Journal of Alzheimer’s Disease

BACKGROUND: Cognitive resilience to Alzheimer's disease (AD) can be modelled in amyloid-expressing rodents through early handling (EH). This study investigated how EH and sex affect cognition and pathology over time. METHODS: We assessed cognition (Open field, Novel object recognition test, Barnes maze) in 6- and 12-month-old APP/PS1 and WT mice (N=180, EH/Ctrl X M/F), performed biochemical and histological analyses of several brain areas to assess effects on amyloid-beta, glial cells, and other markers of pathology, and investigated how behavior correlates with pathology. RESULTS: EH improved non-spatial memory at 6 months, consistent with a reduction of hippocampal microglia density, and normalized locomotor activity at 12 months (both p<0.05). Females demonstrated similar (6 & 12 months) or better (12 months) cognition, despite greater pathology across timepoints. Correlations implicated microglial recruitment in EH-related effects, supported by morphological analysis of prefrontal regions (p<0.05). CONCLUSION: Our findings highlight the critical role of early postnatal experiences and sex in shaping resilience in the context of AD pathology.

INTRODUCTIONInflammation plays a central role in Alzheimers Disease (AD), with oxylipins, endocannabinoids, and polyunsaturated fatty acids (PUFAs) acting as potent modulators. Soluble epoxide hydrolase (sEH), an enzyme with proinflammatory products, is upregulated in the AD brain. Emerging evidence suggests that AD-related inflammation may reflect systemic metabolic changes, however, peripheral organs remain understudied. Because the liver has a pivotal role in lipid metabolism and bioactive lipid mediator homeostasis, we hypothesized that inflammatory lipid mediator changes in the AD brain may be reflected in, and potentially shaped by, hepatic lipid metabolism. METHODSPaired postmortem brain and liver tissues from 16 cognitively normal and 63 AD donors with median postmortem intervals (PMI) of 3.08 hours were analyzed for free and esterified forms of oxylipins and endocannabinoids. ANCOVA models evaluated effects of AD diagnosis, sex, and AD-by-sex interactions, adjusting for analytical batch, age, body mass index, and PMI. RESULTSAD-associated differences in lipid mediator profiles were observed in both brain and liver, with a broader pattern of differences in liver. Differences involved CYP/sEH-related metabolites and fatty acid ethanolamides, with several metabolites also showing AD-by-sex interactions. Sex-associated differences were also more pronounced in the liver than the brain. DISCUSSIONThese results suggest AD-associated lipid dysregulation across both central and peripheral tissues. The prominent hepatic alterations highlight the liver as an important site of peripheral lipid mediator dysregulation in AD and suggest that hepatic metabolic changes may contribute to or reflect inflammatory lipid remodeling in the brain.

Cholinergic neurons in the dorsal motor nucleus of the vagus (DMN) in the brainstem are a key source of efferent vagus nerve fibers that regulate vital functions, including heart rate and inflammation. Whether the integrity of DMN cholinergic neurons is affected during Alzheimer's disease (AD) remains unknown. Here, in female and male mice with experimental AD (5xFAD), which exhibit age-dependent memory impairment, basal forebrain cholinergic neurodegeneration, and microglial alterations, we observe a reduction in cholinergic neuron density in the DMN at 6 and 10 months of age. Furthermore, while an important physiological function of DMN cholinergic signaling, such as suppression of heart rate, is preserved in control mice upon electrical DMN stimulation, the extent of suppression diminishes with age in both female and male 5xFAD mice. In addition, while electrical DMN stimulation lowers pro-inflammatory cytokine levels in control mice subjected to endotoxemia, this anti-inflammatory effect is diminished with age in 5xFAD mice, with females showing earlier dysfunction at 6 months. These results reveal previously unrecognized age-dependent cholinergic deficits in the DMN and disrupted brain - to - periphery vagus nerve circuits in experimental AD. These findings advance our understanding of AD mechanisms and are of interest for the development of conceptually novel therapies.

