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.

BackgroundWhile blood-based biomarkers for Alzheimers Disease (AD) such as p-Tau and NfL characterize established pathology, the systemic biological cascade triggering these events remains incompletely mapped. We hypothesized that proteins exhibiting a rising trajectory in the prodromal phase might reveal novel mechanisms of disease progression. MethodsUsing data from the UK Biobank Pharma Proteomics Project (N = 4,519 incident AD cases), we performed a blind trajectory scan of [~]3,000 plasma proteins. We utilized an elimination strategy, systematically excluding known AD markers (e.g., APOE, NEFL) and verified biological responses (e.g., MMP3, GLRX) to isolate novel signals. ResultsAfter excluding established markers, VSIG10L--a V-set and immunoglobulin domain-containing protein--emerged as the most significant novel marker (beta = - 0.037, P = 0.0019), exhibiting a progressive rise as patients approached diagnosis. Crucially, VSIG10L was accompanied by a cluster of co-regulated proteins involved in embryonic development and cell cycle regulation, including NACC1 (stem cell pluripotency), VASN (vasculogenesis), and ZBTB17 (cell cycle checkpoint). ConclusionThe emergence of VSIG10L and its associated developmental cohort suggests that prodromal AD is characterized by a retrogenesis phenomenon, the unsilencing of developmental programs in a failed attempt at neural repair. These proteins offer a new window into the brains response to neurodegeneration and represent potential therapeutic targets.

ImportanceThe APOE {varepsilon}4 allele is among the best-established genetic risk factor for Alzheimers disease. Different ethnic and racial groups have varying APOE {varepsilon}4 prevalences. The prevalence of APOE {varepsilon}4 also varies among European regions, yet White Americans are treated as a monolith, potentially impacting recruitment decisions and risk profile estimations. ObjectiveTo test whether White Americans of Southern European descent have a lower prevalence of APOE {varepsilon}4 than their Northern European descent peers, and secondarily, if APOE {varepsilon}4-brain health outcomes vary by European descent. Design, setting and participantsCross-sectional analyses of the nationwide All of Us cohort study in the United States. Overall inclusion criteria were reporting only White race, and countries of descent from Northern, Central or Southern Europe without overlap. Enrollment opened in May 2018. Analyses were conducted April-June 2025. ExposuresRegions of European descent (Northern, Central and Southern) from the Basics Survey. Main Outcomes and MeasuresAPOE {varepsilon}4 using variants rs429358 and rs7412, coded as zero, one or two copies. ResultsAmong those aged [≥]18 (n=77,676), the percentage of European descent was 7.7% Southern and 64.7% Northern. Age and female sex at birth were 55.5 years and 55.8% among Americans of Southern and 56.3 years and 57.4% among those of Northern European descent. APOE {varepsilon}4 allele frequency was 17.4% for one and 0.1% for two copies among Americans of Southern, and 24.9% and 2.0% for Northern European descent. Logistic regression models confirmed these differences: compared to Americans of Southern European descent, those of Northern European descent had an Odds Ratio of having one APOE {varepsilon}4 allele of 1.60 (1.49-1.71), and 2.21 (1.71-2.88) of having two APOE {varepsilon}4 alleles. European descent moderated associations between APOE {varepsilon}4 allele frequency and two brain health outcomes (interaction p[≤]0.10). Conclusions and RelevanceThe frequency of APOE {varepsilon}4 among Americans of Southern European descent was lower than that of Northern European descent and associations with some brain health outcomes varied. Future studies need to use probabilistic samples to confirm these findings. The concept of White race might be too broad when making racial comparisons of APOE {varepsilon}4 frequency and its effects. Key PointsO_ST_ABSQuestionC_ST_ABSIs the prevalence of APOE {varepsilon}4 reduced when comparing Southern European to Northern European descent American adults who identify as only White race? FindingsIn this cross-sectional analysis of a cohort study (n=77,676 American adults), those of Northern European descent had 60% higher odds of having one, and 120% of having two copies of APOE {varepsilon}4 compared to those of Southern European descent. MeaningAmong White American adults, the prevalence of APOE {varepsilon}4 differs by region of European descent; future studies need to confirm these findings using genetically inferred ancestry and probabilistic samples with stronger external validity.

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.

