Alzheimer's & Dementia

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.

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.

Blood-based biomarkers could transform Alzheimer disease (AD) detection by enabling scalable, less invasive assessment of underlying pathology, yet their applicability across globally diverse populations remains uncertain. We systematically reviewed 168 publications comprising 139 independent cohorts from Asia, Europe, North America, South America, Africa and Oceania. Random-effects meta-analyses pooled log-transformed ratios of mean biomarker concentrations for AD versus cognitively unimpaired individuals, mild cognitive impairment versus cognitively unimpaired individuals, and amyloid-{beta} PET-positive versus amyloid-{beta} PET-negative individuals. p-tau217, p-tau181 and glial fibrillary acidic protein showed the largest and most consistent group differences. In clinically defined comparisons, p-tau181 separation in mild cognitive impairment was lower in predominantly Asian than White cohorts, whereas glial fibrillary acidic protein separation in AD was higher in predominantly Asian cohorts. No significant between-population differences were observed in amyloid-defined comparisons. These findings support leading blood biomarkers as globally relevant indicators of AD pathology, but rigorous harmonized validation is needed before thresholds can be translated into equitable clinical practice.

INTRODUCTION: Knowledge about how Alzheimer's disease (AD) and AD-related dementia (AD/ADRD) plasma biomarkers relate to global and domain-specific cognitive functioning across diagnostic groups remains limited, particularly in heterogeneous, community-dwelling populations with multiple comorbidities. METHODS: We evaluated associations between baseline plasma biomarker levels (A{beta}42/40, p-tau181, p-tau217, NfL, GFAP) and cognitive performance at baseline and longitudinally (up to 7 years). Participants (n=590) enrolled in the Wake Forest Alzheimer's Disease Research Center Clinical Core (314 cognitively unimpaired [CU]; 206 mild cognitive impairment [MCI]; and 70 dementia) completed annual cognitive assessments including the Uniform Data Set (UDSv3; NACC). Domain-specific cognitive composites including memory, executive function, attention, language, visuospatial ability, and phonemic fluency, as well as a modified Preclinical Alzheimer's Cognitive Composite (PACC5), were evaluated. General linear and mixed-effects models were adjusted for demographics (age, sex, race, education), APOE-{epsilon}4 status, comorbidities (estimated glomerular filtration rate; BMI), and cardiometabolic health factors (hypertension, diabetes). Effect modification by cognitive diagnosis was evaluated. RESULTS: Baseline plasma biomarkers, particularly p-tau217, were associated with poorer baseline cognitive performance and greater longitudinal decline on the PACC5 and all cognitive domains assessed, except phonemic fluency (strongest for memory). Post-hoc analyses indicated associations between plasma biomarker levels and cognition were generally more pronounced in MCI compared with CU participants. Effect modification by baseline cognitive status was limited and attenuated when all biomarkers were modeled simultaneously. Comorbidities and cardiometabolic factors modified select associations. DISCUSSION: Plasma AD/ADRD biomarkers, particularly p-tau217, were associated with cognitive impairment and decline in a heterogenous community cohort.

Blood-based biomarkers have expanded access to biologically supported diagnosis of Alzheimer's disease (AD), particularly through measurement of amyloid-beta (Abeta) and phosphorylated tau species. Among these, plasma tau phosphorylated at threonine 217 (p-tau217) is currently the leading biomarker recommended by clinical guidelines. However, circulating p-tau217 originates from both central nervous system (CNS) and peripheral tissues, potentially limiting specificity, particularly in individuals with common age-related comorbidities. Here we report a next-generation biomarker, brain-derived p-tau217%, which quantifies the proportion of circulating tau that is CNS-derived and phosphorylated at threonine 217. Across neuropathologically defined, Abeta- and tau-neuroimaging-characterized, and memory clinic cohorts, brain-derived p-tau217% consistently identified AD pathology and clinical AD with larger effect sizes, higher discriminative accuracy, and improved sensitivity and specificity, outperforming conventional non-CNS-selective plasma p-tau217, p-tau217/Abeta1-42 and p-tau217% alternatives as well as brain-derived-p-tau217 alone. Furthermore, the CNS-selective biomarker demonstrated more robust prediction of future clinical progression in individuals followed for up to two decades. Importantly, diagnostic performance remained high in older adults with diabetes and cardiovascular disease, populations in which standard p-tau217 showed reduced specificity. Moreover, superiority extended to comparisons against multiple CNS disease-related proteins in targeted proteomic analyses. These findings establish plasma brain-derived p-tau217% as a biologically grounded and clinically robust biomarker that advances molecular definition, detection, and prognosis of Alzheimer's disease.

