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.

INTRODUCTIONWhether Alzheimers disease (AD) blood biomarker-cognition associations differ across cognitive domains, analytic context, and biomarker modeling strategy in population-based cohorts is unclear. METHODSIn 1,170 older adults from the Health and Retirement Study Harmonized Cognitive Assessment Protocol, we examined cross-sectional (2016) and prospective (2016-2022) associations of blood p-tau181, glial fibrillary acidic protein (GFAP), neurofilament light (NfL), and amyloid-{beta}42/40 with memory, executive function, language, visuospatial ability, and global cognition using individual biomarker, principal components analysis-derived composite, and multibiomarker panel models. RESULTSCross-sectionally, NfL and GFAP showed the broadest associations. Prospectively, p-tau181 was independently associated with memory and global cognition, whereas GFAP was associated with executive function, memory, and global cognition. P-tau181 also showed relative memory-versus-executive selectivity. The comparatively best-fitting modeling approach differed by cognitive domain and analytic context. DISCUSSIONAD blood biomarker-cognition associations in community-dwelling older adults are domain-differentiated and context-dependent, supporting domain-specific outcomes and flexible biomarker modeling strategies.

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.

BACKGROUNDWe investigated associations of neighborhood disadvantage with Alzheimers Disease (AD)-related outcomes by biological and social factors in at-risk older adults. METHODS1,880 U.S. POINTER participants with Area Deprivation Index (ADI) and cognition (PACC) were included. 868 had amyloid, tau PET, white matter hyperintensities (WMH), and/or gray matter volumes. We conducted exploratory, linear models testing ADI interactions with sex, race and ethnicity, and APOE {varepsilon}4, adjusting for age and education. RESULTS"White/European American", "Hispanic/Latinx/Spanish" and "Others" showed lower cognitive scores with higher ADI, while "White/European American" showed the highest cognitive scores across ADI levels. APOE {varepsilon}4 carriers from high-ADI areas showed higher WMH and tau, and "Hispanic/Latinx/Spanish" from more deprived areas showed higher WMH. Females from moderate-ADI areas showed higher tau. Amyloid burden was higher in APOE {varepsilon}4 carriers from low-ADI areas. CONCLUSIONDifferential associations of ADI with AD-related outcomes across biological and social factors may reflect systemic health disparities and study design.

ABSTRACT BACKGROUND: Recent studies consisting primarily of white participants have found lowered plasmalogen levels to be associated with lower cognitive function. We explore the association of blood plasmalogen levels with global cognition and brain imaging metrics in older African Americans. METHODS: Included in these cross-sectional analyses were participants in the Minority Aging Research Study (MARS) and the Rush Clinical Core without dementia, available serum lipid levels, and a concurrent cognitive function assessment. A plasmalogen biosynthesis value (PBV) was calculated for each participant utilizing five ratios of four key glycerophospholipids. A linear regression model of global cognition was constructed with PBV, adjusted for sex, age, education, total cholesterol, and body mass index. In participants with 3T MRI brain imaging, the association between PBV and white matter hyperintensities (WMH) was explored. RESULTS: Of the 298 participants, the mean age was 74.6 years, mean education was 15.6 years, and 84% were women. The median PBV was 0.42 (interquartile range: 0.22 to 1.14). A unit higher in PBV was suggestively associated with a 0.17 {beta}-unit higher cognitive z-score (SE =0.09, p = 0.06). In 254 participants with MRI data, an increase in log10 SD of PBV suggested the less white matter hyperintensities (estimate = -0.20, SE = 0.12, p = 0.08). DISCUSSION: In older African Americans, higher PBV was associated with higher level of global cognition, and potentially lower levels of brain white matter hyperintensities. Larger studies are needed in additional cohorts to determine if PBV is associated with annual rate of change in cognitive function.

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.