IntroductionPolygenic risk score (PRS) is effective in predicting AD risk among Europeans but remains understudied in Hispanics. Diverse genome-wide association studies (GWAS) data across multiple ancestries may improve PRS predictions. We evaluated PRS performance to predict AD disease risk using novel methods in the largest available African, European, and Hispanic GWAS for AD. MethodsPrediction performance of APOE, single-ancestry PRS, and multi-ancestry PRS derived from GWAS-focused and method-focused approaches to clinical AD, incident AD, and cognition were evaluated in 2,961 Hispanics from two large studies. The GWAS-focused approach constructs PRS based on multi-ancestry GWAS, while the method-focused approach uses novel multi-ancestry PRS methods, integrating GWAS summary statistics across ancestries. Ten repetitions of 5-fold cross-validation were used. In a subset, plasma biomarker data were used in a tuning-validation split to examine PRS performance in predicting single and combined biomarkers. FindingsThe multi-ancestry PRS excluding APOE, constructed using the method-focused approach, outperformed both single-ancestry and multi-ancestry PRSs from the GWAS-focused approach. The best method-focused PRS, incorporating summary statistics from GWASs of African, European, and Hispanic populations, explained up to 1.6%, 3.9%, and 1.7% of the variance in clinical AD, incident AD, and cognition, respectively - comparable to or even higher than the variance explained by the APOE. Similar findings were observed in biomarker analyses. APOE accounted for more variation in plasma P-tau levels and PRS explained more variation in A{beta} levels. InterpretationIntegrating novel multi-ancestry PRS methods with GWAS across ancestries enhances prediction accuracy for AD risk among Hispanics. APOE and PRS may point to different biological aspects of AD. FundingNational Institutes of Health R01 AG072474, RF1 AG066107, 5R37AG015473, RF1AG015473, R56AG051876, R01 AG067501, and UL1TR001873. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed for research related to PRS prediction of AD in Europeans, Africans, and Hispanics, published from database inception to August 1, 2024, without any language restrictions. The search terms used were "PRS," "PGS," "Hispanics," "Latinos," "AD," and "plasma biomarkers." We considered only peer-reviewed reports in English. Previously, few studies have examined the performance of PRS in predicting clinical AD, incident AD, and mild cognitive impairment (MCI) among Hispanics. However, none of these studies utilized advanced methods for constructing multi-ancestry PRS, validated PRS performance among Hispanics, or examined plasma biomarkers. Added value of this studyThe present study demonstrated that integrating novel multi-ancestry PRS methods with GWAS from African, European, and Hispanic populations enhanced prediction accuracy for AD risk among Hispanics. Among Hispanics, PRS explains a similar or higher amount of variance compared to APOE. Plasma biomarker analyses suggests that APOE may also be strongly related to variation in P-tau levels, while PRS may explain variance in A{beta} levels. Implications of all the available evidenceAmong Hispanics, PRS complements the effects of APOE and has the potential to identify at-risk populations for clinical trial eligibility and early biomarker screening. Although AD genetic studies are still limited among Hispanics, a dynamic combination of advanced methods with GWAS across populations could substantially improve prediction performance in this population, which in turn may reduce health disparities.

IntroductionComprehensive treatment of Alzheimers disease and related dementias (ADRD) requires not only pharmacologic treatment but also management of existing medical conditions and lifestyle modifications including diet, cognitive training, and exercise. The Coaching for Cognition in Alzheimers (COCOA) trial was a prospective randomized controlled trial (RCT) to test the hypothesis that a remotely coached multimodal lifestyle intervention would improve early-stage Alzheimers disease (AD). AD results from the interplay of multiple interacting dysfunctional biological systems. Specific causes of AD differ between individuals. Personalized, multimodal therapies are needed to best prevent and treat AD. COCOA collected psychometric, clinical, lifestyle, genomic, proteomic, metabolomic and microbiome data at multiple timepoints across two years for each participant. These data enable systems-biology analyses. We report analyses of the first COCOA data freeze. This analysis includes an evaluation of the effect of the intervention on outcome measures. It also includes systems analyses to identify molecular mediators that convey the effect of personalized multimodal lifestyle interventions on amelioration of cognitive trajectory. MethodsA total of 55 participants with early-stage AD from Southern California were randomized into two parallel arms. Arm 1 (control; N=24) received standard of care. Arm 2 (intervention; N=31) also received telephonic personalized coaching for multiple lifestyle interventions including diet, exercise, and cognitive training. COCOAs overarching aim was to gather dense molecular data from an AD cohort to improve understanding of pathophysiology and advance treatment. For the RCT, COCOAs objective was to test the hypothesis that the Memory Performance Index (MPI) trajectory would be better in the intervention arm than in the control arm. The Functional Assessment Staging Test (FAST) was assessed for a secondary outcome. Assessments were blinded. The nature of the intervention precluded participant blinding. ResultsThe intervention arm ameliorated 2.6 {+/-} 0.8 MPI points (p = 0.0007; N = 48) compared to the control arm over the two-year intervention. Top-ranked candidate mediators included: albumin, propionylcarnitine, sphingomyelin, hexadecanedioate, acetylkynurenine, tiglylcarnitine, IL18R1, palmitoyl-sphingosine-phosphoethanolamine, acetyltryptophan, and IL17D. These individual molecules implicated inflammatory and nitrogen/tryptophan metabolism pathways. No important adverse events or side effects were observed. ConclusionsClinical trials should include frequent assessment of dense data to maximize knowledge gained. Such knowledge is useful not only in testing a primary hypothesis, but also in advancing basic biological and pathophysiological knowledge, understanding mechanisms explaining trial results, generating synergistic knowledge tangential to preconceived hypotheses, and refining interventions for clinical translation. Data from every trial should allow an intervention to be refined and then tested in future trials, driving iterative improvement. Multimodal lifestyle interventions are effective for ameliorating cognitive decline and may have an effect size larger than pharmacological interventions. Effects may be molecularly idiosyncratic; personalization of interventions is important. Dietary changes and exercise are likely to be beneficial components of multimodal interventions in many individuals. Remote coaching is an effective intervention for early stage ADRD. Remote interventions were effective during the COVID pandemic.

