Journal of Alzheimer’s Disease

Objective: Effective strategies to prevent Alzheimer's disease and related dementias (ADRD) are limited. Implementing our Medication-Wide Association Study (MWAS+), we highlighted varenicline as a candidate. This study evaluated the association between varenicline use and risk of ADRD relative to nicotine replacement therapy (NRT). Methods: Using the All of Us Research Database, we identified adults aged 50 years or older with available lifestyle survey responses regarding tobacco use history who initiated smoking cessation therapy with either varenicline or NRT between 2006 and 2023. We limited our cohort to incident monotherapy users and designated the index date as the first prescription. Individuals with baseline ADRD or no follow-up were excluded. Baseline characteristics included demographics, comorbidities, BMI, and prior medication exposures. Outcomes were incident ADRD and a composite outcome of ADRD or death. Findings: The cohort consisted of 9,584 individuals (1,801 varenicline users and 7,783 NRT users). After propensity score matching, there were 1,758 individuals in each group with balanced baseline characteristics. Varenicline use was associated with a reduced risk of ADRD (HR 0.516, 95% CI: 0.353-0.754) and the composite outcome ADRD or death (HR 0.657, 95% CI: 0.501-0.861). Kaplan-Meier curves also demonstrated varenicline's sustained benefits through the study period. Implications: Varenicline use is associated with a lower risk of ADRD among older adults receiving smoking cessation therapy. Further investigation of varenicline as a potential strategy for ADRD prevention is warranted. These findings underscored the value of explainable AI-guided approaches to drug repurposing.

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.

Vascular dementia (VaD) is a complex clinical syndrome arising from cerebrovascular disease, characterized by cognitive decline and functional impairment, and is projected to double in prevalence over the next three decades. Deficiencies in one-carbon (1C) metabolism are linked to the onset of VaD. Our previous work using mouse models has demonstrated that reduced dietary folic acid intake or genetic disruptions in 1C metabolism exacerbate outcomes in a model of VaD. However, the impact of VaD on one-carbon metabolism remains poorly understood. This study aims to provide a detailed molecular portrait of 1C metabolism within the context of VaD, shedding light on potential molecular mechanisms. In post-mortem medial prefrontal cortex tissue from VaD female and male patients and controls we measured protein expression of the folate receptor (FR) and 1C enzymes including methylenetetrahydrofolate reductase (MTHFR), thymidylate synthase (TS), choline acetyltransferase (ChAT), acetylcholinesterase (AChE), cystathionine {beta}-synthase (CBS) co-localized with NeuN. There was an interaction between VaD and gender for levels of FR. Both male and female VaD had increased levels of ChAT. Female VaD patients had higher levels of MTHFR and CBS when compared to males. VaD is a complex disease; the results of this study demonstrate that VaD impacts neuronal levels of 1C enzymes. Future studies should assess 1C in other cell types of the brain, as well as measure enzyme activity levels.

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.

Persistent racial disparities in dementia raise concerns regarding the validity and generalizability of existing prognostic models across diverse populations. We evaluated the utility of the 2024 Lancet Commission risk factors and resting heart rate (RHR) for race-specific dementia risk prediction using data from 55,004 participants in the National Alzheimer's Coordinating Center cohort. Cox proportional hazards and Random Survival Forest (RSF) models were developed separately for Black, White, Asian, and American Indian participants to predict 1-, 3-, and 5-year time to dementia. RSF consistently outperformed Cox models across all racial groups and prediction horizons, achieving 5-year AUCs of 0.88-0.91 compared with 0.69-0.81 for Cox models. Inclusion of RHR modestly and consistently improved predictive performance across racial groups. Predictor importance varied between racial groups, suggesting heterogeneity in dementia risk profiles and disease presentation. These findings support the potential utility of RHR as a complementary prognostic biomarker and highlight the importance of equitable, personalized dementia risk prediction across diverse populations.

