Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring

Aims. The risk of cognitive decline after losing a spouse remained mixed. This study aims to investigate the association between spousal loss and risk of cognitive decline, assess whether this association varies by sex and age, and identify modifiable factors. Methods. We conducted a prospective cohort study using harmonized data from six population-based aging surveys: the US Health and Retirement Study and its sister surveys in England, Mexico, China, India, and South Africa, incorporating their respective Harmonized Cognitive Assessment Protocol (HCAP) sub-studies. Spousal loss (yes vs no) was the exposure. Cognitive outcomes (i.e., orientation, memory, executive function, and language), were assessed using HCAP neuropsychological batteries. We conducted parallel analyses in six cohorts. Associations between spousal loss and cognitive outcomes were estimated using generalized linear models, and summarised estimates were derived via random-effects meta-analyses. Sex stratification and restricted cubic spines were used to examine how these associations vary by sex and age, respectively. Results. The analytical cohort consisted of 18,551 individuals aged 61.22 (SD 6.30) to 71.37 (SD 7.33) years. Widowhood prevalence ranged from 14.1% in CHARLS to 53.9% in HAALSI and was consistently higher in women. Spousal loss was associated with poorer memory (multivariable-adjusted {beta} = -0.07, 95% CI -0.12 to -0.01) and executive function (multivariable-adjusted {beta} = -0.08, 95% CI -0.13 to -0.03) in the meta-analysis, with no significant associations for orientation or language. While results were generally consistent in five cohorts, the ELSA showed divergent patterns (orientation: {beta} = 0.10, 95% CI 0.06 to 0.13; memory: {beta} = 0.05, 95% CI 0.02 to 0.08; language: {beta} = 0.16, 95% CI 0.12 to 0.19). Sex-stratified analyses indicated poorer executive function among men (multivariable-adjusted {beta} = -0.14, 95% CI -0.19 to -0.08) and poorer memory among women (multivariable-adjusted {beta} = -0.07, 95% CI -0.14 to -0.01) following widowhood. Nonlinear age-related effects on cognition were observed in ELSA, LASI, and HAALSI. Higher education, internet use, and BMI were negatively associated with the risk of cognitive decline among widowed participants. Conclusions. Spousal loss is associated with domain- and sex-specific differences in cognitive performance, with substantial heterogeneity across study populations. Future research should integrate biopsychosocial markers to develop context-sensitive interventions for widowed older adults.

Clinical Dementia Rating (CDR) scores are used to classify the cognitive state of patients and are provided within neuroimaging datasets. This is achieved through a standardized clinical assessment that evaluates participants cognitive and functional abilities in everyday life, after which they are given a score ranging from 0 to 3. Where 0 represents no signs of dementia and three represents severe dementia1. These scores are then used to track the progression of dementia over time2. This study explored if these CDR labels within the OASIS-1 dataset produced consistent volumetric separation across the hippocampus, amygdala, and cortex.

INTRODUCTION: MethylCog is a 29-CpG blood DNA methylation (DNAm) proxy for general cognitive ability (g). Its incremental association with blood biomarkers of Alzheimer's disease and related dementias (ADRD) and prospective cognitive ability remains unclear. METHODS: In the held-out test set from the original MethylCog study, we tested whether MethylCog explained baseline g beyond four ADRD blood biomarkers, and whether it predicted six-year follow-up g beyond baseline g and biomarkers. RESULTS: MethylCog showed a stronger age-adjusted association with baseline g than individual biomarkers (r=.368 vs absolute r=.083-.162). MethylCog added 10.0% variance beyond all four biomarkers cross-sectionally (p<.001) and predicted six-year follow-up g in the biomarker-adjusted model (beta=.108, p=.002). No individual ADRD biomarker independently predicted follow-up g. DISCUSSION: MethylCog may provide cognition-related DNAm information complementary to blood-based ADRD biomarkers.