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.

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.

BackgroundEarly detection of Alzheimers disease (AD) is crucial; however, standard neuropsychological tests often lack sensitivity. Process scores, such as proper name (PN) recall from Logical Memory (LM), may improve the detection of AD-related biomarker positivity. We examined whether baseline PN recall predicted future cerebrospinal fluid (CSF) amyloid (A{beta}42/A{beta}40) and tau (pTau181) status, and whether biomarker status predicted PN recall trajectories. MethodsWe analyzed 271 cognitively unimpaired BIOCARD participants (mean age = 57.3, 60.3% female, mean follow-up = 15.5) using logistic regression and mixed-effects models to examine the associations between PN recall and CSF biomarkers. ResultsHigher baseline PN recall predicted lower amyloid positivity (odds ratio [OR] = 0.72, p = 0.015). Amyloid and tau positivity have been linked to a faster decline in PN. Biomarker-positive participants in the biomarker-negative group lacked practice effects. ConclusionsPN recall predicts future AD biomarker positivity and may enhance early detection of AD-related cognitive decline.

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.

STRUCTURED ABSTRACTO_ST_ABSINTRODUCTIONC_ST_ABSThe NULISASeq CNS Disease Panel has high potential for AD diagnosis, but the comparability of serum vs. plasma remains unclear. METHODSWe compared its performance on 43 matched serum-plasma pairs from a memory clinic cohort. RESULTSThe panel reproducibly quantified 124 targets (mean CV=4.9%) with high detectability (mean=95.7%). Serum-plasma correlations were strong ({rho}>0.7) for 79 targets. 48 targets had significant NPQ differences, with 32 higher in plasma. Plasma had more erythrocyte-enriched proteins (HBA1, PGK1, SOD1, PRDX6), while serum had more platelet-derived proteins (CD40LG, BDNF, VEGFA, A{beta}40). For classical AD biomarkers, serum-plasma correlations were stronger for p-tau, GFAP, and NfL ({rho}>0.9) than for A{beta} targets ({rho}=0.594- 0.785). Tau levels were higher in plasma; GFAP and NfL were similar, and A{beta} peptides were mixed. Twelve targets, along with p-tau217/A{beta}42, were linked to AD diagnosis, with plasma generally showing stronger effects. DISCUSSIONOur results support serum use but suggest plasma performs better for AD using this panel.

STRUCTURED ABSTRACTO_ST_ABSINTRODUCTIONC_ST_ABSThe interpretation of plasma phosphorylated tau (pTau) levels may be influenced by metabolic conditions, such as insulin resistance (IR), type 2 diabetes mellitus (T2DM), obesity, and kidney function. We examined the extent to which metabolic factors are associated with plasma pTau concentrations (pTau181, pTau217, pTau231) and the contribution of these factors on analytical outcomes. METHODSWe analyzed data from 287 participants using partial Spearmans rho, Mann Whitney U, ROC analysis, and linear mixed models. RESULTSConcordance between plasma pTau217 and amyloid PET was not influenced by IR or estimated-glomerular-filtration-rate (eGFR). Accounting for eGFR improved concordance of pTau181 and pTau231 with amyloid PET. Age, binarized waist-to-hip ratio, and amyloid status were associated with all longitudinal pTau concentrations, and eGFR associated with longitudinal pTau231. DISCUSSIONMetabolic health may influence the interpretation of some plasma pTau biomarkers, potentially necessitating adjustments for metabolic factors in research and clinical settings.