Background: Studies indicate that the apolipoprotein E (APOE) {varepsilon}4 allele is the strongest genetic risk factor for Alzheimer's disease (AD), and individuals with this allele are at increased risk of developing AD, there remains debate regarding whether APOE {varepsilon}4 carriers experience more rapid cognitive decline over time compared to non-carriers. This study assessed this question using linear mixed-effects models applied to the placebo arm of EXPEDITION 1, a phase 3 clinical trial evaluating solanezumab in patients with mild-to-moderate Alzheimers disease. Methods: In this study we utilized data from 370 participants in the placebo group of the EXPEDITION 1 trial. After excluding 27 participants with undefined APOE genotype, all models and analyses were applied to the remaining 343 participants (686 ADAS-Cog14 observations) to determine whether APOE {varepsilon}4 carriers exhibit a faster rate of decline over the 80-week follow-up period. Five nested linear mixed-effects models with a participant-specific random intercept were fitted, and also a complementary change-score analysis was done. Results: Over 80 weeks, ADAS-Cog14 worsened by an average of 7.01 points. Carriers did not decline faster than non-carriers (additional decline 1.31 points; 95% CI -1.22 to 3.83; p = 0.310), and the change-score analysis showed the same pattern. Carriers had worse ADAS-Cog14 scores overall, but this difference was no longer significant after adjustment for baseline CDR-SB. Conclusion: In this cohort, APOE {varepsilon}4 carrier status was related to disease severity at baseline rather than to the rate of cognitive decline over 80 weeks.

Objectives Alzheimer's disease (AD) progresses from a cognitively unimpaired stage through mild cognitive impairment (MCI) to dementia. Because language impairment often emerges before dementia, it is a candidate marker of disease stage. Yet the standard batteries of large AD research cohorts rely on a narrow set of tests that mainly evaluate the lexical-semantic domain (i.e., picture naming and verbal fluency), leaving other language domains, such as semantic memory, phonology, morphosyntax, and single-word reading, rarely assessed. We evaluated the diagnostic utility of standard and specialized language tests for distinguishing amyloid-positive MCI and dementia of the Alzheimer's type (DAT) from healthy controls (HC) and from each other. Methods We included 286 participants from the National Alzheimer's Coordinating Center (125 HC, 53 MCI, 108 DAT) assessed with three standard tests from UDSv3 (semantic fluency, letter fluency, and Multilingual Naming Test [MINT]) and nine specialized tests from the FTLD Module (regular and irregular word reading, semantic word-picture matching, semantic associates, Northwestern Anagram Test - Short Form [NAT-S], Northwestern Naming Battery noun and verb naming, sentence repetition, and sentence reading). For each test, the area under the receiver operating characteristic curve (AUC) was computed for DAT vs. HC, MCI vs. HC, and DAT vs. MCI, and AUCs were compared between tests with DeLong's test. Results Eight of 12 measures reached acceptable discrimination (AUC [&ge;] .700) for DAT vs. HC, five for MCI vs. HC, but only semantic fluency and NAT-S for DAT vs. MCI. Semantic fluency showed the highest discrimination in each contrast, though it did not significantly outperform the NAT-S for MCI vs. HC or DAT vs. MCI. MINT, letter fluency, and irregular word reading reached clinically meaningful accuracy in distinguishing MCI and DAT from HC, but not DAT from MCI. The remaining specialized tests reached it only for DAT vs. HC, or not at all. In a post hoc regression, adjusting for cognitive flexibility and working memory attenuated group differences; the DAT difference was no longer significant, whereas the MCI difference remained significant. Discussion Semantic fluency was the strongest single language marker across the AD continuum. Among specialized tests, NAT-S was the most informative, challenging the view that syntax is spared in early AD. Its performance was partly explained by executive function, mainly in DAT, whereas a residual morphosyntactic component remained in MCI, and several specialized tests were limited by ceiling effects. Clinically, the NAT-S may complement semantic fluency for staging, and specialized tests may help characterize heterogeneous language profiles in MCI and DAT.

