Journal of Alzheimer's Disease

BACKGROUND: Neuropsychiatric symptoms (NPS) are prevalent and debilitating in Alzheimer's disease (AD). Existing pharmacologic treatments are often ineffective and associated with serious adverse events. Identifying modifiable risk factors (MRFs) is critical for prevention and treatment. METHODS: Capitalizing on data from 14,497 individuals with AD from the National Alzheimer's Coordinating Center (NACC) database, we examined longitudinal associations between modifiable risk factors, APOE genotype and NPI-Q-assessed NPS using Cox proportional hazards models adjusted for demographics. RESULTS: Diabetes, alcohol consumption, smoking, and TBI were associated with an increased risk of specific NPS in AD. APOE{varepsilon}4 carrier status was linked to multiple NPS, showing a dose-response relationship. Education, LDL-C, and corrective lenses were protective; hypertension showed no associations. CONCLUSION: These findings strongly suggest that individual MRFs are associated with specific NPS in line with a complex etiology underlying these symptoms. Early detection and management of vascular, lifestyle and sensory factors could reduce NPS.

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.

INTRODUCTION: Postmenopausal estrogen decline may contribute to Alzheimer's disease (AD) risk, but longitudinal evidence linking circulating estrogens to cerebrospinal fluid (CSF) biomarkers is lacking. METHODS: We analyzed 866 female participants from the European Prevention of AD Longitudinal Cohort Study with baseline serum estradiol and estrone measured by liquid chromatography tandem mass spectrometry and repeated CSF measurements of amyloid-beta (A{beta})42, phosphorylated (p) Tau181, and total (t) Tau. RESULTS: Neither estradiol nor estrone was associated with longitudinal A{beta}42. Higher estradiol was associated with lower baseline tau and slower tau increases over time. Baseline estradiol-tau associations were stronger in apolipoprotein E (APOE) {epsilon}4 carriers, though APOE{epsilon}4 did not modify longitudinal associations. Amyloid positivity did not moderate hormone-tau associations but was associated with steeper tau increases over time. Estrone showed no significant associations. DISCUSSION: These findings suggest a more consistent relationship between estradiol and tau-related rather than amyloid-related pathology.

Background: The Dementia Supporter Initiative is a national public education program in Japan that aims to foster positive attitudes and appropriate understanding of dementia to support people with Alzheimer's disease and related dementia in the community. However, its influence on the community as a whole remains unclear. Objective: This study examined the relationship between dementia supporter training and residents' attitudes and recognition related to dementia at the municipal level. Methods: This ecological cross-sectional study linked municipal-level data from the Japan Gerontological Evaluation Study 2022 wave with publicly available information on the number of dementia supporters. Residents' beliefs and attitudes toward dementia and recognition of dementia consultation services were assessed by mail questionnaires and aggregated at municipal level. The proportion of dementia supporters in each municipality was calculated as of September 2022. Results: Data from 69 municipalities were analyzed. The mean proportion of dementia supporters was 13.47% (2.62-44.85). A higher proportion of dementia supporters was positively correlated with community support-seeking for a family member with dementia (r = 0.328) and recognition of dementia consultation services (r = 0.501). Regression analysis adjusted for municipal covariates also showed their positive associations (per 10-percentage-point increase: coef. = 1.44, p = 0.047; coef. = 3.12, p < 0.001, respectively). No associations were observed with residents' positive attitudes and appropriate understandings of dementia. Conclusions: Wider dissemination of dementia supporters may contribute to better recognition of community support resources, but may be insufficient to influence broader public attitudes and understanding of dementia at the community level.

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.

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.

Background: Anomia is common in frontotemporal dementia (FTD), although its clinical prominence varies by subtype, with the most marked impairment typically observed in primary progressive aphasia (PPA). It remains unclear whether naming impairment reflects language-specific impairment or broader cognitive severity, and how it relates to other cognitive domains across FTD syndromes. Methods: Fifteen healthy controls and twenty-two individuals across the FTD spectrum, including variant-specified and unclassifiable (NOS) presentations, completed two confrontation naming tasks (Boston Naming Test and Multilingual Naming Test) and a global cognitive screening measure (Montreal Cognitive Assessment, MoCA). Patient participants additionally completed a standardized language battery (Western Aphasia Battery Revised) and a comprehensive neuropsychological assessment (Uniform Data Set). Naming performance was compared between groups and associations with language severity, global cognition, and domain-specific cognitive functions were examined using regression analyses. Results: Naming was impaired in patients relative to healthy controls but did not differ between patient groups. Naming was strongly associated with language severity, but not global cognition. A significant group-by-MoCA interaction indicated that MoCA was positively associated with naming only in the unclassifiable group. In addition, naming was associated with episodic memory across both verbal and non-verbal domains. Conclusions: Naming in FTD primarily reflects language severity rather than global cognitive impairment. A robust association between naming and episodic memory suggests potential contributions from semantic cognition, shared frontally mediated retrieval processes, or parallel cognitive decline. These findings support the use of naming as a marker of language dysfunction while highlighting its relevance to broader cognitive systems in FTD.