INTRODUCTIONThis study employed an integrative system and causal inference approach to explore molecular signatures in blood and CSF, the Amyloid/Tau/Neurodegeneration [AT(N)] framework, MCI conversion to AD, and genetic risk for AD. METHODSUsing the EMIF-AD MBD cohort, we measured 696 proteins in cerebrospinal fluid (n=371), 4001 proteins in plasma (n=972), 611 metabolites in plasma (n=696) and genotyped data in whole-blood (7,778,465 autosomal SNPs, n=936). We investigated associations: molecular modules to AT(N), module hubs with AD Polygenic Risk scores and APOE4 genotypes, molecular hubs to MCI conversion and probed for causality with AD using Mendelian Randomization (MR). RESULTSAT(N) framework associated key hubs were mostly proteins and few lipids. In MR analyses, Proprotein Convertase Subtilisin/Kexin Type 7 showed weak causal associations with AD, and AD was causally associated with Reticulocalbin 2 and sphingomyelins. DISCUSSIONThis study reveals multi-omics networks associated with AT(N) and MCI conversion and highlights AD causal candidates.

BackgroundMultianalyte plasma proteomic panels that can accurately detect initial AD pathology in preclinical populations and simultaneously measure related biological processes relevant for disease risk are critical for advancing early detection and prognosis. MethodsUsing the NULISAseq CNS panel, we measured plasma from 193 clinically unimpaired (CU) older adults enrolled in the Stanford Aging and Memory Study (SAMS). We evaluated correspondence of core AD-relevant biomarkers A{beta}42, A{beta}40, pTau217, pTau181, GFAP, NfL, A{beta}42/A{beta}40, and pTau217/A{beta}42 measured using NULISAseq and established Lumipulse immunoassays. ROC curve analyses compared the accuracy of these biomarkers for detecting Lumipulse CSF A{beta}-positivity across platforms. Linear models were applied across 124 NULISAseq proteins to examine associations with common AD risk factors, including age, female sex, and APOE-{varepsilon}4, as well as with biomarkers CSF A{beta}42/A{beta}40 and pTau181, 18F-PI2620 Tau PET, and memory. Fold change differences in NULISAseq proteins as a function of CSF A{beta} (A+) and pTau181 (T+) status were examined using Wilcoxon rank-sum tests. ResultsModerate to high correlations were observed between NULISAseq and Lumipulse AD plasma biomarkers. Across platforms, plasma pTau217/A{beta}42 exhibited the highest performance in discriminating CSF A+ (NULISAseq AUC: 0.940, 95%CI: 0.885-0.995; Lumipulse AUC: 0.907, 95%CI: 0.849-0.966). Age and sex were associated with differential expression of NULISAseq targets linked to neurodegeneration, microglial activation, and inflammation. CSF A+ was associated with fold change differences in A{beta}42, pTau217, pTau231, pTau181, and GFAP, while CSF T+ was additionally associated with increases in TREM1, TIMP3, SAA1, and S100A12. When stratified by AT groups, A+T-exhibited lower A{beta}42 and elevated pTau217 compared to A-T-, whereas A+T+ exhibited elevated pTau231 and pTau181 compared to A+T-. Temporal cortex tau was positively associated with NULISAseq pTau217, pTau231, pTau181, and pTau217/A{beta}42. Memory function was negatively associated with pTau isoforms and PRDX6, YWHAZ, ENO2, ARSA, CHI3L1, CXCL8, and FCN2. These associations remained when controlling for pTau217 and restricting to A-CU, suggesting these targets may represent AD-independent biological pathways relevant for memory function. ConclusionsNULISAseq immunoassay-based multiplexing accurately detects AD pathology among CU older adults and identifies multiple biological pathways related to early biomarker abnormality and memory function that may become dysregulated in preclinical AD.

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.

