Alzheimer's & Dementia

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.

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.

INTRODUCTION: Alzheimer's 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. METHODS: Plasma 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. RESULTS: Among 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. CONCLUSION: Comprehensive plasma proteomics in Asian cohort supports scalable framework for blood-based biologically informed targets for precision diagnosis and therapeutic stratification.

INTRODUCTION: Herpes simplex virus-1 (HSV-1) has been implicated in Alzheimers disease (AD). METHODS: Reads 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. RESULTS: Across 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-{epsilon}4 carriers; HSV-1 was associated with reduced AD risk in {epsilon}4 non-carriers but increased risk in carriers. GWAS identified host genetic influences on HSV-1 detection and interaction loci affecting AD risk. DISCUSSION: HSV-1 DNA showed an inverse association with AD and is affected by genetics.

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.

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.

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.

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.

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.

Lactate, a well-known metabolite and signalling molecule, holds therapeutic potential for neurodegenerative diseases. Here, we investigated the effects of chronic lactate treatment on cognition and molecular biomarkers in the 5XFAD mouse model of Alzheimers disease (AD) and in wild-type (WT) controls using behavioural testing alongside proteomic and transcriptomic analyses. Mice received lactate or vehicle injections 4 days per week for 11 weeks, with behavioural testing before and after the treatment period. Lactate improved working memory in late-treated AD mice, without eliciting anxiety-like behaviour. At the molecular level, lactate reduced Il1b expression, and in a sex-dependent manner, normalised NEFL, and enhanced synaptic integrity proteins (OPCML, PPFIA2, STXBP3, SYT1, VGLUT2, VSNL1) in AD mice, while also augmenting mitochondrial regulators (ATP5G2, GRPEL1, SLC25A23) across genotypes. Notably, lactate upregulated low-abundance ionotropic glutamate receptor mRNAs (Grik3, Grin2c, Grid2ip) in female AD mice, indicating enhanced glutamatergic signalling. In WT mice, lactate increased expression of neurotrophic factors (Bdnf, Igf1, Vegfa), anti-inflammatory cytokines (Il4 and Il13), and the neuronal lactate transporter Mct2, suggesting promoted neuronal resilience. Together, these findings indicate that lactate treatment can mitigate cognitive decline and enhance molecular pathways of resilience in AD, warranting larger, age-stratified studies to validate its therapeutic potential and elucidate underlying mechanisms.

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.

BackgroundGenome-wide association studies (GWAS), with independent replication in large European consortia, have identified a common nonsense variant in IL-34 (Y213X) as a genetic risk factor for late-onset Alzheimers disease (AD). However, the biological consequences of this IL-34 mutation in humans, its prevalence in the population, and the mechanisms by which IL-34-Y213X alters microglial homeostasis, cerebrospinal fluid (CSF) proteomic networks, and amyloid pathology remain poorly understood. MethodsWe combined human genetics, cerebrospinal fluid (CSF) and serum proteomics, large-scale phenome-wide association analyses, and preclinical experimental models to define the impact of human IL-34 deficiency. IL-34 concentrations were first quantified in CSF and serum from deeply phenotyped AD cohorts stratified by the common IL-34-Y213X nonsense variant. IL-34 levels and IL-34-Y213X status were then integrated with unbiased CSF proteomic networks and AD biomarkers. Using complementary mouse models of IL-34 loss in an APP/PS1 transgenic background, we examined the effects of IL-34 deficiency on microglial survival, tiling, and plaque encapsulation. Finally, we performed postmortem analyses of temporal cortex from AD patients carrying IL-34-Y213X to assess microglial density, spatial organization, and plaque-associated responses. FindingsIL-34-Y213X was a strong, dose-dependent loss-of-function allele that reduced IL-34 levels by up to 2.5 standard deviations in CSF and serum and was common in multiple populations. IL-34 deficiency reshaped CSF proteomic networks, downregulating axon guidance and microglial support modules while upregulating inflammatory and extracellular matrix signatures, and showed pleiotropic associations with neurological, inflammatory, and metabolic traits. In APP/PS1 mice, genetic IL-34 deletion selectively depleted homeostatic gray-matter microglia, disrupted microglial tiling, and impaired plaque encapsulation, resulting in altered amyloid structure and enhancing neuritic injury. Concordantly, AD patients homozygous for IL-34-Y213X displayed markedly reduced cortical microglial density and increased microglial spatial dispersion, indicating a breakdown of the microglial network organization in the human brain. InterpretationA common human IL-34 loss-of-function variant creates a naturally occurring model of IL-34 deficiency that links microglial survival, CSF network signatures, and amyloid pathology in both mice and humans. These findings position IL-34/CSF1R signaling as a critical determinant of microglial resilience in AD and highlight IL-34-dependent pathways as potential targets for disease modification.