BackgroundIn preclinical Alzheimers disease (pAD), regional patterns of amyloid-{beta} (A{beta}) deposition are well characterized but it is unclear how this process varies across functional networks. ObjectiveDetermine how A{beta} accumulation in functional networks ("network-amyloid burden" [NAB]) varies by age, network type (cognitive vs. non-cognitive), and A{beta} status (A{beta}+/A{beta}-), and relates to cognition. Methods157 cognitively unimpaired adults (45-84 years; n=28 A{beta}+ per neuroradiological read) underwent brain MRI, amyloid PET (18F-florbetapir), and neuropsychological testing. NAB was calculated as the mean standard uptake value ratio within 7 networks categorized as cognitive (fronto-parietal, default mode, ventral and dorsal attention, limbic) or non-cognitive (somato-motor, visual). Linear mixed models tested how NAB varies across age, networks (by type and each separately), A{beta} status, and their interactions, and relationships between NAB and cognition. ResultsNAB increased with age, most prominently in fronto-parietal and default mode networks. NAB was higher in cognitive than non-cognitive networks, and this difference was more pronounced in A{beta}+ individuals. NAB was not significantly associated with cognition. ConclusionsCognitive brain networks are more vulnerable to amyloid accumulation with aging and in pAD than non-cognitive networks. Cognitive NAB may be useful for early detection and as a target for intervention in pAD.

Objectives. Despite the body of literature on genetic risk factors for dementia, little is known on protective genetic factors associated with favourable cognitive ageing in the oldest population. In Europe, Italy has a leading position with a swelling population of centenarians, and the urban area of Genoa in the Liguria region has one of the highest prevalence of centenarians. The COOL study is a not-for-profit, multicentric study involving a cohort of centenarians (aged >99) living in the Genoa area. The ultimate aim is the identification of genomic biomarkers associated with cognition in the oldest old population. Results. Participants underwent a semi-structured interview on personal, disease and family history, and a neuropsychological assessment of the main cognitive domains. As of July 2025, we enrolled 88 centenarians (age range: 99-108, median 100.56) with and without cognitive impairment; 32 subjects were followed up. All participants were of Italian ancestry, 81% were female. The cognitive profile in assessed subjects showed a wide range of cognitive health measures (CDR 0-5; MMSE 3-30, median 24). Whole peripheral blood and DNA samples from 67 participants were stored. Conclusions. We demonstrated that the protocol is feasible, and acceptable by participants and their families. A comprehensive phenotype dataset was established, and DNA samples were stored. Centenarians exhibited a broad spectrum of cognitive profiles, from preserved cognition to severe dementia. These findings will eventually allow to interpret the profiles of genomic variants as associated with variability of cognitive performance in centenarians. The molecular underpinnings of healthy cognitive ageing could inform health policy strategies in the general population.

Abstract INTRODUCTION APOE genotype shows well-established dose-dependent associations with higher amyloid in cognitively unimpaired (CU) adults. In contrast, associations with tau burden and cognition are less well characterized. METHODS We performed a cross-sectional analysis of harmonized multi-cohort ADSP-PHC data from 4,380 CU participants across 4 cohorts with APOE genotype, amyloid PET, and cognitive data from four domains of memory, language, executive, and visuospatial function, including a subset of 758 with tau PET imaging. RESULTS APOE {varepsilon}4 showed a strong dose-dependent association with amyloid burden and amyloid positivity, with the highest levels observed among {varepsilon}4 homozygotes. Associations between APOE and global tau burden were more modest and appeared to be driven mainly by {varepsilon}4 homozygotes, while regional analyses showed localized APOE {varepsilon}4-related associations in medial temporal regions. Independently, higher tau burden was associated with lower memory and language performance. CONCLUSIONS In CU older adults, APOE {varepsilon}4 was most strongly associated with amyloid burden, with more modest associations observed for medial temporal tau burden.

