Alzheimer's & Dementia

We examined whether a 24-week resistance training program influenced brain amyloid-{beta} (A{beta}) and Alzheimers Disease (AD)-related blood-based biomarkers. Ninety cognitively normal, physically inactive older adults aged 65-80 years were randomly allocated to a 24-week resistance training program (three [~]60-min supervised sessions/week) or a wait-list control group. Primary analyses assessed exercise-induced changes in brain A{beta} (Centiloid values) and plasma ptau217/A{beta}1-42 IPMS ratio. Secondary analyses examined ptau217/A{beta}42 SIMOA ratio, ptau217, ptau181 and A{beta}42/40, as well as potential interactions with sex, age, education, apolipoprotein {varepsilon}4 (APOE4) status, amyloid PET-positivity, and comorbidities. The intervention produced no significant differences on brain A{beta} or AD-related blood-based biomarkers (p>0.05) compared to the control group. However, the ptau217/A{beta}1-42 IPMS ratio showed a small, non-significant increase in the control group (SMD = 0.162; 95% CI: -0.159 to 0.483) while remaining stable in the exercise group (SMD = 0.01; 95% CI: -0.291 to 0.310) with a similar trend for ptau217/A{beta}42 SIMOA. Moderator analyses indicated differential responses by amyloid PET-positivity and APOE4 status on brain A{beta} (p for interaction<0.05), with increases observed in APOE4 carriers and amyloid PET-positive individuals in the control group, whereas those allocated to the exercise intervention reduced their levels. The specificity observed within our subgroups suggests that resistance exercise may serve as a targeted intervention to modulate AD pathophysiology, raising new questions regarding its broader role in the delay of the disease in vulnerable populations.

Older individuals frequently harbor multiple brain pathologies, including Alzheimers disease (AD) related amyloid-{beta} (A{beta}) and tau alongside -synucleinopathy and vascular pathology. Proteomic profiling offers a strategy to better understand common as well as unique features of these different brain pathologies. We analyzed cerebrospinal fluid (CSF) (n=1,658) and plasma (n=749) samples from participants in the BioFINDER cohorts using the automated NULISAseq CNS Disease panel of 125 proteins. Differentially abundant proteins (DAPs) related to AD pathology (based on A{beta}- and tau-PET positivity), -synuclein (based on synuclein amplification assay [SAA] positivity) and vascular pathology (based on white matter lesion [WML] load) were identified with linear models simultaneously including a binary measure for the three pathologies. In the BioFINDER-2 subcohorts, DAPs were further evaluated for associations with continuous baseline (n=1,137) and longitudinal (n=656) A{beta}-PET, tau-PET, and WML measures in models accounting for all pathologies. Associations with AD-signature cortical atrophy (n=915) and cognitive decline by the MMSE (n=1054) were also examined. We identified 84 CSF DAPs, with largely distinct protein signatures for each pathology (AD, n=66 DAPs; vascular pathology, n=55; -synuclein pathology, n=16). 10 DAPs (e.g., FABP3, UCHL1, NPTXR, NPTX2) were altered across all three pathologies, reflecting general neurodegeneration. AD-associated DAPs included glial/inflammatory markers (CHIT1, CX3CL1, CD63) linked to A{beta} pathology, and synaptic/neuronal injury markers (VSNL1, NRGN, NEFL) and metabolic enzymes (FABP3, MDH1) linked to tau pathology. A{beta}-associated proteomic differences were most evident in CU individuals, while tau-associated differences predominated in MCI. More proteins, particularly neurodegeneration and synaptic markers, were associated with tau change than with A{beta} change. Vascular pathology exhibited a distinct profile, enriched for inflammatory, angiogenic and extracellular matrix proteins (PGF, POSTN, TREM1, VCAM1). DDC was the main protein associated with -synucleinopathy. Only a few proteins, including UCHL1, NPTX2, and NEFL, predicted cognitive decline and cortical atrophy after accounting for all brain pathologies. In plasma, although fewer DAPs were identified (n=20), findings included established AD biomarkers. Only plasma VCAM1 and NEFL were associated with -synuclein and vascular pathology. NULISA identified stage-dependent, disease-specific CSF biomarker signatures with limited overlap, alongside shared neurodegenerative markers, supporting improved biological interpretation and more refined classification of neurodegenerative pathology.