BackgroundMitochondrial dysfunction is an early and central feature of Alzheimers disease (AD). In particular, intercellular mitochondrial transfer has emerged as a mechanism of neuronal support in brain injury and neurodegeneration. However, pathways governing astrocyte-to-neuron transfer and its role in AD pathogenesis remain unknown. MethodsUsing the AppNL-G-F knock-in AD model, we combined high-resolution 4D live-cell imaging with quantitative fluorescence-based reporters to assess synaptic function and mitochondrial network dynamics in neurons and astrocytes. Direct and extracellular vesicle (EV)-restricted neuron-astrocyte co-culture systems were used to investigate bidirectional mitochondrial transfer. We performed the first in-depth structural, proteomic, and functional characterization of astrocyte-derived mitochondrial extracellular vesicles (mitoEVs) using cryo-electron microscopy, quantitative mass spectrometry, and bioenergetic analyses to define their cargo composition and metabolic effects. ResultsWe identified cell-type-specific mitochondrial remodeling in early AD, with compartmentalized synaptic energy deficits in neurons and hyperdynamic, less interconnected, yet metabolically preserved networks in astrocytes, preceding global bioenergetic decline. Bidirectional mitochondrial transfer between astrocytes and neurons, also at axonal terminals, was mediated by specialized mitoEVs but significantly reduced in the AppNL-G-Fmodel. Comprehensive proteomic and functional profiling revealed that WT astrocyte-derived mitoEVs are enriched in inner membrane and matrix proteins, supporting oxidative phosphorylation, lipid and amino acid metabolism, and redox homeostasis. In contrast, AppNL-G-F mitoEVs are selectively depleted of respiratory and fatty acid oxidation components and exhibit impaired respiration with reduced Complex IV activity. Functionally, WT mitoEVs promote mobilization of abnormal accumulation of lipid droplets in AppNL-G-Fneurons, restore fatty acid oxidation, and increase neuronal bioenergetics, including at the synapses. In contrast, disease-derived mitoEVs fail to engage these pathways. ConclusionsTogether, these findings identify mitoEV-mediated mitochondrial transfer as a glia-to-neuron metabolic pathway compromised in early AD and reveal a coordinated role for oxidative phosphorylation and fatty acid oxidation in supporting synaptic energy homeostasis.

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.

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.

Background: The apolipoprotein E (APOE) locus is the strongest genetic risk factor for late-onset Alzheimer's 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 {epsilon}4 and APOE {epsilon}2 carriage on the circulating proteome in middle-age and later life. Methods: In primary modelling, we analysed associations of APOE {epsilon}4 and {epsilon}2 carriage (reference {epsilon}3/{epsilon}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. Results: We identified 351 proteins associated with {epsilon}2 carriage and 480 with {epsilon}4 carriage among individuals of European ancestry (n = 40,092); 130 of these were associated with both {epsilon}2 and {epsilon}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, {epsilon}4 carriage was strongly associated with consistent differences in circulating APOE, MENT, and PLA2G7 levels across ancestries and cohorts. Conclusion: APOE {epsilon}4 and {epsilon}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.

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.

Background. Detection 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/Abeta1-42 plasma ratio test (May 2025) represents the first approved blood-based alternative; however, single-ratio approaches cannot distinguish Alzheimer's disease (AD) from non-AD neurodegeneration or provide multi-dimensional disease characterization. Methods. We 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-beta42/40 ratio, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) - were measured in 1,139 Alzheimer's 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. Results. VSD 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. Conclusions. Blood-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, Parkinson's disease, and cancer.