Importance. Hypertension is among the most important modifiable risk factors for Alzheimers disease and related dementias (ADRD), but whether different antihypertensive drug classes confer different cognitive risk, particularly through differential modulation of angiotensin II receptor signaling, remains uncertain. Prior pharmacoepidemiologic evidence is based largely on a single Medicare cohort, and external validation across distinct healthcare data environments is needed. Objective. To externally replicate and extend prior findings across two structurally independent healthcare data sources, evaluating whether predominant use of antihypertensive medications that stimulate versus inhibit angiotensin II type 2 and type 4 receptor signaling is associated with risk of incident ADRD. Design, Setting, and Participants. Retrospective new user, active comparator cohort study with propensity score matching, conducted in parallel across two independent data sources: the Vanderbilt University Medical Center Synthetic Derivative (VUMC SD; deidentified academic medical center electronic health record through February 2025) and the Merative MarketScan Medicare Database (2015 to 2023). Adults aged 65 years or older with hypertension and at least 365 cumulative days of antihypertensive exposure were included after a 365-day blanking period. Exposures. Predominant use ([&ge;]80% of cumulative exposure days) of receptor-stimulating antihypertensive medications (angiotensin II receptor blockers, dihydropyridine calcium channel blockers, thiazide diuretics) vs receptor-inhibiting antihypertensive medications (angiotensin-converting enzyme inhibitors, {beta}blockers, nondihydropyridine calcium channel blockers); a third group of nonusers comprised participants without predominant use of either class. Main Outcomes and Measures. Time to first incident ADRD diagnosis was identified using ICD9 and ICD10 codes consistent with the CMS Chronic Conditions Data Warehouse definition. Adjusted hazard ratios (HRs) and 95% CIs were estimated using Cox proportional hazards models with time-dependent covariates. Results. The Medicare cohort included 1,596,034 beneficiaries (mean [SD] age, 75.0 [8.0] years; 55% female), and the VUMC SD cohort included 80,267 patients (mean [SD] age, 72.3 [5.8] years; 57% female). Over approximately 7 years of follow-up, ADRD incidence was lower among predominant users of stimulating vs. inhibiting medications in both cohorts (Medicare: 6.7% vs. 8.2%; VUMC SD: 4.9% vs. 5.7%). After adjustment, predominant use of stimulating medications was associated with lower ADRD risk versus inhibiting medications in both cohorts (Medicare: HR, 0.92; 95% CI, 0.90,0.93; P < .001; VUMC SD: HR, 0.92; 95% CI, 0.85,0.99; P = .03). Established cardiovascular and neuropsychiatric risk factors (atrial fibrillation, heart failure, chronic kidney disease, depression) showed expected associations with ADRD risk in both cohorts, supporting internal validity. Conclusions and Relevance. Across two structurally independent data sources, the predominant use of antihypertensive medications that stimulate angiotensin II type 2 and type 4 receptor signaling was associated with a modestly lower risk of incident ADRD compared with predominantly inhibiting agents. By replicating in two distinct data environments, these findings extend prior single-source pharmacoepidemiologic evidence and support evaluation of receptor targeted antihypertensive strategies for cognitive outcomes in randomized comparative-effectiveness trials.

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.

Impairment in the comprehension of morphosyntactic and transitivity information does not feature in current diagnostic guidelines for primary progressive aphasia (PPA) or Alzheimer's Disease (AD), despite research reporting delayed sensitivity or insensitivity of these clinical populations to these linguistic domains. Moreover, studies rarely compare all three PPA variants and AD within a single design, and the literature is weighted toward English, whose reduced morphology may not capture the full range of comprehension difficulties these populations experience. We developed a computer-based acceptability judgment task covering comprehension of the nominal and verbal inflection paradigm in Spanish, transitivity and word order. We recruited Spanish-speaking patients diagnosed with non-fluent/agrammatic, logopenic and semantic variants of PPA and typical AD. Psychometric evaluation confirmed good sensitivity, internal consistency and moderate correlation of task accuracy with language and neuropsychological measures. The four clinical groups retained the ability to endorse grammatical sentences but showed selective difficulty rejecting unacceptable ones. AD and the three PPA variants showed impaired comprehension of inflectional and transitivity information, whereas sensitivity to word order was comparatively preserved. Exploratory analyses revealed that short-term memory, working memory, and verbal semantics were differentially associated with sentence evaluation performance within and across groups. VBM analyses identified the left posterior temporal cortex as the main neuroanatomical correlate of grammaticality judgment performance. These findings extend prior English-language research to Spanish, demonstrating that morphosyntactic and transitivity deficits are a robust and cross-linguistically consistent feature of neurodegenerative language decline, and highlighting the importance of developing language-sensitive assessment tools for underrepresented linguistic populations.