BackgroundBlood-based biomarkers offer a scalable alternative to cerebrospinal fluid and PET imaging for Alzheimers disease (AD) detection, yet traditional venipuncture limits participation among rural and socioeconomically disadvantaged populations. Self-collection using the Tasso+ capillary device could reduce access barriers, but its feasibility and validity for AD plasma biomarkers remain uncertain, particularly with real-world delays prior to processing. MethodsAdults aged 45-90 years from the Wisconsin SHOW cohort who were underrepresented in AD research (Black or Hispanic race/ethnicity, rural residence, or <bachelors degree) were recruited (n=28). At community "pop-up" clinics participants completed: (1) self-collection of capillary blood via Tasso+; (2) experience surveys; (3) Montreal Cognitive Assessment; and (4) standard venipuncture. To simulate home-based collection and mail return, Tasso+ samples were held at room temperature for 24 hours before centrifugation, whereas venous samples were processed within 30 minutes. Plasma A{beta}40, A{beta}42, A{beta}42/40, GFAP, NfL, and pTau217 were measured on the Quanterix Simoa platform. Between-method agreement was evaluated using Pearson/Spearman correlations, Lins concordance correlation coefficients (CCC), Bland-Altman analyses, and relative bias. Predictors of percent difference were explored with univariate regression. ResultsTasso+ collection was successful for 96% of participants; 64% rated it very easy and 86% reported comfort/no pain, yet 57% preferred future venipuncture--particularly Black, lower-income, and lower-education participants. Agreement varied markedly by biomarker. GFAP and NfL demonstrated excellent concordance (CCC 0.97-0.98) with minimal bias (-6% to -8%). A{beta}40 and A{beta}42 showed modest correlations (r=0.40-0.47) and substantial underestimation (-60% to -70%). A{beta}42/40 and pTau217 exhibited poor correlation and extreme positive bias for pTau217 ([~]+2600%). Hemolysis was more frequent in Tasso+ samples and contributed to disagreement for several markers; processing lag and sample volume were not strong predictors. ConclusionsRemote capillary self-collection with a 24-hour delay is suitable for measuring GFAP and NfL but not currently reliable for A{beta} or pTau217 without improved handling (e.g., temperature control, hemolysis reduction). Although user experience was favorable, trust and logistical concerns limited preference among underrepresented groups. Community-informed strategies and optimized pre-analytics are essential before deploying Tasso+ in large AD studies.

BackgroundSubjective cognitive decline (SCD) is common in older adults and may precede mild cognitive impairment (MCI). Whether longitudinal changes in self- or study partner (SP)-reported SCD improve early identification of individuals at risk for clinical progression, particularly along the Alzheimers disease (AD) biological continuum, remains unclear. MethodsWe pooled data from two longitudinal observational cohorts (DELCODE and ADNI). Cognitively unimpaired (CU) participants were recruited through public advertisement or memory clinics and included if baseline amyloid status, [&ge;]2 SCD assessments, and clinical follow-up were available. SCD was assessed using the Everyday Cognition questionnaire (self- and SP-report). Linear mixed-effects models examined longitudinal associations between SCD trajectories, baseline AD biomarkers, and progression to incident MCI. Multivariable Cox proportional hazards models tested whether one-year changes in SCD predicted subsequent progression. FindingsAmong 770 participants (median age 69{middle dot}9years [IQR 66{middle dot}0-74{middle dot}6]; 52{middle dot}6% women; median follow-up 5{middle dot}0years [4{middle dot}0-7{middle dot}0]), amyloid-positive individuals and those who progressed to MCI showed steeper longitudinal increases in both SCD reports. In amyloid-positive participants, only increases in SP-reported SCD differentiated progressors from non-progressors. One-year increases in SP-reported SCD predicted a higher risk of subsequent MCI compared with unchanged scores (hazard ratio 3{middle dot}24 [95%CI 1{middle dot}73-6{middle dot}07]), with effects confined to amyloid-positive participants. InterpretationLongitudinal increases in SP-reported cognitive difficulties, particularly over short intervals, are associated with near-term progression to MCI in amyloid-positive CU older adults. SP-based longitudinal monitoring may represent a low-burden approach to support earlier clinical surveillance in aging populations. FundingGerman Center for Neurodegenerative Diseases, US National Institutes of Health.