IntroductionThe impact of different neuropathologies on deep brain structures remains to be understood. Here, we distinguish subcortical and limbic volumetry in neurodegenerative diseases involving p-tau, -synuclein and TDP-43. MethodsWe acquired neuropathological measures and brain segmentations from postmortem analysis of 132 donors with Alzheimers disease (AD; n=60), Lewy body disease (LBD; n=26), Frontotemporal Lobar Degeneration with TDP-43 (FTLD-TDP; n=21) and FTLD-Tau (n=25). ResultsIn FTLD-TDP and FTLD-Tau, thalamus and striatum volumes were lower than in AD or LBD. While AD had diffuse cortico-subcortical and cortico-limbic morphometric associations, LBD had more limited parieto-occipital cortico-limbic associations. FTLD-TDP had cortico-subcortical associations while FTLD-Tau had cortico-limbic associations. In AD and FTLD-Tau, hippocampal volumes correlated with p-tau burden, neuron loss and gliosis. In LBD, thalamic -synuclein severity was associated with subcortical and limbic volumes. In FTLD-TDP, TDP-43 load had no such significant associations. DiscussionPostmortem neuroimaging reveals unique structure-structure and structure-pathology relationships across regions and diseases. Highlights[bullet] FTLD-Tau and FTLD-TDP show lower thalamic and striatal volumes than AD or LBD groups. [bullet]Subcortical and limbic volume loss significantly correlates with global brain shrinkage in AD. [bullet]LBD exhibits less postmortem subcortical and limbic atrophy compared to other groups. Parieto-occipital atrophy corresponds to limbic but not subcortical volume loss in LBD. [bullet]FTLD-Tau has cortico-limbic morphometric associations while FTLD-TDP has cortico-subcortical associations. [bullet]In AD and FTLD-Tau, hippocampal volume correlates with p-tau load, neuronal loss and gliosis semiquantitative measures. [bullet]In LBD, thalamic -synuclein burden is associated with subcortical and limbic volumes. [bullet]In FTLD-TDP, TDP-43 pathology burden shows no significant volume associations.

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.

STRUCTURED ABSTRACTO_ST_ABSIntroductionC_ST_ABSMetabolic disorders are risk factors for Alzheimers disease (AD), although underlying mechanisms remain unclear. We investigated the relationship between peripheral metabolic markers - adiponectin, FGF-21 and IGFBP-2 - and AD. MethodsParticipants with subjective cognitive decline (SCD), mild cognitive impairment (MCI), AD and cognitively healthy controls (CH) were from the CIMA-Q cohort (n=287). Serum adiponectin, FGF-21, and IGFBP-2 concentrations were measured, compared between groups, and assessed for associations with clinical, cognitive, biochemical and MRI data. ResultsMetabolic dysfunction was linked to lower adiponectin and IGFBP-2, but higher FGF-21. Both FGF-21 and IGFBP-2 increased with age and were inversely associated with cognitive performance. IGFBP-2 was elevated at SCD stage and correlated with plasma pTau181 and amygdala atrophy. Adiponectin was unrelated to cognition. DiscussionThese findings suggest that IGFBP-2, and FGF-21 to a lesser extent, may serve as early biomarkers of cognitive impairment, reflecting intricate links between peripheral dysmetabolism and AD.

BackgroundAccurate prediction of which patients with mild cognitive impairment (MCI) will progress to Alzheimers disease (AD) remains a major unmet clinical need. Current biomarkers detect amyloid pathology with high accuracy but offer limited prognostic value for disease progression. MethodsWe conducted a prospective analysis in the multicentre BALTAZAR cohort (NCT01315639), all diagnosed with MCI at baseline and followed clinically for 3 years. Paired cerebrospinal fluid (CSF) and plasma samples were collected on the same day and analysed with the NULISA ultrasensitive multimarker platform quantifying 120 central nervous system biomarkers. Prognostic performance for conversion to AD dementia was assessed using area under the receiver operating characteristic curve (AUC) and hazard ratios (HRs), both for individual markers and for elastic-net-derived biomarker combinations validated by bootstrap and survival analyses. FindingsDuring the 3-year follow-up, 63% of participants converted to AD. Plasma p-tau biomarkers showed strong accuracy for detecting amyloid positivity (AUC > 0{middle dot}90) but limited prognostic value for conversion (AUC < 0{middle dot}75). In CSF, markers of neurodegeneration (tau, p-tau181, NfL) and synaptic dysfunction (NPTX2) predicted conversion with higher accuracy, matching or exceeding p-tau217 performance. The best-performing CSF combination (IL-16, tau, NPTX2) achieved an AUC of 0{middle dot}86 (95% CI 0{middle dot}80-0{middle dot}91) and an HR of 39{middle dot}8 (95% CI 9{middle dot}6-165{middle dot}2). Plasma combinations (e.g., p-tau181 or p-tau217 with YWHAG) provided only modest improvement, likely reflecting the absence of robust synaptic markers in blood. InterpretationPrognostic assessment of MCI progression to AD is best achieved through CSF biomarker combinations reflecting neurodegeneration and synaptic dysfunction, complemented by inflammatory markers. These findings emphasise the clinical and pathophysiological relevance of downstream processes beyond amyloid and tau, and support the implementation of multimarker panels for prognosis and therapeutic monitoring.