Background and Objectives:The apolipoprotein E (APOE) haplotypes are known to be associated with dementia, with the ε4 haplotype associated with higher risk. It has been suggested that the APOE ε2 allele serves as a protective factor for dementia. However, data on the effects of the homozygous APOE ε2/ε2 genotype are limited, likely due to the rarity of the APOE ε2/ε2 genotype. Furthermore, the association between APOE genotypes and dementia may differ across self-reported race. We aim to investigate the association between APOE genotypes and dementia overall and across self-reported race, with a focus on the potential protective effects of the ε2 haplotype and differences across race. Methods:Data from 7 large, community-based, prospective cohort studies from the Dementia Risk Prediction Pooling Project: Age, Gene/Environment Susceptibility-Reykjavik Study, Whitehall II study, Atherosclerosis Risk in Communities Study, Cardiovascular Health Study, Honolulu-Asia Aging Study, Multi-Ethnic Study of Atherosclerosis, and Framingham Heart Study and its associated cohorts were used. Cox proportional hazard models were used to estimate the cause-specific hazard ratios of dementia by APOE genotypes overall and by self-reported race. Results:The study consisted of 45,022 participants (10% Asian, 15% Black, 75% White, 52% male) with a mean age of 56 years (SD: 14.5) at baseline. Compared with participants with an APOE ε3/ε3 genotype, those with an ε2/ε3 genotype had a lower risk of dementia (HR: 0.87, 95% CI 0.80-0.96). There was an indication of protective effects of the ε2/ε2 genotype compared with the ε3/ε3 genotype (HR: 0.98, 95% CI 0.71-1.37). These associations were similar among Black and White participants. The detrimental effect of an ε4/ε4 genotype compared with an ε3/ε3 genotype was also seen overall and among Black and White participants. Those with an APOE ε4/ε4 genotype experienced dementia onset approximately 8 years earlier than those with an APOE ε3/ε3 genotype. Discussion:In this large, pooled cohort, the presence of at least one APOE ε2 allele was associated with lower risk of dementia overall and by self-reported race, suggesting a protective effect. APOE ε4/ε4 was associated with an earlier age of dementia onset with differences across race.

We demonstrate how Large Language Models (LLMs) accelerate biomedical data harmonization through automated Common Data Element (CDE) generation. We processed 31 datasets including clinical taxonomies and research data dictionaries through OpenAI's Generative Pre-trained Transformer - 4 (API Model gpt-4-0613), generating comprehensive metadata for each element using a template-based system. Subject-matter experts validated outputs, finding 94% of generated metadata fields required no revision overall, with an unweighted accuracy of 83.8%, unweighted, for semi-structured sources. Dramatically faster than manual approaches. Our system uses ElasticSearch with weighted field matching to identify semantic equivalences between variables, avoiding duplicate CDEs while building a standardized repository. Testing with Alzheimer's Disease Neuroimaging Initiative (ADNI) and Global Parkinson's Genetic Program (GP2) datasets showed 32.4% of previously unseen headers successfully mapped to our CDEs, with interoperability scores averaging 53.8/100 based on matching, completeness, and compliance metrics. This approach automates the most tedious aspects of data integration, reducing barriers to cross-study collaboration in biomedical research.