INTRODUCTION: The Framingham Risk Score (FRS) indexes cardiovascular risk (CVR), but age weighting may confound associations with brain and cognitive outcomes. METHODS: In 923 amyloid-positive ADNI participants, we compared FRS against a Multiple Indicators Multiple Causes (MIMIC)-derived age-adjusted measure (CVRmimic) using sex-stratified linear mixed efefcts (LME) and latent growth curve mediation (LGCM) models of hippocampal-to-ventricle ratio (HVR) - cognitive coupling. RESULTS: FRS predicted hippocampal atrophy in all six LGCM models; CVRmimic in none of the six. HVR - cognitive coupling held in four of six FRS and four of six CVRmimic models. Indirect effects reached significance in four of six FRS and none of the six CVRmimic models. LME 3-way interactions (years x risk x HVR) survived FDR correction in all six FRS versus none of the six CVRmimic models. DISCUSSION: FRS "effects" on hippocampal-cognitive decline largely reflect age-related variance. Age adjusted measures complement FRS by isolating cardiovascular effects from aging.

BackgroundIn preclinical Alzheimers disease (pAD), regional patterns of amyloid-{beta} (A{beta}) deposition are well characterized but it is unclear how this process varies across functional networks. ObjectiveDetermine how A{beta} accumulation in functional networks ("network-amyloid burden" [NAB]) varies by age, network type (cognitive vs. non-cognitive), and A{beta} status (A{beta}+/A{beta}-), and relates to cognition. Methods157 cognitively unimpaired adults (45-84 years; n=28 A{beta}+ per neuroradiological read) underwent brain MRI, amyloid PET (18F-florbetapir), and neuropsychological testing. NAB was calculated as the mean standard uptake value ratio within 7 networks categorized as cognitive (fronto-parietal, default mode, ventral and dorsal attention, limbic) or non-cognitive (somato-motor, visual). Linear mixed models tested how NAB varies across age, networks (by type and each separately), A{beta} status, and their interactions, and relationships between NAB and cognition. ResultsNAB increased with age, most prominently in fronto-parietal and default mode networks. NAB was higher in cognitive than non-cognitive networks, and this difference was more pronounced in A{beta}+ individuals. NAB was not significantly associated with cognition. ConclusionsCognitive brain networks are more vulnerable to amyloid accumulation with aging and in pAD than non-cognitive networks. Cognitive NAB may be useful for early detection and as a target for intervention in pAD.

Importance: Alzheimer disease (AD) pathogenesis begins decades before clinical symptoms, yet environmental determinants of early disease risk, particularly during fetal development, remain largely uncharacterized. Prenatal exposure to dichlorodiphenyldichloroethylene (DDE), the primary persistent metabolite of DDT, is a biologically plausible early-life contributor to AD risk given long half-life in human tissue and higher levels observed in AD patients. However, prospective human evidence linking prenatal DDE to midlife AD-relevant outcomes is absent. Objective: To determine whether prenatal DDE exposure is associated with plasma AD biomarkers and cognitive performance in early midlife offspring, and whether APOE {epsilon}4 genotype modifies these associations. Design: Observational cohort analysis nested within the Child Health and Development Studies (CHDS), a population-based birth cohort. Setting: CHDS enrolled pregnant women between 1959-1967 in the San Francisco Bay Area. Participants: Among 367 eligible adult offspring who participated in a follow-up study (2010-2013) at mean age 49.3 years, 179 with available prenatal DDE measurements were included. Main Outcomes and Measures: Prenatal DDE levels from maternal serum. Primary outcomes were plasma A{beta}42/40 ratio and Digit Symbol Substitution Test (DSST) performance. Secondary outcomes included plasma pTau217, GFAP, NfL and APOE genotype. Results: Among 179 participants (56% female; 26% APOE {epsilon}4 carriers), mean prenatal DDE was 47.4 (25.4) ng/mL. Higher prenatal DDE was associated with lower DSST scores ({beta}=-0.021, 95% CI, -0.041 to -0.001, P=0.039) and lower plasma A{beta}42/40 ratio ({beta}=-0.079, 95% CI, -0.133 to -0.024, P=0.005) per ng/mL DDE, adjusting for sex, race, education, and APOE {epsilon}4 status. Associations were strongest among APOE {epsilon}4 non-carriers for DSST ({beta}=-0.033, 95% CI, -0.050 to -0.016, P=0.001) and A{beta}42/40 ratio ({beta}=-0.101, 95% CI, -0.161 to -0.040, P=0.001). No significant associations were observed for pTau217, GFAP, or NfL. Conclusions and Relevance: In this prospective birth cohort study, prenatal exposure to a persistent environmental toxicant was associated with lower plasma A{beta}42/40 ratio and worse cognitive performance in early midlife, consistent with DDE accelerating the preclinical trajectory of AD-related biological changes decades before symptom onset. These findings support a life-course framework for AD risk and identify prenatal DDE as a potentially modifiable determinant of early AD-related pathology amenable to prevention.