BackgroundWomen face greater vulnerability to dementia and Alzheimers disease (AD), potentially due to estrogen fluctuations across the lifespan. However, its role in vascular brain health is unclear. We investigated associations between lifelong estrogen exposure--endogenous (reproductive span) and exogenous (oral contraceptives [OC], menopausal hormone therapy [MHT])--and late-life vascular brain injury, AD-related atrophy, and APOE-{varepsilon}4 modification. Methods and findingsWe included 352 cognitively unimpaired 70-years-old women from the Gothenburg H70-1944 Birth Cohort with brain MRI and 5-year follow-up. Reproductive lifespan was calculated as age at menopause or oophorectomy minus age at menarche. OC and MHT use were self-reported. Outcomes included cerebral small vessel disease (SVD), AD-related cortical thickness, and white-matter integrity (fractional anisotropy). Linear and multinomial regression and mixed-effects models were adjusted for confounders and stratified by APOE-{varepsilon}4. Longer reproductive span (OR=0.90 [95%CI 0.83-0.98]) and MHT use (OR=0.43 [95% CI 0.20-0.92]) were linked to lower SVD burden, particularly fewer perivascular spaces and microbleeds. OC and MHT were associated with greater white matter integrity, with additive use throughout life showing the highest fractional anisotropy (OR=0.45 [95% CI 0.12-0.78]). MHT use was associated with greater thickness in areas often affected in AD among APOE-{varepsilon}4 carriers ({beta}=0.38 [95% CI 0.01-0.76]) but not in non-carriers. Longer estrogen exposure was linked to stable cortical thickness and WMH trajectories over time. ConclusionsExtended estrogen exposure throughout life--both endogenous and exogenous--appear to support late-life cerebrovascular health in women, with potential genotype-specific neuroprotective effects. Given the current absence of sex-specific prevention guidelines for cognitive disorders, future research should clarify estrogens long-term impact on brain health and cognition to inform personalized medicine.

Structured AbstractO_ST_ABSBACKGROUNDC_ST_ABSPositron emission tomography (PET), cerebrospinal fluid (CSF), and plasma assessments are used to measure amyloid abnormality in Alzheimers disease (AD). However, it remains unclear if these three measures are similarly associated with brain structure and cognitive measures. METHODSLinear regressions examined the relationship between amyloid levels measured by PET, CSF, and plasma and brain volumes, white matter hyperintensities (WMHs), and cognitive measures. RESULTSModerate correlations were found between PET and CSF amyloid measurements and PET and plasma measurements, while weak correlations were found between CSF and plasma. PET, CSF, and plasma amyloid measurements differed in their associations with brain volume, WMHs, and cognition. DISCUSSIONUsing different measurement methods, amyloid was not consistently associated with volumetric or cognitive measures. Our findings also suggest that plasma markers may not be associated with cognitive and brain changes in the same manner as CSF and PET.

BackgroundHippocampal atrophy is a key marker of Alzheimers disease (AD)-related neurodegeneration; however, hippocampal volume alone may not fully capture heterogeneity in cognitive decline. Hemispheric hippocampal asymmetry may provide complementary information, but its prognostic value for cognitive decline and clinical progression remains unclear. MethodsWe studied 1,142 dementia-free participants from the Alzheimers Disease Neuroimaging Initiative (ADNI) with available baseline structural MRI, cerebrospinal fluid (CSF) amyloid-{beta} (A{beta}42) and phosphorylated tau (p-tau-181), and longitudinal cognitive follow-up. Total hippocampal volume (left + right) and hemispheric asymmetry (absolute left-right volumetric difference) were modeled simultaneously. Linear mixed-effects models examined associations with baseline performance and longitudinal change across memory, language, executive, and visuospatial domains. Cox proportional hazards models assessed risk of clinical progression to clinical dementia over up to 10 years of follow-up. All analyses adjusted for age, sex, education, APOE {varepsilon}4 status, and CSF biomarkers, with stratification by amyloid status. ResultsThe study cohort included 546 women (47.8%), with a mean age of 72.54 {+/-} 6.98 years. Larger total hippocampal volume was consistently associated with better baseline performance and slower decline across all four cognitive domains, independent of amyloid and tau biomarkers. In contrast, greater hippocampal asymmetry was selectively associated with worse baseline memory performance and faster memory decline, independent of total hippocampal volume. In amyloid-stratified analyses, total hippocampal volume showed broad associations with cognition across all four domains among amyloid-positive participants and more limited, domain-specific associations among amyloid-negative participants, whereas hippocampal asymmetry was associated with memory only in amyloid-negative individuals. Regarding clinical progression to dementia, smaller total hippocampal volume was associated with higher risk of progression in the overall cohort and within both amyloid groups. In contrast, hippocampal asymmetry was associated with progression risk only among amyloid-negative individuals (hazard ratio per SD increase = 1.31, 95% CI: 1.03-1.65). ConclusionsHippocampal total volume and asymmetry capture distinct aspects of neurodegeneration, with asymmetry providing additional prognostic information for memory decline and clinical progression in participants without detectable amyloid pathology.