Background: Alzheimer's disease (AD) is the leading contributor to dementia burden, and the risk of developing it is impacted by a multitude of factors. Among these factors are metabolic conditions like type-2 diabetes (T2D) and metabolic syndrome (MetS), along with ethnicity, which interacts both with AD and the metabolic comorbidities. Previous studies have established associations between methylation patterns at specific CpG sites and risk for AD, T2D and MetS individually, but the underlying etiology that is responsible for interactions between metabolic conditions and AD risk remains unresolved. Objective: We aimed to examine methylation patterns among Mexican American (MA) and Non-Hispanic White (NHW) individuals in the context of AD, alongside T2D and MetS, to identify CpG sites associated with disease-specific and interaction-dependent methylation effects related to those comorbidities. Methods: DNA methylation data from 551 patients of MA or NHW ancestry who were enrolled in the Texas Alzheimer's Research and Care Consortium (TARCC) were available for analysis. Participants were stratified into groups by AD/T2D status or AD/MetS score and Beta-values from the Illumina MethylationEPIC chip array were obtained for each patient. Differential methylation status was analyzed using the lumi and cate packages in R. Results: Five CpG sites had statistically significant differential methylation patterns, including two (cg06322660 and cg25514677) which exhibited significant interactions between AD and T2D status or AD and MetS score respectively, with cg06322660 being significant in the NHW cohort and cg25514677 being significant in the MA cohort. The association at cg25514677 was replicated in an independent MA cohort.

INTRODUCTION: This study examined the extent to which educational attainment, Alzheimer's disease (AD) knowledge, and research attitudes are associated with willingness to participate in AD research, and whether AD knowledge and research attitudes mediate associations between educational attainment and willingness to participate. METHODS: 201 older adults completed self-report measures of AD knowledge, research attitudes, prior research participation, and willingness to participate in diagnostic procedures (neuropsychological assessment, blood draw, brain MRI) and non-pharmacological intervention research (tracking physical activity, aerobic exercise). RESULTS: Favorable research attitudes were consistently associated with greater willingness to participate across all proposed research activities, and research attitudes mediated the relationship between educational attainment and willingness to participate in research. In contrast, AD knowledge did not mediate the association between educational attainment and willingness to participate. DISCUSSION: Research attitudes may be a key, modifiable determinant of willingness to participate in AD research and a promising focus for broadening AD research participation.

Speech-based cognitive monitoring for Alzheimer's employs various tasks, but whether timing measures transfer across tasks is unclear. Twelve senior living residents completed four 60-second tasks: category fluency, two picture descriptions, and a self-generated narrative. Speech timing measures were calculated identically across tasks. Speech-rate correspondence among picture descriptions and narrative was substantial (mean Spearman rho; = 0.72). Correspondence with category fluency increased from Cookie Theft to contemporary picture to narrative in terms of speech rate (Spearman rho; = 0.36, 0.51, 0.64) and pause time ratio (Spearman rho; = 0.14, 0.45, 0.71). Measures were not interchangeable; correspondence followed an ordering consistent with shared retrieval demand.

Objective To examine the association between patient-reported shared decision-making (SDM) and documented advance care planning (ACP) among adults with Alzheimer disease and related dementias (ADRD), and to assess whether this association differed between adults with and without ADRD. Design Retrospective observational study using linked survey and electronic health record (EHR) data. Setting and Participants Participants aged [&ge;]50 years in the All of Us Research Program who completed a patient-reported SDM measure and had linked EHR records. The primary analytic cohort included 3,635 adults with ADRD; 123,681 adults without ADRD comprised a secondary comparison cohort. Methods SDM was measured by how often clinicians asked participants about their opinions or preferences regarding medical care or treatment and was categorized as high (always/most of the time) or low (some of the time/ None of the time). Documented ACP was identified within 3 years before or after the SDM assessment. Modified Poisson regression with robust variance estimated prevalence ratios (PRs) and adjusted PRs (aPRs). Results Among adults with ADRD, 60.6% reported high SDM. Documented ACP prevalence was 5.1% among participants with high SDM and 3.6% among those with low SDM (P=0.027). High SDM was associated with greater ACP prevalence in the unadjusted model (PR, 1.44; 95% CI, 1.04-1.99); the association remained positive but was attenuated after full adjustment (aPR, 1.28; 95% CI, 0.93-1.77). Among adults without ADRD, high SDM was associated with documented ACP (aPR, 1.17; 95% CI, 1.03-1.33). Conclusions and Implications Among adults with ADRD, high SDM was associated with greater ACP prevalence in unadjusted analyses, although the fully adjusted association was not statistically significant. In contrast, higher SDM remained significantly associated with ACP among those without ADRD. The low prevalence of ACP highlights an important opportunity to expand discussions of current and future care preferences as a routine component of patient-centered care.