Amyloid plaques are a hallmark neuropathological feature of Alzheimers disease (AD), composed of insoluble amyloid beta (A{beta}) peptide. A{beta} undergoes post-translational modifications that alter their biophysical properties, aggregation kinetics, and neurotoxicity, creating a heterogeneous pool of species that differentially affect AD pathogenesis. Pyroglutamate-modified A{beta} (pEA{beta}) is a particularly aggregation-prone and proteolytically resistant variant that preferentially accumulates within plaque cores, is implicated in early plaque seeding, and is a major target of emerging anti-amyloid immunotherapies. However, the molecular environment surrounding pEA{beta} versus unmodified A{beta} (pan-A{beta}) in the human hippocampus remains incompletely defined. Here, we used Biotinylation by Antibody Recognition (BAR), an in-situ proximity labeling approach, to map and compare the protein-protein interactions (proteomes) of pEA{beta} and pan-A{beta} in formalin-fixed postmortem human hippocampal tissue from pathologically confirmed AD cases and cognitively normal (CN) controls. Differential proteomic analysis identified 48 significantly enriched proteins in AD pEA{beta} captures, 28 in AD pan-A{beta} captures, and 15 in CN pan-A{beta} captures. Whereas no significant enrichment was detected in CN pEA{beta} captures, supporting pEA{beta} as a pathology-associated species. pEA{beta} in AD demonstrated the largest variant-specific signature with 31 unique proteins, pan-A{beta} showed 11 unique proteins in AD, and 14 unique proteins in CN, 16 proteins were shared between AD pEA{beta} and AD pan-A{beta}, with PCSK1N shared across AD pEA{beta}, and AD/CN pan-A{beta}. Pathway enrichment analysis revealed broader biological disruptions linked to pEA{beta}, including synaptogenesis signaling, clathrin-mediated endocytosis, mitochondrial division signaling, and neurotransmitter release. Shared pathways included SNARE signaling, glutamatergic receptor signaling, and netrin signaling. These findings demonstrate that pEA{beta} engages an expanded, variant-specific interactome in human AD hippocampus and designate intracellular trafficking, synaptic signaling, and mitochondrial pathways as network-level vulnerabilities relevant to pEA{beta} pathology in AD. Notably, comparison of CN versus AD pan-A{beta} further distinguished protein networks associated with physiological A{beta} engagement versus pathological pan-A{beta} deposition.

Importance: Little is known about the impact of returning Alzheimer disease (AD) biomarkers to cognitively unimpaired (CU) research participants. Objective: Does return of research results (RoRR) negatively impact longitudinal symptoms of depression and cognition. Design: Randomized, noninferiority, delayed-start clinical trial, 2021-2025 Setting: AD biomarker research results offered to CU participants in a longitudinal study of aging Participants: CU participants age 65+ were offered research AD biomarker results (APOE genotype and either plasma AB42/40 or amyloid PET and MRI hippocampal volume) with an estimated 5-year risk of symptomatic AD. Intervention(s) (for clinical trials) or Exposure(s) (for observational studies): 147 participants were randomized to receive results either soon after consent (RoRR arm, N=73) or one year later (delayed-start arm, N=74). Main Outcome(s) and Measure(s): Longitudinal change in Geriatric Depression Scale (GDS), Clinical Dementia Rating sum of boxes (CDR-SB), and global cognitive composite. Outcomes were measured at annual assessments for a longitudinal study of aging. Results: 187 participants received results: 70 in RoRR arm (average age 75, 60% female), 66 in delayed-start arm (average age 73, 53% female). The observed changes in annual measures did not differ between arms in both those with elevated amyloid (AB+) and in those without elevated amyloid (AB-) for GDS (AB+ difference 0.7, 95% CI 0.0-1.3; AB- difference -0.1, 95% CI -0.7-0.5; clinically significant decline >4.0), CDR-SB (AB+ difference 0.0, 95% CI -0.1-0.1; AB difference 0.0, 95% CI 0.0-0.1; clinically significant decline >0.5), and cognitive composite (AB+ difference -0.10, 95% CI -0.25-0.06; AB- difference -0.05, 95% CI -0.17-0.07; clinically significant decline < -0.26). Secondary analyses found no evidence of association between RoRR and proximity to follow-up testing. Conclusions and Relevance: In the first randomized, delayed-start clinical trial of returning AD research results to CU older-adult participants, no effect was seen on longitudinal changes in symptoms of depression or cognition. This supports evidence that there are no harms to returning AD research results, although the results may not apply to more diverse populations not included in this study. Trial Registration: NCT04699786