BACKGROUND AND OBJECTIVES:Plasma biomarkers such as phospho-tau species are increasingly used in clinical practice for the diagnosis of Alzheimer disease (AD). Phosphorylated-tau at threonine 181 (p-tau181) values also provide prognostic information about incident dementia. Cognitive status similarly conveys prognostic information, but the relationship between plasma biomarkers for AD and cognitive status requires clarification. METHODS:Participants from the Atherosclerosis Risk in Communities (ARIC) study who were adjudicated as free of dementia in 2011-2013 had plasma samples analyzed for p-tau181 and other biomarkers. Participants were surveilled for incident dementia through December 31, 2022. Cumulative incidence curves, Cox models, and Fine-Gray models were used to evaluate the independent and combined discriminatory accuracy of cognitive status and plasma biomarkers for incident dementia. RESULTS:The sample comprised 1,577 ARIC participants (age 76.5 years, 60% women, 73% White, 27% Black). The risk of incident dementia was higher in persons with a baseline status of mild cognitive impairment (covariate-adjusted hazard ratio [HR] 2.94, 95% CI 2.61-3.33) compared with those who were cognitively unimpaired independent of biomarker status. The risk of dementia was also higher in persons with more abnormal concentrations of p-tau181 and other biomarkers independent of cognitive status. When age, cognitive status, and p-tau181 were included in the same models, the risk was attenuated relative to models where only cognitive status or plasma biomarkers were included. For continuous p-tau181 concentrations, the covariate-adjusted HR without cognitive status was 1.45 (95% CI 1.36-1.54), but when cognitive status was included, the HR decreased to 1.37 (95% CI 1.29-1.46). Models showed that when combined with age, p-tau181 alone, cognitive status alone, or the combination of p-tau181 and cognitive status had similar discriminatory accuracy. DISCUSSION:Cognitive status and plasma biomarker concentrations convey independent but overlapping information about the risk of incident dementia. Although cognitive status and plasma p-tau181 have similar discriminatory accuracies, the far lower incidence rate of dementia in persons who are initially cognitively unimpaired highlights the importance of an accurate clinical diagnosis.

BACKGROUND:White matter hyperintensities (WMH) are widely used to assess cerebral small vessel disease but reflect late-stage injury. Diffusion magnetic resonance imaging (MRI) biomarkers have been proposed to capture earlier small vessel disease-related microstructural damage but their temporal progression relative to WMH and risk factors associated with progression remain unexplored. METHODS:We identified 2077 participants from the population-based cohort study of the Mayo Clinic Study of Aging in Olmsted County, Minnesota (aged 50-101 years) collected between 05/2005 and 09/2024 with longitudinal neuroimaging. Using multioutput nonlinear mixed-effects models in those with at least 2 fluid-attenuated inversion recovery-MRI and diffusion MRI scans, we characterized the temporal progression of WMH and 4 diffusion MRI biomarkers: fractional anisotropy of the genu of the corpus callosum, peak width of skeletonized mean diffusivity, free water, and Arteriolosclerosis-score, which were automatically estimated. Models incorporated participant-specific time shifts, correlations between biomarkers, and effects of risk factors (sex, education, APOE ε4 status, cardiometabolic conditions). RESULTS:The study population had a mean age of 78 years, 47% were women, 28% were APOE ε4 allele carriers, and 80% were cognitively unimpaired, with an average follow-up of 5.2 years (SD, 4.3 years) for fluid-attenuated inversion recovery-MRI and 4.3 years (SD, 3.9 years) for diffusion MRI. Arteriolosclerosis-score, fractional anisotropy of the genu of the corpus callosum, free water, and peak width of skeletonized mean diffusivity became abnormal in 50% of the study population 16, 12, 10, and 7 years before WMH become abnormal (half-width of CI <1 year), respectively. Global markers (Arteriolosclerosis-score, free water, peak width of skeletonized mean diffusivity, and WMH) were correlated, indicating shared substrates of widespread white matter injury. Fractional anisotropy of the genu of the corpus callosum, a vascular risk microstructural injury biomarker, was weakly coupled with WMH and had an earlier but more linear worsening across adulthood. Cardiometabolic conditions predicted earlier worsening of all biomarkers. Female participants showed earlier WMH, fractional anisotropy of the genu of the corpus callosum, and Arteriolosclerosis-score abnormalities, whereas male participants exhibited earlier peak width of skeletonized mean diffusivity and free water abnormalities. CONCLUSIONS:Diffusion MRI biomarkers were abnormal at least a decade before WMH become abnormal in the population, revealing a prolonged phase of early small vessel disease and highlighting their potential for small vessel disease prevention.