PURPOSE: Alzheimer disease (AD) is associated with cognitive impairment, brain atrophy, and elevated amyloid-beta and tau. The study aimed to characterize regional atrophy associated with elevated amyloid-beta and tau, as measured by [18F]florbetapir (FBP) and [18F]flortaucipir (FTP) positron emission tomography (PET), respectively, and determine whether combining PET and atrophy data improves the prediction of cognitive impairment. METHODS: Alzheimer Disease Neuroimaging Initiative data (n = 381) were retrospectively analyzed. PET results were correlated with cortical thickness, gray matter (GM) volumes, Mini-Mental State Examination, and Montreal Cognitive Assessment. Linear/logistic regression and area under the curve (AUC) were used to evaluate for significant correlations and compare performances in distinguishing cognitive impairment, respectively. RESULTS: Incremental loss of cortical thickness and GM volume was observed from FBP-/FTP- (n = 205) to single PET-positive (FBP+/FTP-, n = 133; FBP-/FTP+, n = 5) and FBP+/FTP+ (n = 38) groups, particularly in the temporal and parietal lobes. FBP+/FTP+ showed the most severe cortical thickness loss in the entorhinal cortex, temporal lobe GM atrophy, and cognitive impairment. Adding brain atrophy as the third variable resulted in higher odds ratios and improved AUCs for cognitive impairment, with FBP+/FTP+/temporal GM or entorhinal cortical atrophy+ demonstrating the strongest associations with cognitive impairment. CONCLUSION: A multimodal approach combining PET and MRI may help improve the assessment of cognitive impairment in AD.

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.

Objectives: To investigate the association between pulse pressure and dementia incidence, independent of other blood pressure measurements and established risk factors, and to assess whether this association differs across dementia subtypes. Design: Prospective population-based study. Setting: UK Biobank. Participants: Of the 502,211 participants in the UK Biobank, 470,986 completed at least one blood pressure measurement and were included in the analysis. These participants were recruited between March 2006 and July 2010 and were followed for up to four assessments through to February 2024. Main outcome measures: Incidence of dementia, identified through linked health records using ICD-9 and ICD-10 diagnosis codes, self-reported diagnoses or records of dementia-specific medication use. The association between pulse pressure and risk of dementia was investigated using Cox proportional hazard models. Models were adjusted for age, sex, education, hearing problems, lipid levels, depression, traumatic brain injury, physical activity, diabetes, smoking, hypertension, body mass index, alcohol consumption and mean arterial pressure. Dementia subtype-specific associations were examined using competing risk models, with cause-specific Cox analyses included as supplementary sensitivity analyses. Results: During a median follow-up of 13 years, 9,028 persons developed dementia (Alzheimer's disease: 3,011; Vascular dementia: 1,270; Dementia with Lewy bodies: 234; Frontotemporal dementia: 191; Other/Mixed dementia: 4,322). Each 10mm Hg increase in pulse pressure was associated with a 5.4% higher risk of dementia (95% confidence interval on hazard ratio: 1.036 to 1.071), even after adjustment for age, mean arterial pressure and other established dementia risk factors. The effects were disproportionately stronger for Alzheimer's disease and vascular dementia, with no clear evidence for increased risk for dementia with Lewy bodies or frontotemporal dementia. Results were robust across sensitivity analyses including alternative blood pressure metrics, complete-case models, and alternative dementia classifications. Conclusions: Pulse pressure is independently associated with incidence of dementia beyond conventional blood pressure measures.

BackgroundMultiple studies suggest bidirectional links between delirium and Alzheimers Disease and Related Dementias (ADRD). Although they establish a strong association between delirium and subsequent ADRD, it has not been explored using statistical causal inference which makes the best use of observational data to minimize biases. MethodsWe conducted an emulated clinical trial to estimate the effect of experiencing delirium during hospitalization between April 2017 and September 2019 on the cumulative incidence of ADRD over two years following hospital admission in patients 65 and older. The emulated trial used observational data from individuals in the Mass General Brigham Electronic Medical Record (EMR). We carried out statistical causal survival analysis using methods that adjust for confounding, censoring, competing risks, and immortal-time bias, including inverse propensity weighting (IPW) and g-formula approaches. ResultsOf the 6029 patients hospitalized in this time frame who were 65 or older with evidence of a PCP in the EMR, 5901 were included in the analysis based on no history of dementia diagnosis or medications 12 months prior to admission. At two years post-admission, the adjusted cumulative incidence of ADRD in individuals who did not experience delirium was 7.6% (95% Confidence Interval [CI] 4.0-12.1%) while it was 20.2% (95% CI 13.2-27.9%) for those who did experience delirium when calculated using the IPW method. ConclusionsOur emulated trial results argue for a strong association between delirium during hospitalization and the risk of developing ADRD in the two years following hospital admission in individuals 65 and older. Key PointsO_ST_ABSQuestionC_ST_ABSWe sought to answer whether statistical causal inference would show the same association between delirium and the onset of dementia in the two years following hospitalization. FindingsOur emulated trial results argue for a strong association between delirium during hospitalization and the risk of developing ADRD in the two years following hospital admission in individuals 65 and older. MeaningThe implications of demonstrating this relationship underscore the importance of delirium-mitigating interventions for long-term cognitive outcomes.