Summary Background Although CAIDE (Cardiovascular Risk Factors, Aging, and Dementia) score estimates 20 year dementia risk, prior studies have largely focused on global or composite measures. Only a few studies investigated on cognitive functions and structural neuroimaging markers, and the available structural neuroimaging evidence has largely been derived from subsamples or highly selected small cohorts rather than full population based cohorts. We therefore not only investigated associations between CAIDE score and cognitive performance but also explored structural neuroimaging markers in middle to older aged population. Methods Of 2,864 participants who were available for structural magnetic resonance imaging (MRI) data at baseline, we excluded 230 participants who have neurological and cardiovascular disease at baseline. We also further excluded 209 participants without having exposure, covariates, and cognitive assessments data, including 2,425 participants for the final analysis. The main exposure is CAIDE score (0 to 15) were calculated from age, sex, education, systolic blood pressure, body mass index, total cholesterol, and physical activity and categorized as low risk (<6), moderate risk (6 to 7), and high risk (7<) at baseline. The main outcomes were neuropsychological assessment battery included Story recall, Visual reproductions, Verbal fluency, Trail making, Digit symbol coding, and Stroop tests. Findings Of 2,425 healthy participants (mean age of 58.5 [6.5]; men 1,189 [49.0]), higher CAIDE risk groups were associated with poorer cognitive performance. Compared with low risk group, the high risk group showed significantly lower performance across all 12 cognitive assessments (all p <.001). The moderate risk group also showed lower performance in visual reproduction (immediate and delayed recall), digit symbol oding, and Stroop (word and color) reading tests. Interpretation This large based population study showed the highest risk group were independently associated with lower cognitive performance across all domains compare to the lowest risk group, suggesting the potential importance of managing these features for preserving neurological health in middle and older aged adults.

Recently, the amyloid-beta (A{beta}) targeting antibody lecanemab has demonstrated modest therapeutic efficacy in slowing cognitive decline in people with Alzheimer's disease (AD). Lecanemab clears amyloid plaques from the brain; however, plaque load does not correlate strongly with cognitive function. The strongest neuropathological correlate of cognitive decline in AD is synapse loss, which is exacerbated in the halo surrounding neuritic amyloid plaques where A{beta} accumulates in remaining synapses. Here, we hypothesised that, through clearing plaques and the associated halo of soluble A{beta} that can directly damage synapses, lecanemab could temper plaque-associated synapse loss. High-resolution imaging of temporal cortex tissue from people who died with AD (N=20) and age-matched controls (N=19) reveals lecanemab staining within individual pre and post-synaptic excitatory terminals in addition to plaque staining. The percentage of pre-synapses containing lecanemab-positive A{beta} was over 200% higher in AD and the percentage of post-synapses was over 150% higher in AD than control tissue, with highest levels of synaptic lecanemab staining observed near plaques. These data demonstrate that lecanemab antibody recognises A{beta} within synapses, warranting future work to determine whether lecanemab treatment slows cognitive decline, at least in part, through both clearing plaques and facilitating clearance or neutralisation of synaptic A{beta}.