IntroductionSleep-dependent memory consolidation differs by sex and maybe disrupted by Alzheimers disease (AD) risk. Whether sex moderates associations between apolipoprotein E {varepsilon}4 (APOE {varepsilon}4) status, non-rapid eye movement (NREM) sleep, and memory remains unclear. MethodsEighty cognitively unimpaired older adults completed a word-pair memory task with encoding and immediate testing occurring prior to overnight polysomnography with high-density electroencephalography (hdEEG) and delayed recall occurring after sleep. Sleep-memory associations were examined as a function of sex and APOE {varepsilon}4 status. ResultsIn this sample, a sexxAPOE {varepsilon}4 interaction was associated with overnight memory retention, with female carriers exhibiting less overnight forgetting than female non-carriers and male {varepsilon}4 carriers. NREM sleep differed by sex and APOE {varepsilon}4 status and was associated with memory retention in{varepsilon} 4 carriers. DiscussionThese findings indicate sex-specific, sleep-dependent memory mechanisms associated with genetic AD risk, highlighting sleep as a potential early target for intervention, pending replication in larger samples.

BackgroundThe AT(N) biological framework classifies Alzheimers disease (AD) pathology using CSF biomarkers, with the A+T+ profile defining biological AD and the A-T+ profile representing a biologically distinct entity consistent with suspected non-Alzheimers pathophysiology, such as primary age-related tauopathy. Functional assessment capable of differentiating these profiles non-invasively remains limited. This study investigates whether cognitive vergence and pupillary temporal dynamics during a visual oddball task can distinguish A-T+ from A+T+ biological profiles in individuals with mild cognitive impairment (MCI). MethodsThirty-eight participants with MCI (12 A-T+, 26 A+T+) classified by CSF biomarkers completed a visual oddball task (80% distractors, 20% targets) under continuous eye-tracking. Linear mixed-effects models examined profile x condition interactions on full time series and six trial-level temporal features. Participant-level differentiation was assessed using binomial logistic regression, adjusting for age, sex, and MMSE. ResultsBoth profiles showed comparable overall oculomotor response magnitudes but diverged markedly in temporal organization. Significant profile x condition interactions emerged for cognitive vergence global slope, time to peak, and pupillary time to peak. Logistic regression confirmed that timing features discriminated biological profiles at the participant level, with differentiation reversing direction between distractor and target conditions. A-T+ participants also maintained superior target detection accuracy (89.3% vs. 82.4%, p = 0.001). ConclusionCognitive Vergence and pupillary temporal dynamics during an oddball task provide condition-dependent functional oculomotor signatures that systematically differentiate AT(N) biological profiles in MCI, suggesting that oculomotor assessment may offer an accessible, non-invasive complement to CSF-based profile characterization.

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.

INTRODUCTIONHealthful dietary patterns may attenuate dementia risk by preserving cerebrovascular health. Prior work has focused on systemic arterial stiffness, but cerebrovascular measures may be more sensitive to neuroprotective effects of diet. We examined associations between Mediterranean diet adherence, prefrontal cortex (PFC) arterial elasticity, and cognition in older adults. METHODSParticipants were 198 older adults (58% female; mean age 65.6 years) from the Newcastle ACTIVate cohort. Mediterranean Diet (MedDiet) scores were derived from the Australian Eating Survey food frequency questionnaire. Pulse Relaxation Function (PReFx), an index of PFC arterial elasticity, was measured using pulse Diffuse Optical Tomography. Cognition was assessed with CANTAB and a cued task-switching paradigm. RESULTSHigher MedDiet was associated with higher PFC arterial elasticity. MedDiet was not associated with cognition, and PReFx did not mediate diet-cognition associations. DISCUSSIONGreater Mediterranean diet alignment was cross-sectionally associated with PFC arterial elasticity, suggesting a pathway through which diet may influence brain health in ageing.