Although the associations between cerebrovascular dysfunctions and Alzheimer's disease are increasingly appreciated, the relationship of cerebral blood flow and white matter hyperintensities with tau and amyloid-{beta} pathology remains unclear, particularly in the longitudinal context. This study investigated cross-sectional and longitudinal associations of cerebral blood flow and white matter hyperintensities with tau and amyloid-{beta} pathology using multimodal imaging and blood biomarkers in 179 participants from the ADNI3 cohort. Participants underwent structural (T1-weighted, T2-weighted FLAIR) and arterial spin labelling perfusion MRI, tau and amyloid-{beta} PET, and plasma assay tests for amyloid-{beta} 42, amyloid-{beta} 40, and phosphorylated tau-217. Tau from PET was negatively associated with cerebral blood flow both cross-sectionally and longitudinally in the posterior brain, independent of amyloid-{beta} quantified from PET. Higher white matter hyperintensities volumes were associated with higher levels of tau and amyloid-{beta} at baseline, but the associations were significantly attenuated after further adjusting for amyloid-{beta} and tau, respectively. Plasma amyloid-{beta} 42/40 ratio was negatively associated with white matter hyperintensity volumes both cross-sectionally and longitudinally. In conclusion, tau pathology showed spatially specific associations with cerebral hypoperfusion, independent of amyloid-{beta}, particularly in posterior regions. The attenuation of associations of white matter hyperintensities with amyloid-{beta} and tau after adjustment may reflect shared disease-related variance rather than distinct independent effects. Keywords: Alzheimer's disease, Cerebral blood flow, White matter hyperintensities, Tau pathology, Amyloid-{beta}.

Objectives: To describe secondary mental healthcare utilisation and associated costs among patients diagnosed with dementia or mild cognitive impairment (MCI). Design: Retrospective cohort study using routinely collected electronic health record data. Setting: Secondary mental healthcare services within a large NHS mental health provider in South London, UK. Participants: Adults aged 18 years or older with a recorded diagnosis of dementia or MCI between 1 January 2010 and 31 December 2020. Patients surviving less than one year after diagnosis were excluded. The final cohort comprised 16,081 individuals. Primary and secondary outcome measures: Service utilisation and NHS mental health service costs during the 12 months before and after diagnosis, including inpatient, outpatient and memory clinic contacts. Results: The proportion of patients with at least one recorded mental health service contact declined from 91% in the 12 months before diagnosis to 69% after diagnosis. Among service users, mean NHS mental health costs increased from GBP 1,497 to GBP 2,177 per person following diagnosis (mean increase GBP 680; p<0.001), driven primarily by inpatient care. Dementia diagnosis, younger age, male gender, living alone, greater cognitive impairment and higher clinical symptom burden were independently associated with higher costs. Ethnic differences in service use and costs were also observed. Conclusions: Although overall service engagement declined following diagnosis, costs increased among those continuing to access care, indicating greater intensity of service use. Understanding patterns of secondary mental healthcare utilisation and associated costs may help inform planning and resource allocation within dementia services.

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.

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: Frontotemporal dementia (FTD) lacks widely accessible disease-specific biomarkers. Optical coherence tomography (OCT) and OCT angiography (OCTA) may provide non-invasive measures of retinal changes associated with neurodegeneration. We conducted a systematic review and meta-analysis evaluating retinal biomarkers in FTD compared with Alzheimer disease (AD) and controls. Methods: A systematic search of PubMed and Embase was conducted through April 25, 2026 according to PRISMA guidelines. Studies evaluating OCT/OCTA biomarkers in FTD with comparator groups were included. Inverse weighted random-effects models, publication bias assessments, and meta-regressions were performed. Results: Ten studies involving 139 individuals with FTD, 87 with AD, 29 with mild cognitive impairment, 14 with TDP-43 proteinopathy, 5 with tauopathy, and 255 controls were included in the systematic review; five studies were eligible for meta-analysis. Compared with AD, individuals with FTD demonstrated significantly thinner retinal nerve fiber layer (RNFL) thickness (SMD = -0.61, 95% CI -0.98, -0.24). Compared with controls, individuals with FTD exhibited significantly thinner ganglion cell layer-inner plexiform layer (GCL-IPL) thickness (SMD = -0.55, 95% CI -1.02, -0.08), whereas pooled analyses across multiple retinal biomarkers were non-significant (SMD = -0.19, 95% CI -0.52, 0.14). RNFL thickness correlated negatively with female % in FTD and positively with age in both AD and controls. Conclusions: Individuals with FTD exhibit lower RNFL thickness than AD and lower GCL-IPL thickness than controls, suggesting retinal alterations may reflect neurodegeneration. However, larger longitudinal studies with standardized OCT/OCTA protocols are needed to determine the diagnostic and prognostic utility of retinal biomarkers in FTD

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.

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.

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: 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.