INTRODUCTION: Observational studies suggest that angiotensin receptor blockers (ARBs) are associated with lower dementia risk than angiotensin-converting enzyme inhibitors (ACEIs). Whether dementia risk differs across individual ARBs remains uncertain and was investigated in this study. METHODS: This retrospective cohort study emulated target trials using electronic health record and claims data from 44 US health care organizations in the TriNetX Linked Research Network. ACEI/ARB-naive adults aged 55 to 80 years initiating an ARB or lisinopril were eligible. Separate 1:1 propensity-score matching was performed for each comparison. Individual and pooled ARBs were compared with lisinopril (between-class), and non-losartan ARBs with losartan (within-class). The primary outcome was incident all-cause dementia; secondary outcomes included Alzheimer disease, vascular dementia, cerebral infarction, death, and dementia or death. Cox models estimated hazard ratios (HRs) and 95% CIs. Sensitivity analyses included lagged and treatment-persistence analyses, control outcomes, and E-values. RESULTS: Of 22,025,599 individuals screened, 2,051,275 were eligible; matched cohorts ranged from 10,113 to 857,773, with median follow-up of 4.7 to 7.2 years. Pooled ARBs were associated with lower dementia risk than lisinopril (HR, 0.86; 95% CI, 0.85 to 0.87), with substantial variation across individual agents (HR range, 0.66 to 0.93). Within-class comparisons showed similar heterogeneity (HR range, 0.68 to 0.94) and reproduced between-class agent ordering by HR estimates. Considerable agent-level variation was also observed across secondary outcomes. Losartan, the most commonly prescribed ARB, had the least favorable dementia associations. Negative-control associations were near null within class, and sensitivity analyses supported robustness. DISCUSSION: Individual ARBs were associated with differing dementia risks, suggesting clinically relevant within-class heterogeneity pending confirmation in randomized trials.

Objectives: To determine whether distinct anxiety phenotypes (rumination, global anxiety and worry; RAW) are associated with plasma brain-derived (BD) phosphorylated-tau (p-tau) biomarkers of Alzheimer's disease (AD) in older adults. Design: Cross-sectional observational study. Methods: Participants were 89 older adults aged 50[&ge;]years (mean age 64.3{+/-}8.8 years) enrolled in the RAW Brain study (R01 MH108509) in Pittsburgh, Pennsylvania. Anxiety phenotypes were assessed using the Penn State Worry Questionnaire (PWSQ[&ge;]50), Rumination Subscale from the Response Style Questionnaire (RSQ>50), and Hamilton Anxiety Rating Scale (HARS>17). Participants were classified as High-RAW if they exceeded established severity thresholds on [&ge;]1 domain; continuous anxiety scores were used for primary analyses. Plasma BD-tau, BD-p-tau181, BD-p-tau217, and BD-p-tau231, and matched non-BD versions were quantified using the NULISAseq CNS Panel. Associations between anxiety phenotypes and tau biomarkers were examined using multivariable linear regression adjusted for age, sex, and APOE4 status, with Benjamini-Hochberg false discovery rate correction. Results: Greater global anxiety was associated with higher plasma BD-p-tau181 ({beta}=0.308, 95% CI [0.003,0.048], p=0.047). This association was also observed categorically (adjusted Cohen's d=0.462, p=0.049). Worry and rumination were not associated with BD-p-tau181, and no anxiety phenotypes were associated with BD-tau, BD-p-tau217, BD-p-tau231, or corresponding non-BD alternatives. Conclusions: Greater late-life global anxiety, but not worry or rumination, was selectively associated with higher plasma BD-p-tau181. These findings extend epidemiologic evidence linking anxiety to AD risk by identifying a biologically specific blood-based correlate linking anxiety with AD-related p-tau biology. Longitudinal studies incorporating amyloid and tau biomarker confirmation are needed to determine whether anxiety precedes, accompanies, or results from early AD pathophysiology.