Blood-based biomarkers have emerged as a promising tool for the detection and monitoring of neurodegenerative diseases such as Alzheimers disease (AD), yet broad implementation of ultrasensitive protein quantification remains constrained by reliance on specialized instrumentation and centralized laboratory infrastructure. Here we present SPLASH (Solid Phase Ligation Assay with Single wasH), an ultrasensitive proximity ligation assay platform that achieves sub-pg/mL sensitivity using only standard benchtop qPCR equipment. We developed five assays targeting Alzheimers disease biomarkers - pTau-217, A{beta}1-40, A{beta}1-42, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) - with limits of detection ranging from 0.0005 to 0.119 pg/mL. Direct comparison with Simoa demonstrated high concordance (R2 = 0.95) for plasma pTau-217 quantification across AD-positive and AD-negative samples. We further established compatibility with dried plasma spot samples, enabling decentralized collection and quantitation without cold-chain storage. A multiplexed five-analyte panel was applied to 69 plasma samples, revealing heterogeneous biomarker profiles consistent with AD-associated patterns. By eliminating dependencies on proprietary instrumentation, SPLASH facilitates broad implementation of ultrasensitive protein quantification for neurodegenerative disease research and diagnostics.

INTRODUCTIONDementia reflects vascular and neurodegenerative processes in late life, yet studies often examine risks and outcomes individually. This study tested whether the cumulative burden of risks relates to structural brain pathology and cognition, and whether brain markers mediate these associations. METHODSCross-sectional data were drawn from 38,414 older adults in the National Alzheimers Coordinating Center database. A composite score summed ten binary risk factors: hypertension, diabetes, hypercholesterolemia, alcohol misuse, smoking, depression, obesity, hearing loss, vision loss, and low education. Outcomes included white matter hyperintensities (WMH), infarcts, hippocampal atrophy, global cognition, cognitive status, delayed recall, and semantic fluency. RESULTSHigher burden was associated with poorer global cognition, greater clinical severity, worse memory and fluency, and higher odds of WMHs, infarcts, and hippocampal atrophy. Structural equation models identified hippocampal atrophy as the primary mediator, with smaller effects for WMHs and infarcts. DISCUSSIONFindings support multidomain prevention strategies targeting clustered modifiable risks.

Background and ObjectivesBlood-based biomarkers (BBMs), especially tau phosphorylated at threonine 217 (p-tau217), offer a minimally invasive approach to diagnose Alzheimers disease (AD) with strong potential for clinical implementation. However, the robustness and transferability of diagnostic thresholds across sites remain uncertain. This study aimed to evaluate BBMs ability to predict amyloid and tau status in a deeply phenotyped AD research cohort and to test p-tau217 cutoffs across diverse clinical populations and analytical instruments. MethodsWe included four Western European cohorts (total n=411): an exploration cohort from Brussels with amyloid and tau-positron emission tomography (PET) data (n=215), and clinical validation cohorts from Paris (memory clinic, n=117, and monogenic FTLD, n=43) and Bordeaux (early-onset neurodegenerative disorders, n=36). BBMs concentrations (p-tau217, p-tau181, NfL, BD-tau, A{beta}42, A{beta}40) were measured. Of these, p-tau217 was measured at each site using three Lumipulse analyzers (G600II in Brussels and Bordeaux; G1200 in Paris). Amyloid status was determined by PET or CSF A{beta}42, and tau status by tau-PET or CSF p-tau181. ResultsPlasma p-tau217 outperformed other BBMs, and their related ratios. In the exploration cohort, p-tau217 closely related to amyloid and tau PET, clearly separating A{beta}+ from A{beta}- individuals (AUC=0.96; optimal cutoff 0.193 pg/mL with [~]92% sensitivity/specificity) and tracking tau-PET Braak stages (AUC=0.93-0.98). Using amyloid-derived thresholds, p-tau217 detected medial temporal and neocortical tauopathy with >90% sensitivity and specificity at stricter dual 95-97.5% sensitivity/specificity cutpoints (0.142/0.256 pg/mL and 0.110/0.319 pg/mL). In validation cohorts, the 0.193 pg/mL cutoff accurately discriminated clinical-biological AD from non-AD in routine care (AUC=0.98; [~]93% sensitivity/specificity), in early-onset dementia (AUC=0.94; >92% sensitivity/specificity), and in the monogenic FTLD cohort (89% specificity). In routine care, gray zones (8-25%) were largely resolved with second-line CSF testing (>75%). Elevated p-tau217 was rare in non-AD, mainly in FTLD-ALS and some older individuals with possible AD copathology. p-tau217/A{beta}42 and p-tau217/A{beta}42/A{beta}40 ratios added no diagnostic value. Discussionp-tau217 thresholds maintained high diagnostic accuracy (>90%) across independent sites, analytical platforms, and various clinical situations, supporting their robustness and transferability. These observations support implementing p-tau217 as a reliable, scalable test for detecting AD pathology, for diagnostic work-ups of patients with objective cognitive impairment, not for general population screening.