Growth/differentiation factor-15 (GDF15) is a secreted cytokine strongly associated with dementia risk. However, the extent to which GDF15 represents a biomarker and driver of dementia risk remains unclear. Across multiple cohorts, we demonstrated that plasma GDF15 is associated with greater dementia risk over 15- to 25-year follow-up periods when measured in midlife, with stronger associations observed for vascular, compared to Alzheimer's disease (AD), dementia. Two-sample Mendelian randomization supported plasma GDF15's mechanistic role in AD and related dementias, while cohort studies linked it to cerebral small vessel disease, neurodegeneration, phosphorylated tau, and a cerebrospinal fluid proteomic signature indicative of neuroimmune activation. Exposure of cultured myeloid cells to recombinant GDF15 altered biological pathways that we subsequently demonstrated are predictive of dementia risk, including interferon/antiviral responses. These findings support circulating GDF15's role as an early biomarker-particularly for vascular dementia and neuroinflammation-and identify the mechanisms by which it may drive dementia risk.

​Background: To optimise management of patients with covert brain infarction (CBI), personalised estimates of stroke and dementia risks are needed. We determined age- and sex-specific stroke and dementia risks in individuals with CBI and identified clinical and imaging prognostic indicators. Methods: We included 2287 participants with MRI-defined CBI from eight community-based cohorts across Europe and the USA, who were age/sex-matched within each cohort to 6861 participants without CBI (1:3). We used Cox models to determine relative risks of stroke and dementia, and subdistribution hazard models to estimate 10-year absolute risks and prognostic indicators among participants with CBI. Findings: Of 9148 participants (mean age 74 years, 53% women), 716 (7·8%) were diagnosed with a stroke and 1311 (14·3%) with dementia during 10-year follow-up. Individuals with CBI had a 2·01-fold (95%CI: 1·66−2·42) increased risk of stroke and a 1·34-fold (1·11−1·62) increased risk of dementia compared to those without CBI. Stroke and dementia risks relative to no CBI were higher with multiple CBI than with single CBI (hazard ratio stroke: 2·51 [1·94–3·26] vs 1·79 [1·49–2·15]; dementia: 1·74 [1·39–2·17] vs 1·22 [1·04–1·44]), but did not differ between lacunes, cortical infarcts or cerebellar infarcts. In individuals with CBI, smoking, hypertension, diabetes, atrial fibrillation, education, APOE-ε4 genotype, and multiple CBI predisposed to stroke and/or dementia. With CBI, ten-year absolute stroke risk was 10·9% (95%CI: 7·4%–15·1%) and 10-year absolute dementia risk was 18·9% (95%CI: 10·5%–29·4%). Absolute risks increased with age from 5·4% (50-59 years) to 16·2% (aged >80) for stroke and from 2·5% to 31·2% for dementia. Interpretation: Community-dwelling individuals with CBI are at increased risk of stroke and dementia, particularly in the presence of multiple infarcts. Demographic, clinical, and imaging characteristics may guide risk factor management, interventions, and trial inclusion.

INTRODUCTION:Limited data exist on the utility of plasma biomarkers to predict incident abnormal amyloid positron emission tomography (PET). In this study we evaluate the association of plasma Alzheimer's disease (AD) biomarkers with amyloid PET progression among initially amyloid PET negative (A-) individuals. METHODS:We included 290 A-, cognitively unimpaired Mayo Clinic Study of Aging participants. We estimated the association of each baseline plasma biomarker with progression from A- to A+ and with rate of amyloid PET change. RESULTS:Interquartile range differences in amyloid beta 42/40, percent phosphorylated tau 217 (%p-tau217), and Amyloid Probability Score 2 were associated with 1.29 (P = 0.09), 1.38 (P < 0.001), and 1.20 (P = 0.05) increases, respectively, in the hazard of progression from A- to A+ and 0.27 (P = 0.16), 0.50 (P = 0.007), and 0.28 (P = 0.15) Centiloid/year increases, respectively, in annual rate of amyloid PET change. DISCUSSION:Plasma %p-tau217 may be a useful screening tool to enrich for participants with increased likelihood of progressing from normal to abnormal amyloid PET in a primary prevention trial. HIGHLIGHTS:Plasma phosphorylated tau 217 was associated with amyloid positron emission tomography progression, negative to positive. The associations were weaker for amyloid beta 42/40 and Amyloid Probability Score 2. Age and apolipoprotein E ε4 carriership were also important predictors. These markers may be useful for enrichment of a primary prevention trial.