Background and ObjectivesCarotid plaque reflects systemic atherosclerosis and may serve as an early marker of cognitive decline, but its longitudinal association with cognitive trajectories remains unclear. We investigated whether carotid plaque status (small-to-medium size) was associated with cognitive performance over time in a population-based cohort. MethodsThis prospective cohort study followed-up neuropsychological assessment battery quadrennially in two cycles (2015-2018 and 2019-2022) from the baseline (2011-2014). Of 2,819 participants, 2,176 participants who were free of dementia and cerebrovascular disease at baseline with cognitive function testing at least two time points over the follow-up time were analyzed. Carotid plaque assessed by B-mode ultrasound sonography five segments were scanned in both left and right sides. The plaques were graded based on vessel thickness and the diameter of the lumen (none, small-to-medium, and large). We categorized our participants into without (none) and with the plaques (small-to-medium, and large combined) at baseline. The main outcomes were multivariable adjusted mean differences of cognitive test performances by baseline plaque status over time. The neuropsychological assessment battery included story recall, visual reproductions, verbal fluency, trail making, digit symbol - coding, and Stroop tests. ResultsOf the total, 291 (13.4%) participants had carotid plaque at baseline. There were no differences at baseline and 4-year. At 8-year follow-up, participants with carotid plaque performed significantly worse than participants without carotid plaque in visual reproduction delayed recall [mean difference -0.525 (95% CI: -0.915 to -0.135), p=.008], Stroop word reading [mean difference -2.732 (95% CI: -5.164 to -0.300), p=.028] and color reading [mean difference -3.573 (95% CI: -5.199 to -1.948), p<.001]. Additionally, participants with carotid plaque performed lower than those without carotid plaque on logical memory delayed recall [mean difference -1.577 (95% CI: -2.843 to -0.311), p=.015] at 8-year follow-up period. DiscussionIn this large cohort study, carotid plaque status at baseline was independently associated with in cognitive function decline, especially in non-verbal memory and executive functioning over 8-year follow-up period in the general population. Therefore, it may be important for earlier intervention on carotid plaque to preserve neurological health in middle-aged to older population.

BackgroundOdor identification impairment is an early marker of Alzheimers disease (AD) that predicts memory decline, yet its underlying microstructural basis remains unclear. We hypothesized that mild cognitive impairment (MCI) involves early myelin and lipid disruption within olfactory-limbic circuits, detectable using a synthetic MRI-derived contrast that provides complementary sensitivity to myelin volume fraction (MVF). MethodsThirty-three older adults (healthy controls [HC], n = 16; mild cognitive impairment [MCI], n = 17) completed olfactory and cognitive testing and underwent 3T brain MRI using a QALAS sequence. An MVF map and synthetic FLAIR and DIR images were generated, and a FLAIR-DIR-derived metric (FD) was computed as FD = (FLAIR - DIR) / FLAIR. We investigated ROI-based group differences in olfactory-limbic gray-matter regions and associated white-matter tracts, voxel-wise regressions investigating FD-odor identification associations, and ROI-based MCI vs HC classification using cross-validated logistic regression models. ResultsCompared with HC, MCI showed significantly lower FD across olfactory-limbic gray-matter regions and white-matter pathways--including hippocampus, amygdala, orbitofrontal cortex, thalamus, and corpus callosum--whereas MVF differences were more limited. FD achieved moderate discrimination, with baseline performance comparable to MVF. Voxel-wise analyses revealed that better odor identification was associated with higher FD in the hippocampus/parahippocampal and insula; the association persisted after adjusting for voxel-wise MVF. MVF also showed significant positive voxel-wise associations with odor identification in the insula and genu of the corpus callosum. ConclusionFD is a practical, myelin- and lipid-sensitive contrast derived from routinely acquired synthetic FLAIR & DIR images that complement quantitative MVF. It captures behaviorally relevant variance beyond local myelin content and may improve detection of early olfactory-limbic microstructural changes in MCI. These findings support FD as a scalable candidate marker linking early network disruption to olfactory symptoms across the AD continuum.