BackgroundTraumatic brain injury with loss of consciousness (TBI-LOC) is an established risk factor for dementia, yet the pathways linking remote TBI to Alzheimers disease (AD) biology remain incompletely defined. APOE {varepsilon}4 is the strongest genetic predictor of amyloid accumulation in late-onset AD, it may moderate the long-term consequences of head injury. This study investigates whether history TBI-LOC independently contributes or synergistically interacts with APOE {varepsilon}4 to amplify late-life amyloid and tau burden. Methods429 participants completed the Ohio State University TBI screening tool and an amyloid PET scan (centiloids). A subcohort (n=352) also underwent tau PET. TBI history was classified by recency (<10 vs >10 years) and severity (no TBI, dazing/confusion [TBI-DZ], TBI-LOC). Analyses were stratified by degree of clinical impairment as assessed by Clinical Dementia Rating (CDR=0 vs CDR>0). Logistic and linear regression models examined associations between TBI and amyloid, adjusting for age, sex, education, and APOE {varepsilon}4, including an APOE*TBI-LOC status interaction term, while Fishers exact tests evaluated TBI recency and biomarker positivity. ResultsIn CDR=0 participants (n=365), 119 reported a history of TBI, comprising 56 TBI-DZ and 63 TBI-LOC. TBI-LOC but not TBI-DZ, correlated with elevated amyloid PET levels (p<0.001; [4.6-17]). Furthermore, an interaction between APOE {varepsilon}4 and TBI-LOC indicated that TBI-LOC augmented the amyloid-related risk associated with the APOE {varepsilon}4 allele (p=0.003; [4.3-21]). The interaction persisted when stratified by TBI recency with only remote TBI-LOC (occurring more than 10 years prior) associated with increased amyloid PET (p=0.003 [5.2-25]). No association between TBI and tau was identified in a subset with tau PET, and no TBI-amyloid correlations were observed among symptomatic participants (CDR>0; n=64) suggesting a ceiling effect of pathology once clinical dementia is present. ConclusionsHistory of remote TBI-LOC is linked to elevated amyloid PET levels in later life, particularly among APOE {varepsilon}4 carriers with a CDR=0. The robust findings for amyloid, contrasted with null tau results and the reduced association in symptomatic cases underscore the importance of considering TBI history when screening for preclinical AD and assessing early-stage risk.

BackgroundOxidative stress and maladaptive neuroimmune activation contribute to cognitive decline in Alzheimers disease (AD) and represent therapeutic targets beyond amyloid-centered approaches. ObjectiveTo determine whether oral D-methionine (D-Met), a redox-active amino acid, reduces amyloid pathology and lipid peroxidation and confers disease-modifying benefits in AD mouse models. MethodsMale and female APP/PS1 and APPNL-F mice with advanced AD pathology received oral D-Met or vehicle. Behavioral assessments included locomotor activity and hippocampal-dependent spatial learning and memory. Amyloid burden, lipid peroxidation, peripheral metabolic and inflammatory markers, and hippocampal microglial phenotypes were evaluated using biochemical and histological analyses. ResultsD-Met did not alter locomotor or exploratory behavior but improved spatial memory recall in both sexes of APP/PS1 mice and in female APPNL-F mice. APPNL-F males exhibited improved learning during Morris water maze (MWM) acquisition. Amyloid pathology was modestly and region-specifically reduced, including decreased hippocampal plaque size in male APPNL-F mice, reduced cortical plaque size in female APP/PS1 mice, and lower soluble amyloid-{beta} (A{beta})42 in male APP/PS1 mice. Lipid peroxidation, assessed by malondialdehyde, was reduced only in female APPNL-F mice. D-Met induced pronounced sex-dependent peripheral effects, increasing adiposity and pro-inflammatory adipose signaling in males, while reducing perigonadal white adipose tissue (pgWAT) IL-6 expression in female APPNL-F mice. In the hippocampus, D-Met remodeled microglial signatures, with female APPNL-F mice showing reduced Iba1 and disease-associated microglial (DAM) markers and increased Axl expression. ConclusionShort-term D-Met acts as a metabolic and redox modulator with modest amyloid-lowering effects mediated by improved microglial function. Therapeutic efficacy is strongly sex- and model-dependent, with the greatest benefit observed in female APPNL-F mice.