Background: Alzheimer's Disease and Related Dementias (ADRD) is a growing global public health challenge, and caregivers experience high rates of burden, unmet needs, and system failures. These challenges vary by caregiver role and relationship to the care recipient, reflecting the heterogeneous nature of caregiving. Yet prior work has largely studied burden, unmet needs, and system failures as separate domains rather than examining how they co-occur within individual caregivers. Methods: We applied an LLM-based classification framework (Claude 3.5 Sonnet) to 7,198 posts from three ALZConnected caregiver forums (general, spouse/partner, and adult child caregivers), coding each post for burden, unmet needs, and system failures across 9, 12, and 10 categories respectively. We compared expression rates by caregiver role (primary vs. secondary) and relationship to the care recipient (spousal vs. child) and used post-level co-occurrence networks to map how categories cluster within and across domains. Results: Burden was expressed in 89.0% of posts and unmet needs in 93.3%, while system failures appeared in 34.8%. Primary caregivers reported burden more often than secondary caregivers (91.6% vs. 84.7%), while secondary caregivers reported more unmet needs (94.6% vs. 92.5%) and more system failures (37.2% vs. 33.4%). Child caregivers reported higher rates than spousal caregivers across all three domains. Co-occurrence networks showed dense within-domain clustering (density 0.61-0.65) and 84 significant cross-domain connections, with the strongest links between behavioral/safety burden and safety-management needs (21.7% of posts) and between emotional burden and emotional-support needs (20.9%). Conclusion: Burden, unmet needs, and system failures are not independent problems but form interconnected challenge ecosystems that vary by caregiver role and relationship. This suggests caregiver support should be designed around these connected patterns rather than treated as separate, single-domain interventions.

Background The genetic architecture of Alzheimer disease remains incompletely understood. Founder populations such as the Amish offer a unique opportunity to identify additional genetic variation influencing the disease. Method Using extensive pedigree and genomic data from Midwestern Amish communities, we estimated both pedigree- and SNP- based heritability of AD. In addition, genome-wide association studies and gene-based rare variant tests were performed. Results Heritability estimates suggested that common variants explain much of genetic risk among APOE-{varepsilon}4 carriers, while unexplained heritability remains in non-carriers in the Amish. GWAS confirmed APOE-{varepsilon}4 as the strongest genetic determinant of AD in the Amish. Rare variant analyses identified RIN3 and PILRA as significantly associated with risk of cognitive impairment; suggestive signals including CYP24A1 were also identified. Discussion These findings highlight the contributions of common and rare variants to Alzheimer disease and suggest factors beyond common variants may contribute to disease susceptibility particularly among the APOE-{varepsilon}4 non-carriers.

INTRODUCTION: Neurodegenerative research identifies biomarkers to confirm presence of disease and inform about risk for clinical symptoms. Expert guidance advises caution about disclosing individual research results (IRR), but participant interest remains high even when IRR may not inform individual prognosis. Existing studies of stakeholder attitudes emphasize Alzheimer's disease (AD) biomarkers. We explore participant attitudes toward IRR from the United States CADASIL Consortium (USCC), an observational study of Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), the most heritable form of vascular dementia. METHODS: Since CADASIL research participant attitudes are unstudied and AD-focused guidelines for IRR may not generalize to populations with dominantly inherited conditions, we surveyed USCC participants using three 5-point Likert items and one open-ended question. Descriptive statistics were analyzed for Likert items. The distribution of responses to one item was directly compared to an AD participant survey. Open-ended responses underwent qualitative content analysis. RESULTS: We received 152 responses. The highest-rated reason to return IRR was "learn about my disease and its predicted course". The highest-rated IRR were imaging/MRI scans and cognitive testing. Hypothetical negative outcomes were rated as a little to somewhat concerning. USCC respondents rated reasons to return IRR higher than AD counterparts, with statistically significant differences for seven of eight items. In open-ended responses, the most frequent code was "IRR return will help improve my health and well-being". DISCUSSION: Most respondents expressed support for disclosure upon participant request. These findings could inform IRR guidance for CADASIL and other disorders and investigations of personal utility.