INTRODUCTIONThalamic nuclei support multiple cognitive processes, yet their integrity in biologically-defined Alzheimers disease (AD) remains unknown. METHODAmyloid status was determined using PET Centiloids >24 in 1,327 participants from ADNI. Combined with clinical diagnosis, this yielded six groups: amyloid-negative or positive CN-MCI-dementia/AD. Thalamic nuclei volumes were extracted from T1-weighted MRI using the HIPS-THOMAS algorithm. RESULTSLarge volume reductions in the anteroventral, mediodorsal, and pulvinar nuclei were observed in amyloid-positive MCI and AD. Reduced volumes were also evident in amyloid-positive CN, supporting preclinical AD. Adding the anteroventral nucleus improved cognitive status classification in Random Forest analyses. A phenotypic model integrating thalamic nuclei clearly distinguished amyloid-positive groups from amyloid-negative CN and reclassified non-AD patients with 68% of amyloid-negative MCI subjects as CN-like, and 27% of amyloid-positive CN as MCI-like. DISCUSSIONThalamic volumetry from conventional T1-weighted MRI enhances clinical insight into AD and provides a practical biomarker for disease intervention.

Abstract INTRODUCTION APOE genotype shows well-established dose-dependent associations with higher amyloid in cognitively unimpaired (CU) adults. In contrast, associations with tau burden and cognition are less well characterized. METHODS We performed a cross-sectional analysis of harmonized multi-cohort ADSP-PHC data from 4,380 CU participants across 4 cohorts with APOE genotype, amyloid PET, and cognitive data from four domains of memory, language, executive, and visuospatial function, including a subset of 758 with tau PET imaging. RESULTS APOE {varepsilon}4 showed a strong dose-dependent association with amyloid burden and amyloid positivity, with the highest levels observed among {varepsilon}4 homozygotes. Associations between APOE and global tau burden were more modest and appeared to be driven mainly by {varepsilon}4 homozygotes, while regional analyses showed localized APOE {varepsilon}4-related associations in medial temporal regions. Independently, higher tau burden was associated with lower memory and language performance. CONCLUSIONS In CU older adults, APOE {varepsilon}4 was most strongly associated with amyloid burden, with more modest associations observed for medial temporal tau burden.

MotivationAD and PD transcriptomic cohorts can reveal disease-associated neuronal, glial, mitochondrial, myelin, proteostasis, vascular, and immune programs, but these signals are difficult to compare reproducibly across studies without endpoint-locked, sample-level biological summaries. ResultsWe present NeuroFate, a command-line research package that converts compact transcriptomic cohorts into curated neurodegeneration-axis scores, exploratory research-use risk scores, and conservative evidence reports. The software locks disease-state endpoints before scoring, maps genes or probes onto a 10-axis NeuroFate panel, records axis-gene coverage, and grades external cohort evidence by direction, effect size, nominal/FDR support, and claim-safety rules. Demonstrations across AD and PD resources show nominal independent AD support for a neuronal vulnerability axis, mixed PD convergence, and a PD-divergent synuclein-mitochondrial example while avoiding clinical or mechanism-overstating claims. Availability and implementationNeuroFate is implemented in Python and available at https://github.com/sinhakrishnendu/NeuroFate.git. Contactnabanitaghosh89@gmail.com; dr.krishnendusinha@gmail.com. Supplementary informationDocumentation, examples, tests, and reproducibility notes are included in the repository.

The leptomeninges (arachnoid and pia) are the inner layers of the meninges that envelope the brain. They define the borders of the subarachnoid space (SAS) where cerebrospinal fluid (CSF) circulates. Leptomeninges act as the barrier tissue and contribute to fluid exchange and immune function of the brain. These processes are identified as key factors in the development of neurodegenerative diseases. The extracellular matrix (ECM) is a critical structural component of leptomeninges. However, it remains insufficiently characterized in health and disease. Here, we performed complete proteomic profiling of ECM proteins (matrisome) of human leptomeninges from individuals with Alzheimers disease (AD) and cognitively normal controls (CN) using sequential biochemical fractionation coupled with mass spectrometry. We resolved leptomeningeal matrisome based on the biochemical properties reflected by the protein solubility. This approach identified 211 ECM proteins in human leptomeninges and revealed disease-associated shifts in leptomeningeal solubility consistent with altered matrix organization and signaling. We found that ECM-linked regulators and secreted factors extracellular sulfatase SULF2, antithrombin-III (SERPINC1), secreted frizzled-related protein 3 (sFRP3) and integrin beta-5 (ITGB5), which is a receptor for fibronectin, were differentially expressed in AD leptomeninges based on the disease status. Seven ECM proteins were identified only in AD samples, and two ECM proteins in CN samples. Pathway enrichment implicated TGF-{beta} and Wnt-related signaling and coagulation as critical for leptomeningeal function. Our findings provide the first comprehensive proteomic characterization of the human leptomeningeal matrisome and establish a biochemical framework for investigating how meningeal matrix remodeling contributes to AD.