Background: People affected by dementia experience intersecting care inequalities. We explored relationships between ethnicity and health and social care resource use among people with dementia in an ethnically diverse urban region. Methods: We conducted a retrospective observational cohort study using Discover-NOW, including patients with dementia between 1.4.2015 and 1.4.2025. We calculated ethnic density as the percentage of the Middle Layer Super Output Area (SOA) population self-identifying with the same ethnic group. Regression models, clustered by Local SOA, tested whether ethnic density moderated relationships between ethnicity and primary care, outpatient, inpatient, emergency and social care service use, controlling for sociodemographic characteristics, deprivation, comorbidities and time of diagnosis. Findings: We included 30,704 people with dementia. People from Black and Mixed ethnic groups used more primary care, and those from Asian ethnic groups less primary and secondary care, than White ethnic groups. Rates of local authority social care packages were similar across ethnic groups. High ethnic density predicted fewer GP consultations in Black ethnic groups, but more in South Asian groups. Interpretation: Among Black ethnic groups, primary care use was relatively high, especially in areas of low ethnic density, perhaps reflecting greater needs among communities at risk of racism and isolation. The trend towards increased primary care use among South Asian people in areas of higher ethnic density may reflect communities mitigating help-seeking hesitancy related to cultural and language barriers. Greater care integration could reduce care inequalities among minority ethnic communities who may experience fewer barriers to social relative to health care.

Summary Background Although CAIDE (Cardiovascular Risk Factors, Aging, and Dementia) score estimates 20 year dementia risk, prior studies have largely focused on global or composite measures. Only a few studies investigated on cognitive functions and structural neuroimaging markers, and the available structural neuroimaging evidence has largely been derived from subsamples or highly selected small cohorts rather than full population based cohorts. We therefore not only investigated associations between CAIDE score and cognitive performance but also explored structural neuroimaging markers in middle to older aged population. Methods Of 2,864 participants who were available for structural magnetic resonance imaging (MRI) data at baseline, we excluded 230 participants who have neurological and cardiovascular disease at baseline. We also further excluded 209 participants without having exposure, covariates, and cognitive assessments data, including 2,425 participants for the final analysis. The main exposure is CAIDE score (0 to 15) were calculated from age, sex, education, systolic blood pressure, body mass index, total cholesterol, and physical activity and categorized as low risk (<6), moderate risk (6 to 7), and high risk (7<) at baseline. The main outcomes were neuropsychological assessment battery included Story recall, Visual reproductions, Verbal fluency, Trail making, Digit symbol coding, and Stroop tests. Findings Of 2,425 healthy participants (mean age of 58.5 [6.5]; men 1,189 [49.0]), higher CAIDE risk groups were associated with poorer cognitive performance. Compared with low risk group, the high risk group showed significantly lower performance across all 12 cognitive assessments (all p <.001). The moderate risk group also showed lower performance in visual reproduction (immediate and delayed recall), digit symbol oding, and Stroop (word and color) reading tests. Interpretation This large based population study showed the highest risk group were independently associated with lower cognitive performance across all domains compare to the lowest risk group, suggesting the potential importance of managing these features for preserving neurological health in middle and older aged adults.

INTRODUCTION: Cognitive trajectories may clarify how type 2 diabetes (T2D) and impaired fasting glucose (IFG) relate to dementia risk, but longitudinal associations remain unclear, particularly in the context of stroke. METHODS: Data from 5,631 dementia- and stroke-free older adults (mean age 75 years) from 7 international population-based cohorts were analyzed. Linear mixed-effects models estimated cognitive trajectories during stroke-free and post-stroke follow-up. Glucose status was defined by fasting glucose and prior T2D diagnosis. RESULTS: Over 6.6 years of follow-up (4.5% with incident stroke), T2D was associated with lower baseline cognitive performance compared with normal fasting glucose (-0.14 SD, 95% CI -0.21 to -0.07), but not with faster cognitive decline during stroke-free or post-stroke follow-up. IFG was not associated with lower cognitive performance or faster decline. DISCUSSION: In older adults, T2D was associated with persistently lower cognitive performance but not faster decline, suggesting adverse cognitive effects may be established before late life.