Growth/differentiation factor-15 (GDF15) has been associated with dementia risk, yet its predictive value across cohorts and sub-population, as well as its relationship with endophenotypes relevant to dementia, remains unknown. Using the Atherosclerosis Risk in Communities (ARIC) study as the discovery cohort, we examined the relationship between plasma GDF15 levels (SomaScan) and risk for incident all-cause dementia (ACD) in late-life (N=4,287, 7-year follow-up, M age =75±5) and in midlife (N=11,595, 20-year follow-up, M age =57±6). Utilizing the UK Biobank (UKB; replication cohort), we related plasma GDF15 (Olink) to incident ACD (N=35,673, 14-year follow-up, M age =61±5), vascular dementia (VaD) and Alzheimer’s disease dementia (AD). Finally, we examined the cross-sectional association of plasma GDF15 (SomaScan) with brain volume (N=994), white matter lesions (N=911), and plasma biomarker levels (Aβ 42/40 , GFAP, NfL, and pTau-181) in cognitively normal Baltimore Longitudinal Study of Aging (BLSA) participants. Analyses were stratified by APOEε4 status, cardiometabolic diseases, education, sex, race, and obesity. Late-life GDF15 abundance was associated with ACD risk in the full ARIC sample (HR=1.61 per log 2 increase; [95% CI: 1.36-1.90]) and in all but one subgroup – obese individuals (Figure 1A-B). GDF15 measured during late-life predicted 7-year ACD risk with an AUC of 0.63 (AUC for GDF15+Age: 0.71). Midlife GDF15 was also associated with ACD risk in the full ARIC sample (HR=1.55 per log 2 increase; [1.32-1.82]) and in each subgroup (Figure 1C-D). GDF15 measured during midlife predicted 20-year ACD risk with an AUC of 0.65 (AUC for GDF15+Age: 0.75). We replicated GDF15’s relationship with ACD risk in the UKB sample and found that GDF15 has a much stronger association with VaD (HR=1.76 per log 2 increase; [1.48-2.10]) compared to AD (HR=1.11; [1.01-1.23]; Figure 1E). In the BLSA, higher GDF15 was significantly associated with lower total and regional brain volume, a pattern of accelerated structural brain aging (SPARE-BA), and elevated plasma NfL and pTau181 (Figure 2A-G). Plasma GDF15 is associated with incident dementia risk across multiple cohorts, particularly vascular dementia, independent of cardiometabolic diseases and obesity. While our analyses indicate that GDF15 may play a role in dementia risk as early as midlife, GDF15, alone, provided only modest accuracy for dementia prediction.