Menopause is a hallmark process in biological aging that has been associated with later life neurodegenerative risk. We leveraged proteomics data from multiple cohorts (N>3,000) to identify biological changes underlying menopause and its links to brain aging. In N=80 rigorously-phenotyped pre-, peri-, and postmenopausal women with serum NULISAseq proteomics, spontaneous menopause was characterized by dysregulation in inflammatory, synaptic, metabolic, and Alzheimers disease (AD) biologic processes, which tracked with hormones and not age. Pro-inflammatory protein upregulation was especially pronounced in women with vasomotor symptoms. In two cohorts of older women (N=94; N=100), menopause-related proteomic elevations associated with poorer cognitive outcomes and plasma AD biomarkers. Finally, validation analyses in age-matched pre- and postmenopausal women with plasma Olink proteomics (N=2,814) replicated the observed proteomic shifts and revealed menopause-related upregulation of additional inflammatory and catabolic processes. The molecular signatures of menopause may inform biomarkers or therapeutic targets for brain health in women.

INTRODUCTIONPlasma biomarkers for Alzheimers disease (AD) pathology promise scalable diagnostic access, yet their performance in diverse, population-representative cohorts remains uncharacterized. We evaluated equity and transportability of plasma amyloid-tau-neurodegeneration (ATN) biomarkers in a nationally representative U.S. aging cohort. METHODSCross-sectional analysis of 4,427 adults aged [&ge;]50 years from the 2016 Health and Retirement Study Venous Blood Study. Plasma biomarkers (A{beta}42/40, pTau181, NfL, GFAP) were classified using established ATN criteria. Survey weights produced population-representative estimates. Outcomes included biomarker-cognition associations, fairness metrics (sensitivity, specificity, predictive values) stratified by race/ethnicity and sex, and education-stratified analyses. RESULTSAmong 4,427 participants representing 36.6 million U.S. adults (weighted: 68 years, 55% female, 79% White), survey-weighted analysis revealed tau as the only biomarker maintaining robust cognitive associations ({beta}=-0.74, p<0.001), while amyloid ({beta}=0.11, p=0.43) and neurodegeneration ({beta}=-0.27, p=0.08) lost significance. White participants demonstrated 12-percentage-point higher sensitivity than Black participants (23.4% vs. 11.4%), with Black women showing lowest sensitivity (8.8%). Educational attainment modified biomarker effects: low-education groups showed paradoxical positive amyloid associations ({beta}=0.74, p=0.01) and amplified neurodegeneration effects ({beta}=-1.02, p=0.006). Race-specific optimal cutpoints differed by 40%. Vascular comorbidity burden was higher in Black (82%) and Hispanic (73%) versus White (65%) participants, yet associations persisted after vascular adjustment. DISCUSSIONPlasma ATN biomarkers demonstrate significant equity gaps and differential transportability across demographic subgroups. The 12-percentage-point sensitivity disparity and education-dependent effect modification highlight barriers to equitable implementation. Population-based validation with fairness metrics should be prerequisite for clinical deployment.