Background: A recent Lancet Commission estimated that up to 45% of Alzheimers Disease and Related Dementias (ADRD) cases could be prevented by addressing modifiable lifestyle risk factors. Meanwhile, genome wide association studies (GWAS) have shown that common genetic variants also account for substantial ADRD risk. Whether a favorable lifestyle can offset risk in genetically predisposed individuals remains unclear. Methods: We conducted a retrospective cohort study of 105,886 participants from the All of Us Research Program enrolled between 2018 and 2023. Participants were over age 49, assigned male or female at birth, of European ancestry, and without ADRD at baseline. ADRD diagnoses were identified via electronic health records (EHR). Fourteen potentially modifiable risk factors for ADRD were assessed using surveys, EHR records, and wearable data. Genetic risk was quantified as a polygenic risk score (PRS) based on 81 independent GWAS loci and APOE E4 genotype. Results: Overall, 967 incident ADRD events occurred over a median follow-up of 3.7 years. Ten out of 13 modifiable risk factors were significantly associated with ADRD. When grouped into risk factor profiles, intermediate and unfavorable modifiable risk factor scores were associated with substantially higher ADRD risk (HR 3.07, 95% CI 2.47, 3.83; HR 8.01, 95% CI 6.39, 10.05, respectively) compared to a favorable lifestyle; APOE E4 dosage and polygenic risk score were also independently associated with ADRD risk. Among individuals in the highest polygenic risk group, a favorable lifestyle reduced ADRD risk from HR 18.63 (95% CI 10.25, 33.86) to 1.90 (95% CI 0.94, 3.81), whereas APOE E4 homozygotes remained at elevated risk even with a favorable lifestyle (HR 6.52, 95% CI 2.97, 14.33). Conclusions: Our data suggest ADRD risk is driven more by modifiable risk factors and APOE genotype than polygenic risk score. Future genomic informed risk assessments for ADRD should calibrate their findings to accurately identify high risk individuals.

Background The majority of family dementia caregivers in the United States (U.S.) are now young and middleaged adults. However, little research has been conducted to understand how caregiver needs and preferences for support differ depending on their phase of adulthood. This study evaluated differences in mental health, caregiving readiness, desired supports, and intervention preferences among early (<46 years), middle (46 to 60 years), and late (>60 years) adulthood dementia caregivers. Methods A cross sectional survey was conducted with 202 family dementia caregivers aged 22 to 88. Caregivers completed validated measures of burden, anxiety, depression, well being, time pressure, dementia knowledge, caregiving preparedness, and positive aspects of caregiving. Desired supports and preferences for intervention format, program type, and frequency were assessed. Analyses examined both categorical adulthood phase and continuous age associations with caregiver outcomes, with alpha thresholds of p<.05. Results Early adulthood caregivers self reported higher anxiety symptoms (relative to late adulthood caregivers) and perceived time pressure (relative to middle and late adulthood caregivers). Relative to late adulthood caregivers only, early adulthood caregivers more frequently endorsed desired support for supplemental care and safety tools for the person with dementia, as well as willingness to engage in individual counseling and automated, digital supports. Relative to both middle adulthood and late adulthood caregivers, they also more frequently expressed desired support for their own mental health. Conclusions Dementia caregiving in early adulthood is associated with distinct psychological and practical support needs, suggesting life course informed interventions may enhance relevance and engagement.

Importance: Little is known about the impact of returning Alzheimer disease (AD) biomarkers to cognitively unimpaired (CU) research participants. Objective: Does return of research results (RoRR) negatively impact longitudinal symptoms of depression and cognition. Design: Randomized, noninferiority, delayed-start clinical trial, 2021-2025 Setting: AD biomarker research results offered to CU participants in a longitudinal study of aging Participants: CU participants age 65+ were offered research AD biomarker results (APOE genotype and either plasma AB42/40 or amyloid PET and MRI hippocampal volume) with an estimated 5-year risk of symptomatic AD. Intervention(s) (for clinical trials) or Exposure(s) (for observational studies): 147 participants were randomized to receive results either soon after consent (RoRR arm, N=73) or one year later (delayed-start arm, N=74). Main Outcome(s) and Measure(s): Longitudinal change in Geriatric Depression Scale (GDS), Clinical Dementia Rating sum of boxes (CDR-SB), and global cognitive composite. Outcomes were measured at annual assessments for a longitudinal study of aging. Results: 187 participants received results: 70 in RoRR arm (average age 75, 60% female), 66 in delayed-start arm (average age 73, 53% female). The observed changes in annual measures did not differ between arms in both those with elevated amyloid (AB+) and in those without elevated amyloid (AB-) for GDS (AB+ difference 0.7, 95% CI 0.0-1.3; AB- difference -0.1, 95% CI -0.7-0.5; clinically significant decline >4.0), CDR-SB (AB+ difference 0.0, 95% CI -0.1-0.1; AB difference 0.0, 95% CI 0.0-0.1; clinically significant decline >0.5), and cognitive composite (AB+ difference -0.10, 95% CI -0.25-0.06; AB- difference -0.05, 95% CI -0.17-0.07; clinically significant decline < -0.26). Secondary analyses found no evidence of association between RoRR and proximity to follow-up testing. Conclusions and Relevance: In the first randomized, delayed-start clinical trial of returning AD research results to CU older-adult participants, no effect was seen on longitudinal changes in symptoms of depression or cognition. This supports evidence that there are no harms to returning AD research results, although the results may not apply to more diverse populations not included in this study. Trial Registration: NCT04699786