BACKGROUND: The magnitude of cognitive changes after incident heart failure (HF) is unclear. We assessed whether incident HF is associated with changes in cognition after accounting for pre-HF cognitive trajectories and known determinants of cognition. METHODS: This pooled cohort study included adults without HF, stroke, or dementia from 6 US population-based studies from 1971 to 2019. Linear mixed-effects models estimated cognitive change with incident HF diagnosis and the rate of cognitive change over the years after HF, controlling for pre-HF cognitive trajectories and participant factors. Outcomes included change in global cognition (primary outcome), executive function, and memory (secondary outcomes). Cognitive outcomes were standardized to a t score metric (mean [SD], 50 [10]); a 1-point difference represented a 0.1-SD difference in cognition. RESULTS: We included 29 614 adults (mean [SD] age was 61 [10] years, 55% female, 70% White). During a median follow-up of 6.6 (Q1–Q3, 5.0–19.8) years, 1407 (5%) adults received an incident diagnosis of HF. Incident HF diagnosis was associated with initial decreases in global cognition (−1.1 points [95% CI, −1.4 to −0.8]) and executive function (−0.6 points [95% CI, −1.0 to −0.3]). Larger decreases in global cognition after HF were seen with older age, female sex, and White race. Participants with incident HF diagnosis demonstrated faster and long-term declines in global cognition (−0.1 points per year [95% CI, −0.2 to −0.1]) and executive function (−0.2 points per year [95% CI, −0.2 to −0.1]). The change in memory with incident HF diagnosis was not statistically significant but showed a similar trend with an initial decline of −0.5 points (95% CI, −1.4 to +0.3) and a slope of −0.1 points per year (95% CI, −0.3 to 0.0). CONCLUSIONS: In this pooled cohort study, incident HF diagnosis was associated with initial decreases in global cognition and executive function and faster, persistent declines in these domains at follow-up.

Mobility and cognition impairments are common in older adults, but neurodegenerative pathology contributions are unclear. We examined cross-temporal associations of Alzheimer’s Disease (AD)-specific and nonspecific neurodegenerative plasma biomarkers neurofilament light (NfL) with incident mobility and cognitive impairment in the Atherosclerosis Risk in Communities (ARIC) study. We hypothesized NfL would show stronger associations with mobility impairment than p-tau181 in a subset of 1,227 cognitively normal participants with biomarker data and no mobility impairment (mean age=75.5±5.0, 56% female, 23% Black) at visit 5 (2011-13). Participants were classified into five functional groups using data from up to four exams: no impairment (n = 587; referent), mobility impairment only (n = 266; gait speed< 0.8m/s), cognitive impairment only (n = 69; adjudicated dementia), dual impairment (n = 243; both) or decline-free death (n = 262) over a mean 6.3 years (0-11 years) of follow-up. A multinomial regression model estimated association of functional groups with p-tau-181 and NfL jointly, adjusted for cardiovascular and demographic factors, BMI, and kidney function. Relative prevalence ratios (RPR; 95% CI) are presented per one-unit higher log-base-2 transformed biomarker (doubling). For mobility and cognitive functional outcomes, p-tau-181 was more robustly supported [Mobility: RPR=1.36, (1.04,1.77); Cognitive: RPR=1.73, (1.10,2.70); Dual: RPR=1.78, (1.15,2.77)] than NfL [Mobility: RPR=1.14, (0.85,1.53); Cognitive: RPR=1.20, (0.70,2.05); Dual: RPR=1.65, (0.86,3.16)]; higher pTau-181 [RPR=1.60, (1.23,2.09)] and higher NfL [RPR=1.94, (1.39,2.71)] were associated with higher risk of decline-free death. A p-tau-181-x-NfL interaction term was not supported. Findings did not support NfL associations with functional outcomes with consideration of p-tau-181. AD blood biomarkers may help identify individuals at greater risk for multifaceted disability.