INTRODUCTIONAlzheimers disease (AD) diagnostic guidelines emphasize subjective cognitive decline (SCD) preceding mild cognitive impairment (MCI), implicitly assuming awareness of cognitive decline (ACD) is preserved in preclinical AD. This study aimed to evaluate associations of decreased ACD with multimodal core AD biomarkers in cognitively unimpaired (CU) individuals. METHODSWe analyzed data from CU individuals with baseline CSF biomarkers and 3-year longitudinal neuropsychological assessment (ALFA+ cohort). Decreased ACD was defined by concurrent decline in episodic memory and awareness using robust longitudinal references (Free and Cued Selective Reminding Test, Memory Binding Test, Wechsler Memory Scale, and Subjective Cognitive Decline Questionnaire). Biomarker outcomes included plasma and CSF p-tau181, p-tau181/A{beta}42, p-tau217; A{beta} ([{superscript 1}F]flutemetamol) and tau PET ([{superscript 1}F]RO948). Associations of ACD with AD biomarkers were evaluated using linear regression models. Sensitivity analyses were restricted to individuals with memory decline. RESULTS350 CU individuals were included (mean age 61 years; 60% female; mean education 14 years; 35% CSF A{beta}-positive). Episodic memory decline was identified in 61 (17%) individuals, of whom 25 (41%) also exhibited awareness decline; meeting criteria for decreased ACD. This group demonstrated greater levels of AD pathology compared to the remaining sample. Among fluid biomarkers, CSF p-tau217 showed the strongest association. Neuroimaging revealed elevated frontoparietal A{beta} PET, alongside temporal, insular, and frontal tau PET deposition. Sensitivity analyses showed that, at the same threshold of memory decline, decreased ACD reflects greater AD pathology. DISCUSSIONStandardized assessment of cognitive awareness, integrating objective neuropsychological performance with subjective reports, may provide a crucial extension of current clinical frameworks.

ObjectiveTo evaluate associations between an in vivo (MRI) marker of arteriolosclerosis (ARTS) and multimodal neuroimaging and plasma ATN(V) biomarkers. MethodsAmong 238 participants with both amyloid and tau PET scans within one year of MRI, we examined multivariable adjusted models relating ARTS with structural MRI (cortical thickness/volume, white matter hyperintensities [WMH]), diffusion MRI (fractional anisotropy [FA], mean diffusivity [MD], NODDI free water [FW]), cerebral blood flow, plasma biomarkers (p-tau217, A{beta}42/40, neurofilament light, glial fibrillary acidic protein [GFAP]), and PET imaging. ResultsAs expected, ARTS was most strongly linked to age and greater WMH burden and diffusion-based indices of microstructural disruption (FA, MD, FW). ARTS was elevated in ATN biomarker-positive groups (highest in A+T+N+) and was associated with greater neurodegeneration and higher plasma biomarker levels, GFAP in particular. ConclusionsARTS relates to other markers of vascular brain injury, neurodegeneration, amyloid and tau pathology within the ATN(V) framework, and inflammation. HighlightsO_LIARTS scores are elevated in ATN-positive individuals, most prominently in A+T+N+ C_LIO_LIARTS may exert stage-specific effects on neurodegeneration rather than track A/T burden. C_LIO_LIStrong ARTS-GFAP association suggests role of astroglial activation in vascular-related neurodegeneration C_LIO_LIFindings underscore the importance of vascular contributions to AD/ADRD pathophysiology, especially in high-cardiometabolic-risk populations C_LI

Brains from cognitively intact centenarians offer a unique window into mechanisms of neuroprotection. We quantified 3,448 proteins by LC-MS/MS in middle temporal gyrus (MTG) from 88 Alzheimers disease (AD) patients, 53 controls (50-99 years) and 49 centenarians (100+). After adjustment for cell type composition, A{beta} abundance associated with only five proteins, revealing upregulation of HTRA1, LRP1 and NRXN1 as early AD-associated changes. Conversely, tau abundance associated with [~]20% of the quantified proteome, revealing GPRIN1 as the top tau-associated protein. One-third of centenarians had high A{beta} abundance, often with Braak neurofibrillary tangle stages IV/V, yet all maintained low local tau abundance. Centenarians showed maintained proteostasis (low ubiquitin peptides, high proteasome components), high PCSK1 (prohormone maturation), high PFKFB2 (glycolysis regulation), mitochondria-coupled lipid {beta}-oxidation and lower APOE levels. Together, these findings suggest a model of neuroprotection in which A{beta} facilitates tau seeding, and where proteostatic and metabolic adaptations buffer against additional tau accumulation in centenarians.