Objective: Dysregulation of the immune system is increasingly recognized as a contributor to Alzheimer's disease (AD) progression, partly through neutrophil adhesion to the cerebral vasculature, which promotes hypoperfusion in AD. Because sialic acid (SA) residues on membrane glycoproteins regulate neutrophil-endothelial interactions, we investigated whether neutrophil sialylation is altered in AD and whether reducing it improves cerebral vascular function. Approach and Results: Lectin blots of isolated neutrophils showed increased SA levels in two AD mouse models, 5xFAD and APP-SAA. We identified 2,3 sialyltransferase-IN-1 as a small-molecule inhibitor that reduces sialylation in vivo. Treating 5xFAD mice with this inhibitor decreased SA on neutrophil membranes, increased cerebral blood flow, and reduced capillary stalling. Leukocytes from patients with preclinical AD and mild cognitive impairment also had higher SA levels than those from age-matched healthy controls. Conclusions: Elevated terminal sialylation of neutrophil glycoproteins contributes to capillary stalling and cerebral hypoperfusion in AD. Neutrophil sialylation may serve as both a biomarker and a therapeutic target for improving cerebral blood flow and slowing disease progression.

INTRODUCTION: Individual lifestyle, behavioural and health-related factors are associated with the risk of developing dementia. However, the co-occurrence of these factors, which are likely to form distinct patterns, in relation to dementia risk has been understudied. METHODS: The sample included 151,832 UK Biobank participants aged 60-69 years. Latent class analysis was used to identify patterns among participants with two or more of the following risk factors: high alcohol consumption, high body weight, depression, diabetes, poor diet, hypertension, physical inactivity, visual impairment, hearing impairment, sleep disturbance, smoking, social isolation, traumatic brain injury, and vitamin D deficiency. Multivariate Cox proportional hazards models were used to determine the associations between identified risk factor patterns and incident dementia ascertained through hospital and death records. RESULTS: Over a median follow-up of 13 years, 5,304 participants developed dementia. Six risk factor classes were identified. Compared to participants with zero or one risk factor, all classes were associated with dementia risk: 'multiple risk factors' (hazard ratio [HR] 2.38, 95% confidence interval [CI] 2.11-2.68), 'hearing loss and unhealthy lifestyle' (HR=1.37, 95% CI 1.22-1.55), 'sleep and psychosocial factors' (HR=1.34, 95% CI 1.20-1.49), 'poor cardiometabolic health' (HR=1.32, 95% CI 1.19-1.46), 'heavy drinking and unhealthy lifestyle' (HR=1.20, 95% CI 1.07-1.35), and 'vitamin D deficiency, sedentary and psychosocial factors' (HR=1.18, 95% CI 1.03-1.35). DISCUSSION: We identified risk factor patterns that were differentially associated with dementia risk. These findings suggest that accounting for the co-occurrence of risk factors might be an effective approach for risk stratification and developing effective dementia prevention strategies.

Background: Blood-based biomarkers (BBMs) may facilitate early detection of Alzheimers disease (AD), yet data in Latino populations remain limited. We examined associations of plasma biomarkers with cognition and depressive symptoms in Spanish-speaking Latino older adults enrolled in the Boston Latino Aging Study (BLAST). Methods: Baseline data from 122 older adults without dementia were analyzed. Plasma AB42/40, brain-derived phosphorylated tau (p-tau) 217, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) were measured using NULISA. Cognition was assessed with the Latin American Spanish version of the Preclinical Alzheimers Cognitive Composite (LAS-PACC5) and depressive symptoms with the Geriatric Depression Scale (GDS). Regression models were adjusted for age, sex, and education. Results: Cognitively impaired participants had higher p-tau217 and GFAP than cognitively normal participants. Higher p-tau217 and GFAP were associated with poorer LAS-PACC5 performance, while higher NfL was associated with greater depressive symptoms. AB42/40 showed no significant associations. Conclusions: Distinct biomarker associations with cognitive and emotional functioning support further longitudinal evaluation of BBMs for risk characterization in Latino older adults and potential disease monitoring applications.

