE1 at 14 years, and NfL at 6 years. Differences in AChE were seen in symptomatic individuals, likely reflecting cholinesterase inhibitor use. Conclusion Multiple plasma proteins are elevated in presymptomatic and symptomatic autosomal dominant AD mutation carriers relative to non-carriers. Changes in eight biomarkers occur sequentially from 26 to 6 years prior to symptom onset. Combining biomarkers may help in staging presymptomatic AD and optimise clinical trial inclusion. Further work is needed to assess how these findings generalise to non-monogenic AD.

BackgroundCharacterizing longitudinal patterns of brain atrophy that distinguish Alzheimers disease (AD) and related neurodegeneration along with normative aging remains a major challenge. We aimed to identify data-driven longitudinal brain atrophy components and evaluate their associations with plasma AD biomarkers and cognitive outcomes in a community-based cohort. MethodsWe analyzed 756 MRI scans from 300 participants in the Framingham Heart Study (mean 2.52 scans per participant; range 2-4). Linear mixed-effects models were used to identify MRI features associated with diagnostic group (cognitively normal [CN], mild cognitive impairment [MCI], and dementia). Significant features (n=211) were entered into a longitudinal multivariate decomposition framework (ANOVA Simultaneous Component Analysis with Assorted Linear functions; ALASCA) to derive principal components (PCs) capturing patterns of structural change over time. Associations between PCs and plasma AD biomarkers (p-Tau181, total Tau(t-Tau), glial fibrillary acidic protein [GFAP], neurofilament light chain [NfL], amyloid-{beta}40 [A{beta}40], and amyloid-{beta}42 [A{beta}42]) were evaluated using multivariable mixed-effects models adjusted for age, sex, education, and APOE {varepsilon}4 status. Cognitive measures and neuroethological measures in a subset were used to assess the functional relevance and biological associations, respectively. ResultsThe first three PCs explained [~]95% of the variance within the modeled MRI feature (n=211) set (PC1: 75.8%, PC2: 13.8%, PC3: 5.4%). PC1 captured medial temporal atrophy involving hippocampal subfields and basolateral amygdala and was associated with worse cognition and higher plasma AD biomarkers. Neuropathological analyses showed stronger associations of PC1-related atrophy with AD-related tau pathology in the absence of concomitant TDP-43 pathology. In contrast, PC2 reflected diffuse cortical gray-white matter contrast alterations across association cortices and showed distinct associations with biomarkers and cognition compared to PC1, consistent with overlapping aging- and neurodegeneration-related processes. PC3 showed limited variance and no consistent associations. ConclusionLongitudinal MRI-derived components capture distinct patterns of brain structural change associated with neurodegeneration. Medial temporal trajectories are closely associated with AD and related dementia, whereas cortical alterations likely reflect mixed aging- and disease-related processes. Integration of structural MRI with plasma biomarkers provides complementary information on disease expression and heterogeneity, supporting multimodal approaches for disease characterization and risk stratification.

INTRODUCTIONAlpha-synuclein (Syn) is the most common co-pathology in Alzheimers disease (AD), yet its role within the amyloid-tau-neurodegeneration (ATN) cascade is unknown. METHODSWe analyzed 636 ADNI participants with CSF Syn seed amplification assay, amyloid PET, regional tau PET (Braak I-VI), structural MRI, and cognitive composites. Interaction models tested whether Syn modifies the amyloid-tau and tau-cognition associations. RESULTSSyn positivity (19.0%) amplified the amyloid-tau association across all Braak stages (meta-temporal interaction {beta} = 0.258, 95% CI 0.104-0.411, p = 0.001), with strongest effects in Braak III-IV. Syn did not modify tau-cognition associations in any domain (all interaction p > 0.18). DISCUSSIONSyn co-pathology selectively amplifies amyloid-driven tau propagation without modifying downstream tau-cognition relationships, identifying a node-specific effect within the ATN cascade with implications for patient stratification. Research in ContextO_ST_ABSSystematic reviewC_ST_ABSWe searched PubMed for studies combining -synuclein seed amplification assays with amyloid and tau PET in Alzheimers disease. One recent study (Franzmeier et al., 2025) demonstrated that -synuclein co-pathology accelerates amyloid-driven tau accumulation. No study has examined whether -synuclein modifies the downstream tau-cognition relationship or assessed regional tau specificity across all Braak stages. InterpretationIn 636 ADNI participants, -synuclein co-pathology amplified the amyloid-tau association across all Braak stages but did not modify tau-cognition relationships. This dissociation identifies -synuclein as a node-specific modifier of the ATN cascade, acting at the amyloid-to-tau transition. Future directionsLongitudinal studies with serial tau PET and -synuclein SAA are needed to establish temporality. Clinical trials should evaluate whether -synuclein stratification improves prediction of anti-amyloid treatment response.