BackgroundAPOE-{rho}.4 is the strongest genetic risk factor for Alzheimers disease (AD), and plasma phosphorylated tau217 (P-tau217) is a highly sensitive and specific biomarker for AD pathology. Their combined utility to predict cognitive decline before onset of AD has not been systematically evaluated. MethodsUsing longitudinal data from multiple cohorts, we evaluated plasma P-tau217 as a predictor of when cognitive impairment occurs in AD. P-tau217 concentrations were analyzed as continuous and binary variables using cohort-specific biomarker positivity thresholds. Association of plasma P-tau217 with prevalent and incident cognitive impairment were assessed using logistic regression and Cox models, stratified by APOE genotype. Adjusted survival curves and restricted mean survival time characterized when the onset of cognitive impairment occurred. Cohort-specific estimates were pooled using random-effects meta-analyses, and analyzed by discrimination performance with AUC, incremental R{superscript 2}, and Harrells C-index. ResultsElevated P-tau217 levels were significantly associated with the onset of cognitive impairment. Among APOE-{varepsilon}4 allele carriers, increased P-tau217 levels anticipated subsequent cognitive impairment. While P-tau217 levels reached clinically significant levels up to four years before onset of cognitive impairment independent of APOE, the symptom-free interval was briefest for APOE-{varepsilon}4 carriers with elevated P-tau217. ConclusionsPlasma P-tau217 levels and the presence APOE genotype can be used to estimate the interval before the onset of overt cognitive impairment and the diagnosis of AD. The findings here support the use of commercially available APOE genotyping and plasma P-tau217 to determine optimal timing for therapeutic intervention, particularly during the preclinical phase of the disease.

BackgroundThe benefits of amyloid-{beta} monoclonal antibodies for Alzheimers disease are tempered by the risk of amyloid-related imaging abnormalities (ARIA). Detailed real-world characterization of ARIA, including incidence, timing, radiologic severity and localization, natural history, and risk factors, is essential to optimize treatment safety. This study provides a comprehensive description of ARIA in a large real-world cohort of patients receiving lecanemab. MethodsIn this retrospective cohort study from the Mass General Brigham Alzheimers Therapeutic Program, we analyzed data from 468 patients with early Alzheimers disease who were at least 90 days from their first lecanemab infusion, including those whose treatment was modified or discontinued. ARIA was monitored using a standardized MRI protocol. High-dimensional analysis of baseline clinical, laboratory, and biomarker variables was performed using univariate correlations and Cox proportional hazards models with data-driven cutpoints. FindingsThe overall incidence of any ARIA was 25.2%, with ARIA-H occurring in 22.4% of patients and ARIA-E in 12.2%. Symptoms developed in 4.5% of all patients. Both subtypes demonstrated significant occipital involvement, with ARIA-H showing additional frontotemporal predominance. ARIA-H was typically mild and persistent with rare radiologic resolution, whereas ARIA-E was transient, resolving with a mean time to resolution of 75.6 days. Key baseline predictors of ARIA-H included CSF A{beta}42 [&le;]683.8 pg/mL (HR 6.39), [&ge;]1 microhemorrhage (HR 2.55), and at least one APOE {varepsilon}4 allele (HR 1.77). ARIA-E was predicted by diastolic blood pressure >75 mmHg (HR 3.12), serum chloride >105 mmol/L (HR 2.79), at least one APOE {varepsilon}4 allele (HR 2.51), and serum sodium >141 mmol/L (HR 1.70). ARIA-Mixed was associated with elevated serum chloride >105 mmol/L (HR 3.92), at least one APOE {varepsilon}4 allele (HR 2.87), and diastolic blood pressure >75 mmHg (HR 2.60). InterpretationThis comprehensive real-world characterization of ARIA, together with the identification of novel modifiable risk factors for ARIA-E, including elevated diastolic blood pressure and high-normal serum electrolytes, enables personalized risk assessment and tailored monitoring, thereby advancing the safe implementation of disease-modifying Alzheimers therapies. FundingFunding for this project was provided by the Mass General Neuroscience Transformative Scholar Award.

INTRODUCTIONIt is unknown whether biomarkers of neurodegeneration collected from dried blood spots (DBS) in large-scale population settings are useful in predicting cognitive decline many years later. METHODSIn 2015, we collected DBS of 13,679 individuals aged 58 and older. All DBS were assayed for ApoE4 protein, and a smaller subsample for pTau217, GFAP, and NfL. In 2022, we obtained detailed cognition measures for 6,523 respondents. Regression analyses tested the likelihood of cognitive impairment as a function of biomarker levels. RESULTSRespondents with ApoE4 detection have worse cognitive performance seven years later as measured by six different cognitive performance measures (p<0.001). The combination of all four biomarkers is a statistically significant predictor for five cognitive performance measures, with pTau217 having the most systematic association. DISCUSSIONDBS-based biomarkers of neurodegeneration provide a cost-efficient and scalable early warning signal enabling preventive measures against AD/ADRD before the onset of serious symptoms.