INTRODUCTION: Voice data combined with large language models may detect cognitive impairment, yet an interpretable framework has not been formally established. We developed and validated a scalable and interpretable framework, the Neurocognitive Speech Taxonomy (NST). METHODS: NST maps 314 voice features to 7 neurocognitive domains derived from neuropsychology, speech pathology, neurology and related fields. The domains capture features including articulatory precision, cognitive-linguistic, executive fluency & planning, phonation & laryngeal control, prosodic modulation, lexical-semantic, and morphosyntactic complexity. We evaluated NST structural stability, clinical validity and racial-educational equity in three cohorts (total N = 1,479). Cohort data included demographic and neuropsychological evaluations and AD biomarker status. We tested whether NST scores distinguish cognitive status (unimpaired vs impaired) and AD-biomarker status, track cognitive change, and correlate with AD neuroimaging measures. RESULTS: NST showed stable cross-cohort structure (Mantel r = 0.71-0.77) and differentiated MCI (d = -0.39) and AD biomarker status (d = -0.23). NST tracked longitudinal cognitive change, correlated with hippocampal volume (r up to 0.28, P < .001), and showed smaller racial and educational disparities relative to standard cognitive testing (NST d = 0.03-0.33, MoCA d = 0.37-0.72). DISCUSSION: NST provides a validated neurocognitive construct that facilitates interpretation of AI-driven voice biomarkers of AD. This study was not registered in a public trials registry.

Objectives: The rising prevalence of financial exploitation among older adults has prompted research on the cognitive mechanisms underlying financial decision making in later life. Prior work has demonstrated a link between cognitive impairment and financial vulnerability. The present study examined the unique contributions of composite measures of memory and executive functioning to scam susceptibility in middle-aged to older adults without dementia. Methods: One hundred and fifty-one participants (age= 68.2 {+/-} 8.0 years, 72.2% female, years of education= 16.4 {+/-} 2.2) completed standard neuropsychological measures from the Uniform Data Set (UDS), Version 3, and the California Verbal Learning Test, Second Edition, and a self-report scam susceptibility measure. Psychometrically robust composite scores, the UDS-M+ and UDS3-EF, were computed to represent memory and executive functioning domains. Linear regression models examined independent associations between UDS-M+ and UDS3-EF performance and scam susceptibility. Nested model comparisons evaluated unique contributions of the UDS-M+ and UDS3-EF when included in a joint model. Results: Lower UDS-M+ (b= -0.25, 95% CI [-0.45, -0.04], p= .018) and lower UDS3-EF (b= -0.33, 95% CI [-0.54, -0.12], p= .002) scores were independently associated with greater scam susceptibility after adjusting for age, sex, years of education, and income. However, only UDS3-EF remained significant in a joint model. Post hoc analyses revealed that only memory was associated with scam susceptibility in middle-aged adults whereas only executive functioning was significant in older adults. Conclusions: These findings highlight the importance of monitoring memory and executive functioning across middle to older adulthood when considering susceptibility to scams.

Background: Alzheimer's disease (AD) is a complex neurodegenerative disorder strongly influenced by genetic factors, with apolipoprotein E (APOE) {epsilon}4 allele being the most established risk variant. Although DNA-based genotyping remains standard, plasma proteotyping may provide scalable, isoform-specific alternatives. Methods: Plasma APOE4 protein were quantified using the NULISAseq CNS panel across four cohorts (ADRC, HeartSCORE, LATTICE, and ALPS). DNA-based APOE genotyping was the reference standard. Proteotyping thresholds for APOE {epsilon}4 carrier status and copy number were derived in ADRC and externally validated in the other cohorts. Logistic, proportional-odds, and Cox proportional-hazards models compared genotype- and proteotype-defined groups in relation to amyloid positivity, cross-sectional CDR global scores, and time to CDR-SB worsening, respectively. Results: Plasma APOE4 accurately classified APOE {epsilon}4 carrier status in ADRC (AUC=0.977, 95%CI 0.967-0.985; threshold 5.78 NULISA protein quantification [NPQ] value) and achieved near-perfect external validation in HeartSCORE, LATTICE, and ALPS (all AUCs=1.000, 95%CI 1.000-1.000). Plasma APOE4 also well-differentiated heterozygous from homozygous {epsilon}4 carriers (ADRC AUC=0.879, 95%CI 0.834-0.921; threshold 12.23 NPQ value). Genotype- and proteotype-defined {epsilon}4 carrier status showed similar associations with amyloid positivity (OR=4.40 vs 4.45), higher CDR global scores (OR=1.50 for both), and CDR-SB worsening (HR=1.22 for both). Discussion: Plasma APOE4 proteotyping accurately distinguished genotype-defined APOE {epsilon}4 carrier status and copy number while demonstrating AD-related associations comparable to DNA genotyping.

Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) frequently co-occurs with Alzheimer's disease (AD) pathology and has been studied mainly in older populations. We examined its frequency and expression in 196 individuals with autopsy-confirmed intermediate-to-high AD neuropathologic change, enriched for younger-onset cases, integrating neuropathology with antemortem clinical, cognitive and neuroimaging data. LATE-NC occurred in 31% overall and 19% of individuals with symptom onset [&le;]65 years. Its frequency increased with older age at symptom onset, and its presence was associated with greater episodic memory impairment and smaller amygdala and hippocampal volumes. Among individuals with LATE NC, older age at symptom onset was associated with memory-first presentation and greater medial temporal involvement, including higher inferior-to-medial temporal metabolism ratios on FDG PET. Despite its lower frequency, LATE-NC co-pathology should still be considered in early-onset AD, where selected clinical features and neuroimaging markers described in older populations may be less applicable.

INTRODUCTION: The locus coeruleus (LC) is one of the earliest sites of Alzheimers disease (AD) pathophysiological changes. LC magnetic resonance imaging (MRI) intensity may reflect effects of AD pathophysiology on the LC, providing a biomarker of early-stage AD. This study examined relationships among MRI-derived LC intensity, plasma phosphorylated tau 217 (pTau217), and memory in older adults without dementia. METHODS: Independently living adults aged 59-89 years (N = 163) underwent neuropsychological assessment and T1-weighted fast spin-echo MRI. We quantified a bilateral LC contrast ratio relative to a pontine reference region, averaged across axial slices. Plasma pTau217 was measured using the Quanterix ALZpath p-Tau217 Advantage PLUS assay. For a subset (n = 127), a memory composite score was calculated. RESULTS: After adjustment for age, sex, and APOE4 carrier status, lower LC intensity was associated with higher plasma pTau217 concentrations (B = 0.17, P = .02). Each 1-SD decrease in LC intensity was associated with 53% higher odds of pTau217 positivity (P = .03). In models additionally adjusted for education, a significant LC x pTau217 interaction for memory (B = 0.18, P = .009) indicated that lower LC intensity was associated with worse memory at low (P = .01), but not high (P = .64) pTau217 levels. DISCUSSION: These findings support MRI-derived LC intensity as a marker of early AD-related processes and suggest that LC intensity may provide complementary information not captured by plasma pTau217 alone. Longitudinal studies are warranted to determine how these relationships change across the early stages of AD.

INTRODUCTION: Existing cell-cell communication (CCC) studies of Alzheimer's disease dementia (ADD) using cortical snRNAseq data do not account for the distinct cell-type and gene-expression profiles within cortical layers. Cortical-layer-aware CCC analysis may clarify biological mechanisms associated with ADD and mild cognitive impairment (MCI). METHODS: We applied our recent analytical tool STACCato to identify CCC events associated with ADD and MCI within cortical layers, using a large-scale prefrontal cortex snRNAseq dataset (~1.4M nuclei, n=395) with cortical layers annotated from reference spatial transcriptomics data. RESULTS: We identified ADD/MCI-related CCC events with distinct patterns within cortical layers, including ADD-related interactions involving the known AD risk genes APOE and APP that were detected only in microglia in layer 5, and those with opposite effects of ADD and MCI in layers 5 and 6. DISCUSSION: Our findings on cortical-layer-aware ADD/MCI-related CCC events underscore the importance of spatially-aware genomics studies of AD.