Alzheimer's disease (AD) pathology including amyloid beta (A{beta}) plaques and tau tangles accumulate with age in Down Syndrome (DS). Cholinergic abnormalities such as expression of nicotinic acetylcholine receptors (nAChRs) adversely contribute to cognitive decline and neurodegeneration in AD with similar features possible in DSAD. As a radiotracer for 4{beta}2* nAChRs, [18F]nifene was quantitatively evaluated in the frontal cortex (FCX) and temporal cortex (TCX) of DSAD, AD, and cognitively normal (CN) brain tissue using autoradiography. Anti-tau and anti-A{beta} immunostaining in adjacent sections confirmed the presence of tau tangles and A{beta} plaques. [18F]Nifene binding in brain sections demonstrated significantly more binding in gray matter (GM) than white matter (WM), with FCX exhibiting more binding than TCX (OptiQuant). Nicotine substantially displaced [18F]nifene binding in adjacent sections, resulting in average GM/nicotine ratios (DSAD=9.74, AD=10.5, CN=17; suggesting a 38% decrease in AD and a 43% decrease in DSAD) and WM/nicotine ratios (DSAD=2.73, AD=3.31, CN=5.62; suggesting a 41% decrease in AD and a 51% decrease in DSAD). [18F]Nifene was correlated with [125I]IBETA (A{beta}), showing a strong positive relationship between 4{beta}2* nAChRs and A{beta} in DSAD. [18F]Nifene GM/nicotine and WM/nicotine ratios were positively correlated with age in TCX and FCX. The findings of this study suggest that [18F]nifene has potential use in diagnostic investigations of the cholinergic system in DSAD using positron emission tomography. The study also points to a possible need for earlier therapeutic interventions to address the 4{beta}2* nAChRs deficit in DSAD.

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.

Importance. Metformin may influence risk of dementia, with prior conflicting observations of protection or harm. Objective. To determine the association of randomization to metformin vs. placebo or intensive lifestyle intervention (ILS) in the Diabetes Prevention Program (DPP) with cognitive outcomes (cognitive impairment syndromes and trajectories of cognitive test performance) during the DPP Outcomes Study (DPPOS). Design, Setting & Participants. Prospective long-term follow-up of DPP/DPPOS participants at 27 U.S. centers among adults who were at high risk for type 2 diabetes (T2D) at baseline. Exposures. Randomization to metformin, placebo, or ILS (1996-1999) for 3.2 years followed by open-label metformin in the original randomized metformin group until 2021. Main Outcomes & Measures. Cognitive impairment syndromes were adjudicated in 2022-2024 in 1,483 participants (median age 74 [IQR 68, 80]) using the National Alzheimer's Coordinating Center Uniform Dataset version 3. Cognitive performance in executive and memory domains was ascertained with repeated cognitive tests between 2009 and 2024. Multinomial logistic regression and mixed-effects models were fit to examine associations of randomization to metformin with cognitive outcomes. Results. Total metformin exposure (mean {+/-} SD) was 15.5 {+/-}7.7 years/person in the metformin group. Persons in the placebo and ILS groups received out-of-study metformin usually after developing diabetes with mean metformin total exposure of 4.5 {+/-}5.1 and 3.8 {+/-}4.8 years/person in the placebo and ILS groups, respectively. Overall, the frequency distributions of the cognitive syndromes did not differ significantly by treatment group; however, randomization to metformin was associated with a 60% (OR 0.40 [95%CI 0.17, 0.97]) and 62% (OR 0.38 [95%CI 0.16, 0.89]) lower odds of dementia compared with placebo and ILS, respectively, after adjustment for demographics, education, income, and APOE-{varepsilon}4 genotype. Randomization to metformin was also associated with significantly better memory performance over time ( {beta} =0.58; 95%CI: 0.09, 1.1; p=0.02; Cohen's d=0.1). Conclusions and Relevance. Long-term metformin treatment is associated with a reduced risk of dementia and better memory performance among persons with pre-diabetes or T2D. Estimates were imprecise due to a limited number of dementia cases. Longer follow-up with more dementia cases is needed to confirm our findings.