ImportanceAdverse neighborhood conditions can lead to poorer health outcomes, potentially through accelerated biological aging. However, whether these relationships are explained by individual- or neighborhood-level factors remains unclear. ObjectiveTo examine the association between neighborhood deprivation, measured by the Area Deprivation Index (ADI), and epigenetic age acceleration and assess whether individual- and neighborhood-level characteristics mediate or modify these associations. DesignCross-sectional study using data from a Yale Stress Center study between 2008 and 2012. Data analysis was conducted from July 2025 to January 2026. SettingCommunity-based sample from the greater New Haven, CT area. ParticipantsA total of 370 healthy adults aged 18 to 50 years without major psychiatric, medical, or cognitive disorders who provided blood samples for DNA methylation analysis. Main Outcomes and MeasuresEpigenetic age acceleration measured from DNA methylation using four second-generation epigenetic clocks, with associations assessed among aging, neighborhood deprivation, and individual- and neighborhood-level factors. ResultsData were analyzed from 370 participants (212 women [57.3%], 158 men [42.7%]; mean [SEM] age, 29.3 [0.46] years). Greater neighborhood deprivation was associated with greater lifetime adversity ({beta}=0.112, p<.001) and lower educational attainment ({beta}=-0.019, p=.012), and accelerated epigenetic aging as measured by GrimAge ({beta}=0.037, p<.001), PCGrimAge ({beta}=0.019, p<.001), and PCPhenoAge ({beta}=0.041, p<.001), but not PhenoAge (p=.23). In multivariable models accounting for individual factors, neighborhood deprivation remained associated with these three clocks. Lifetime adversity partially mediated the association between ADI and accelerated GrimAge (20.3% of total effect) and PCGrimAge (23.3%). Race moderated the direct association between ADI and epigenetic aging, with stronger associations between neighborhood deprivation and accelerated GrimAge ({beta}=0.061, p=.004) and PCPhenoAge ({beta}=0.057, p=.02) observed among Black participants compared to White. ConclusionsGreater neighborhood deprivation was associated with accelerated epigenetic aging across multiple second-generation clocks, with lifetime adversity partially mediating these associations. Stronger effects were observed among Black participants. These findings suggest that neighborhood environments and cumulative stress may contribute to biological aging and racial disparities in aging trajectories. Key PointsO_ST_ABSQuestionC_ST_ABSIs neighborhood deprivation associated with epigenetic age acceleration, and if so, how do neighborhood- and individual-level factors impact this relationship? FindingsIn this cross-sectional study of 370 adults, greater neighborhood deprivation was associated with accelerated epigenetic aging across multiple second-generation clocks. Lifetime adversity partially mediated these associations, and the relationship between neighborhood deprivation and accelerated aging was stronger among Black participants than White participants. MeaningThese findings suggest that neighborhood conditions and lifetime stress contribute to accelerated biological aging and suggest that epigenetic aging may represent one biological pathway through which neighborhood-level racial inequalities contribute to health disparities.

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.

Structured AbstractO_ST_ABSINTRODUCTIONC_ST_ABSEducational attainment is a key proxy of cognitive reserve (CR), but whether its association with cognition persists after accounting for multimodal brain pathology remains unclear. METHODSData from PREVENT-AD and CIMA-Q were analyzed using cross-sectional, longitudinal, and residual-based models adjusted for multimodal pathology, including MRI-based white matter hyperintensities and atrophy measures, and plasma Alzheimers disease biomarkers. Education was examined in both cohorts. A multidimensional CR questionnaire was also examined in CIMA-Q. RESULTSHigher education was associated with better performance across multiple cognitive domains after accounting for pathology (p < 0.05). The CR composite score showed less consistent associations, and non-education subdomains showed limited added value. Longitudinally, education was more consistently associated with baseline cognitive levels than cognitive change, with executive-function trajectory differences observed in PREVENT-AD. DISCUSSIONFindings support a CR framework in which education relates to better cognition despite pathology, while effects on decline are limited and domain-specific.

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.