Background: In clinical practice, 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) evaluation of neurodegenerative diseases relies primarily on visual interpretation, which is inherently subjective. Although current international guidelines recommend incorporating quantitative tools to support visual reading, the magnitude of the incremental diagnostic benefit and the clinical contexts in which it is most pronounced have not been formally synthesized in a systematic meta-analytic framework. Methods: Following the Preferred Reporting Items for Systematic reviews and Meta-Analyses for Diagnostic Test Accuracy (PRISMA-DTA) guidelines, we searched PubMed, EMBASE, Cochrane Library, and KoreaMed from inception to August 2025 for studies comparing visual-only versus visual-plus-quantitative FDG-PET interpretation within identical patient cohorts. Pooled sensitivity and specificity were estimated using random-effects models. Relative diagnostic performance was summarized as odds ratios (ORs), obtained by exponentiation posterior contrasts between visual analysis combined with quantitative analysis, and visual analysis. Subgroup analyses were conducted based on the clinical experience of the readers. Results: Ten studies met the inclusion criteria. In the overall analysis (k = 9), visual analysis alone yielded a pooled sensitivity of 0.85 and specificity of 0.78 , versus a sensitivity of 0.87 and specificity of 0.88 for the combined approach. The most pronounced gain was observed in differentiating Alzheimers disease (AD) from healthy controls, with specificity increasing from 0.69 to 0.94 (Bayesian OR 4.29). Quantitative augmentation conferred a larger sensitivity gain among beginner readers (increasing from 0.75 to 0.87; Bayesian OR 2.39) than among expert readers, narrowing the performance gap between experience levels. Conclusion: Adding quantitative analysis to visual FDG-PET interpretation yields modest overall improvements in diagnostic accuracy, with the largest gains observed in distinguishing AD from cognitively normal individuals and among less experienced readers. These findings are consistent with current international guidelines that position quantitative assessment as a complementary aid to visual interpretation rather than a replacement, with particular utility for less experienced practitioners and for specific differential-diagnostic scenarios.

Digital health technologies (DHT) offer a promising solution to the timely identification of early Alzheimer's disease (eAD) to enable early treatment. This study evaluated the feasibility, acceptability, adherence, reliability, and preliminary clinical and content validity of the novel AD Digital Assessment Suite (AD-DAS). 123 individuals (32 healthy controls (HC), 31 amyloid-PET negative (SCDn), 30 amyloid-PET positive (SCDp) with subjective cognitive decline, and 30 early AD (eAD)) participated. AD-DAS was remotely deployed for 28 days. Remote testing was feasible (97.6% completers), acceptable (>85% ''good''), and associated with high adherence (96%). Metrics showed moderate to excellent test-retest reliability (ICC 0.53-0.91), associations with clinical comparators (adjusted R2 0.01-0.24), differentiated eAD from other known groups (absolute log odds differences 0.6-3.28), and correlated with brain atrophy in expected regions. Episodic and working memory AD-DAS metrics differentiated SCDp from SCDn participants. These preliminary findings suggest that AD-DAS may be a promising tool for detecting cognitive impairments in early AD stages.