Insulin resistance is increasingly recognized as a metabolic factor associated with Alzheimers disease (AD); however, its relevance to hippocampal structural changes--a key pathological feature of AD--across disease stages is not fully understood. To address this issue, we investigated the relationship between insulin resistance, hippocampal gray matter volume, and cognitive performance using data from the Alzheimers Disease Neuroimaging Initiative (ADNI), a large-scale neuroimaging dataset. Insulin resistance was assessed using the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), and its relationship with brain structure and cognitive performance was evaluated across diagnostic groups. In the mild cognitive impairment (MCI) group, higher insulin resistance was associated with larger anterior hippocampal gray matter volume, whereas in the AD group this association was reversed in direction. Furthermore, in the MCI group, anterior hippocampal gray matter volume was also positively associated with higher Mini-Mental State Examination (MMSE) scores, and an exploratory mediation analysis suggested a significant indirect association linking HOMA-IR, anterior hippocampal volume, and cognitive performance through anterior hippocampal volume. These findings suggest that the relationship between insulin resistance and AD-related brain changes differs across diagnostic groups, highlighting the importance of considering metabolic alterations in relation to disease status.

Importance: Patients are increasingly learning Alzheimers disease (AD) genetic and biomarker results through electronic health portals. Evaluation of alternative scalable delivery models for return of AD risk information is needed to best support patient understanding and psychological well-being. Objective: To determine whether a patient-centered digital platform is comparable to clinician-mediated telehealth sessions for returning APOE and plasma pTau-217 results on outcomes of knowledge and psychological well-being. Design: The Evaluation of Self-Mediated Alternatives for Risk Testing Education and Return of Results (eSMARTER) study was a noninferiority trial of a patient-centered digital platform compared to clinician-mediated disclosure of APOE genotype and optional pTau-217 disclosure. Setting: Decentralized, fully remote trial enrolled participants in the contiguous United States (U.S.) between October 2024 and February 2025, with follow-up completed in November 2025. Participants: Eligible participants were aged 60-80 and had previously undergone APOE genotyping (without disclosure) via the GeneMatch program, passed psychological screening, had internet access, and were English-speaking. Interventions: Participants were randomized, 2:1, to the eSMARTER digital platform or clinician-mediated disclosure of APOE genotype. Following the 6-month post-APOE assessment, participants were offered optional pTau-217 disclosure via the same randomized modality. Main Outcomes and Measures: Primary outcomes at 1-7 days following APOE disclosure included changes in anxiety, disease-specific distress, and AD-related knowledge within a priori non-inferiority margins. Results: 674 persons (mean [SD] age 68 [4.7] years; 451 [67%] female; mean [SD] telephone MoCA=19 [2]) were eligible and provided demographic information. 651 participants were randomized to clinician-mediated (n=216) or digital disclosure (n=435) and completed APOE disclosure (66 [10%] APOE4 homozygotes, 377 [58%] heterozygotes, 208 [32%] non-carriers). 604 participants completed the study; 500 completed optional pTau-217 disclosure. Baseline characteristics were balanced across groups. At 1-7 days following APOE disclosure, scores on AD-related knowledge, PROMIS Anxiety, and disease-specific distress measures met non-inferiority. Conclusions and Relevance: Disclosure of APOE genotype by the eSMARTER digital platform is non-inferior to clinician-mediated telehealth disclosure. No significant between group differences were found following disclosure of pTau-217 results. Together, these results suggest that this digital platform may provide an evidence-based scalable approach for returning AD genetic and biomarker results.