Individuals who carry two copies of the apolipoprotein E {varepsilon}4 (APOE{varepsilon}4) allele are at high risk of developing Alzheimers disease (AD), yet the effects of APOE {varepsilon}4 homozygosity on biological pathways related to AD over the lifespan are unknown. Here we analyzed the plasma proteomes of APOE {varepsilon}4/{varepsilon}4 individuals with and without AD-related cognitive impairment (n=413) and compared them to the proteomes of cognitively unimpaired individuals with APOE {varepsilon}3/{varepsilon}3 genotype (n=2764) from ages 20 to 90. Multiple biological pathways were altered in young adulthood in {varepsilon}4 homozygotes including metabolism and glucagon-like peptide 1/insulin growth factor (GLP-1/IGF), mitochondrial, microtubule, proteostasis, and synaptic pathways. Semaglutide--a GLP-1 receptor agonist--demonstrated reversal effects on metabolic and synaptic pathway alterations in {varepsilon}4 homozygotes at preclinical and clinical AD stages. Targeting metabolic and other pathways for therapeutic intervention in {varepsilon}4/{varepsilon}4 individuals by at least age 50 will likely be the most effective approach to decrease risk for AD in this special population.

ImportanceSome individuals are capable of tolerating Alzheimer disease neuropathological changes (ADNC) without manifesting clinical symptoms. Elucidating the neuropathological, and molecular mediators may facilitate the identification of more accurate in vivo biomarkers and inform the development of targeted therapeutic strategies. ObjectiveTo investigate cellular distribution of tau pathology, microglial responses, and gene expression profiles associated with divergent clinical outcomes (dementia vs. no dementia) in individuals exhibiting comparable ADNC. Design, Setting and ParticipantsWe analyzed postmortem brain tissue from 97 participants from the ROSMAP study:49 with high likelihood of AD (25 demented [demented AD] and 24 cognitively normal [resilient]), and 48 with low likelihood (22 demented [impaired-other (IMP-O)] and 26 cognitively normal [control]). Cases were matched for age, gender, and co-pathologies. Main outcomes and measuresAmyloid-{beta} plaques, phospho-tau pathology (tangles and tau-positive neurites), tau oligomers in synaptic-fractions, tau seeding activity, neurons, synapse density, and astrocyte and microglia activation were quantified. The relationships with bulk and microglia-specific RNA-sequencing were also examined. Statistical analyses employed ANOVA with Tukeys HSD/Bonferroni corrections for pathological and clinical variables, and the Wald test for differential gene expression ResultsDemented AD and resilient brains exhibited comparable tau tangle and amyloid-{beta} plaques; however, demented AD showed higher total pTau burden (tangles and tau-positive neurites) (Mean[SD], 27.39%[21.89%] vs. 10.60%[14.71%]; p= 0.0004) and elevated pTau oligomer levels in synaptic-enriched fractions (0.48[0.52] vs. 0.16[0.19]; p=0.0010). Both demented AD (0.21x107[0.14x107]; p<0.0001) and IMP-O (0.62x107 [0.42x107]; p<0.0001) showed greater synaptic loss than resilient (1.54x107[0.55x107]; p=0.0008) and controls (2.92x107[1.13x107]). CD68+ microglia burden was increased in demented (1.14%[0.27%]; p<0.0001) and IMP-O (0.97%[0.36%]; p<0.0001) but not in resilient (0.72% [0.17%]; p=0.2835) compared to controls (0.59%[0.17%]). Synaptic pTau oligomers and CD68+ microglia were the strongest correlates with antemortem cognition. Resilient brains exhibited downregulation of neuroinflammation-related genes and possessed a distinct microglial subpopulation supporting resilience, characterized by overexpression of CD83, DUSP1, and NAMPT. Conclusion and relevanceOur findings suggest that aberrant accumulation of tau in neurites and synapses, rather than tangles within neuronal soma, may trigger a microglial pro-inflammatory activation linked to synaptic loss and impaired cognition. Cell-specific transcriptomic analysis identified a distinct microglial cell subpopulation associated with resilience to ADNC.