INTRODUCTION: Knowledge about how Alzheimer's disease (AD) and AD-related dementia (AD/ADRD) plasma biomarkers relate to global and domain-specific cognitive functioning across diagnostic groups remains limited, particularly in heterogeneous, community-dwelling populations with multiple comorbidities. METHODS: We evaluated associations between baseline plasma biomarker levels (A{beta}42/40, p-tau181, p-tau217, NfL, GFAP) and cognitive performance at baseline and longitudinally (up to 7 years). Participants (n=590) enrolled in the Wake Forest Alzheimer's Disease Research Center Clinical Core (314 cognitively unimpaired [CU]; 206 mild cognitive impairment [MCI]; and 70 dementia) completed annual cognitive assessments including the Uniform Data Set (UDSv3; NACC). Domain-specific cognitive composites including memory, executive function, attention, language, visuospatial ability, and phonemic fluency, as well as a modified Preclinical Alzheimer's Cognitive Composite (PACC5), were evaluated. General linear and mixed-effects models were adjusted for demographics (age, sex, race, education), APOE-{epsilon}4 status, comorbidities (estimated glomerular filtration rate; BMI), and cardiometabolic health factors (hypertension, diabetes). Effect modification by cognitive diagnosis was evaluated. RESULTS: Baseline plasma biomarkers, particularly p-tau217, were associated with poorer baseline cognitive performance and greater longitudinal decline on the PACC5 and all cognitive domains assessed, except phonemic fluency (strongest for memory). Post-hoc analyses indicated associations between plasma biomarker levels and cognition were generally more pronounced in MCI compared with CU participants. Effect modification by baseline cognitive status was limited and attenuated when all biomarkers were modeled simultaneously. Comorbidities and cardiometabolic factors modified select associations. DISCUSSION: Plasma AD/ADRD biomarkers, particularly p-tau217, were associated with cognitive impairment and decline in a heterogenous community cohort.

INTRODUCTION: Neuroinflammation and immune dysregulation are increasingly recognized as early drivers of Alzheimer's disease (AD) and AD-related dementias (AD/ADRD), often emerging decades before the onset of clinical symptoms. Despite this, there remains a critical need for non-invasive biomarkers that can capture these early processes, particularly in African Americans, a population at elevated risk for AD/ADRD yet underrepresented in neuroimaging research. In this study, we investigated the relationship between systemic plasma inflammatory markers and brain microstructural integrity in cognitively unimpaired older African Americans. METHODS: Forty-one participants (mean age = 68.68 years) underwent MRI scanning and multi-plex plasma-based inflammatory marker quantification. Microstructural changes were quantified using Diffusion Weighted Imaging (DWI) metrics, including mean diffusivity (MD), radial diffusivity (RD), mean kurtosis (MK), and radial kurtosis (RK). Voxel-wise general linear models, and cluster-based models were used to examine associations between plasma-derived inflammatory markers and brain microstructure. RESULTS: Higher TARC levels were associated with widespread increases in MD and RD across both gray and white matter, implicating reduced microstructural integrity and potential myelin disruption. In contrast, kurtosis-based metrics demonstrated more spatially selective and generally weaker associations, with MK and RK showing limited decreases primarily within white matter tracts. Cluster-level analyses confirmed the robustness of diffusivity findings and highlighted consistent effect sizes across multiple regions. DISCUSSION: These findings suggest that elevated TARC is linked to early microstructural alterations detectable with diffusion MRI, with diffusivity metrics demonstrating greater sensitivity to inflammation-related changes than kurtosis measures in this cohort. This work underscores the importance of incorporating inflammatory biomarkers in neuroimaging studies of aging and highlights diffusion MRI as a promising tool for detecting early neurobiological signatures of AD/ADRD risk in African American populations. Keywords: Systemic Inflammation, TARC, Eotaxin-3, Diffusion MRI, African Americans, ADRD, Aging

Background: Low-dose levetiracetam is under investigation as a potential treatment for slowing Alzheimer's Disease progression. This study tests whether levetiracetam enhances executive function in mid-age adults, and whether drug effects differ by Apolipoprotein e4 (APOE4+) genetic risk status. Methods: Fifty-eight adults (aged 45-65 years; 27 APOE33; 31 APOE4+) participated in a double-blind, placebo-controlled study of low-dose levetiracetam (125mg bidaily for two-weeks). At the end of each treatment phase, participants completed a switch-inhibition task. Results: Mid-age APOE4+ carriers were significantly slower and showed a greater cost of increasing executive demand than APOE33 individuals. Response times were quicker under levetiracetam, with increased benefits reported in APOE33 individuals, at younger ages, and in individuals with reduced levels of plasma-based biomarkers. Levetiracetam selectively benefitted accuracy in APOE33 individuals. Conclusion: Low-dose levetiracetam enhances executive function in midlife, particularly in individuals at lower risk of Alzheimer's Disease based on age, APOE4 genotype, and proxies of neuropathology.

Introduction: Alzheimers disease and related dementias (AD/ADRD) pathology begin decades before diagnosis, yet scalable risk detection infrastructures for midlife adults remain limited. The Biomarker Evaluation of Young Onset Dementia from Diverse Populations (BEYONDD; R56AG075744) pilot study was designed to address this gap through a decentralized, community-engaged research (CER) model for neurodegenerative risk detection in midlife adults with subjective cognitive or behavioral complaints (sCBC). Methods: This cross-sectional pilot assessed the feasibility of CER-based digital recruitment and participant completion of remotely-acquired screening, cognitive, clinical, and phlebotomy assessments with support of Community Research Navigators (CRNs). Feasibility was evaluated using digital recruitment metrics, yield, retention, and geographic reach. Results: Our approach generated 1.8+ million advertisement impressions,161,100 clicks, and 4,089 web-registrants. 2,117 individuals completed the online screener, exceeding the prespecified screening goal by 141%. We enrolled a multi-ethnic, midlife cohort of 579 participants (Mage=51.6[6.5]; 75% female; 44% Latinx, 31% non-Latinx Black-American, and 26% all other race/ethnicities), exceeding the enrollment goal by 290%, and 476 participants completed the remote protocol (82% retention). Participants were recruited from 49 U.S. states, Puerto Rico, Australia, and Canada. CRN engagement was concentrated during study stage transitions. Discussion: BEYONDDs decentralized, CER-based screening infrastructure demonstrated wide geographic reach, strong early-stage engagement, and efficient recruitment among diverse midlife adults. These findings support the feasibility of scalable CER-based digital recruitment for decentralized early detection initiatives and AD/ADRD trials.

Spousal caregivers of individuals with Alzheimers disease and related dementias frequently experience elevated perceived stress, caregiver burden, and loneliness, which are associated with adverse health outcomes. Early identification is therefore critical for timely intervention. Existing approaches commonly rely on wearable sensor data and standardized psychological questionnaires, while recent multimodal methods aim to improve prediction by integrating behavioral and linguistic information. In this study, we explored three modality configurations, wearable-derived features, interview-based text, and their combination, to classify caregiver psychological risk using the Perceived Stress Scale (PSS), Zarit Burden Interview, and UCLA Loneliness Scale. We compared traditional machine learning models and large language models (LLMs) (Gemini 2.0, Llama 4, and GPT-4o) under psychometrician-centered and caregiver-centered prompting strategies. Traditional machine learning models performed better under multimodal settings, while LLMs achieved stronger performance with Interview-Only input. We further demonstrate that PSS was the most predictable construct and prompting strategies substantially influenced LLM performance.

INTRODUCTION: The Framingham Risk Score (FRS) indexes cardiovascular risk (CVR), but age weighting may confound associations with brain and cognitive outcomes. METHODS: In 923 amyloid-positive ADNI participants, we compared FRS against a Multiple Indicators Multiple Causes (MIMIC)-derived age-adjusted measure (CVRmimic) using sex-stratified linear mixed efefcts (LME) and latent growth curve mediation (LGCM) models of hippocampal-to-ventricle ratio (HVR) - cognitive coupling. RESULTS: FRS predicted hippocampal atrophy in all six LGCM models; CVRmimic in none of the six. HVR - cognitive coupling held in four of six FRS and four of six CVRmimic models. Indirect effects reached significance in four of six FRS and none of the six CVRmimic models. LME 3-way interactions (years x risk x HVR) survived FDR correction in all six FRS versus none of the six CVRmimic models. DISCUSSION: FRS "effects" on hippocampal-cognitive decline largely reflect age-related variance. Age adjusted measures complement FRS by isolating cardiovascular effects from aging.