Estimates of the prevalence of preclinical amyloid positivity in the US general population are of great interest to the field, but difficult to measure and thus unavailable in representative studies. A statistical approach from causal inference, ‘transport’, may allow for improved generalizability of findings from a sample of persons from one population to another. We aimed to explore the feasibility and validity of extending results from a deeply-phenotyped convenience sample, the Alzheimer’s Disease Neuroimaging Initiative (ADNI), to a representative target sample, the Atherosclerosis Risk in Communities Study PET Amyloid Imaging Study (ARIC-PET) — with “proof of concept” defined by the performance of the transport estimator in recovering the observed prevalence of amyloid positivity in ARIC-PET. Eligible ARIC-PET and ADNI participants were either white or Black and had normal cognition or mild cognitive impairment. Amyloid positivity was defined using study-specific cutoffs for standardized uptake value ratio (SUVR). Probability of selection into ADNI (vs. into ARIC-PET), given harmonized sociodemographic and clinical covariates, was estimated using gradient boosted trees (GBM). The resulting study participation probability scores were used to transport the prevalence of amyloid positivity from ADNI to ARIC using inverse odds of sampling weights. Estimates of amyloid positivity prevalence derived from ADNI and from transporting from ADNI to ARIC-PET were compared to the observed prevalence in ARIC-PET, overall and by age, sex, race, education, and APOE e4 status. Transported prevalences substantially underestimated observed prevalences of amyloid positivity in most groups, with the exception of white, non-Hispanic individuals and persons with at least one APOE e4 allele, where prevalence was slightly overestimated. Prevalence of preclinical amyloid positivity based on transporting ADNI was further from the prevalence in ARIC-PET than the raw prevalence of amyloid positivity in ADNI except for white, non-Hispanic individuals and those with mild cognitive impairment. Transport estimators rely on adequately modeling the selection process. Available data may be insufficient to capture selection biases into deeply-phenotyped convenience samples, particularly for groups who are under-represented in research. Transport estimators will have greatest utility when applied to samples derived from known sampling strategies, and with increased diversity in dementia research.

Introduction Optimal management of covert brain infarction (CBI) is hampered by a lack of personalised estimates of dementia risk, for which individual studies are usually underpowered. We aimed to determine age- and sex-specific dementia risks, and identify clinical and imaging prognostic indicators in individuals with CBI. Methods We included participants from 7 population-based cohorts across Europe and the USA, and aggregated data through coordinated meta-analysis. Within each cohort, participants with CBI on MRI were matched 1:3 on age and sex to individuals without CBI. We used Cox models to estimate the relative risk of dementia, and subdistribution hazard models to compute 10-year absolute risks accounted for competing mortality. In participants with CBI, we also applied subdistribution hazard models to identify prognostic indicators of dementia. Results Of a total 8176 participants (mean age 73 years, 54% women), 2044 had a CBI. During a mean follow-up of 7.0 years, 369 (18%) participants with CBI developed dementia, compared to 859 (14%) without CBI. Individuals with CBI had a 1.4-fold (95%CI: 1.1−1.7) increased risk of all-cause dementia, and a 3.0-fold (1.3−6.7) increased risk of vascular dementia. In individuals with CBI, ten-year absolute risk of dementia ranged from 2.1% (0.4−7.2%) in those aged 50-59 years, to 34.9% (23.9-46.2%) in those aged ≥80.Dementia risk was elevated with CBI particularly from age 70 onwards (Figure 1). Dementia risk was higher among individuals with multiple CBI than in those with a single CBI (22.9% [10.4−38.4%] versus 17.9% [9.0−29.2%]; hazard ratios of 1.8 [1.5−2.2] versus 1.2 [1.0−1.5]), but was similar for cortical infarcts, cerebellar infarcts, and lacunes. Age, lower education, hypertension, diabetes, history of smoking, APOE-e4 genotype, and multiple CBI were risk indicators of dementia in people with CBI. Excess risk of dementia with CBI was only slightly attenuated by accounting for occurrence of ischemic stroke during follow-up (HR: 1.3 [1.1−1.6]). Conclusions Individuals with CBI are at increased risk of dementia, particularly after age 70 and with multiple infarcts. Demographic, clinical, and imaging characteristics may further guide personalised interventions and future trial design.

Impaired kidney function is a risk factor for cognitive decline and dementia, but most studies use serum creatinine-based equations to estimate kidney function as estimated glomerular filtration rate (eGFR); these equations include age, also a strong driver of cognitive impairment, and produce eGFR estimates with substantial error compared to gold-standard objective measures of GFR (mGFR). The purpose of this study was to determine eGFR and mGFR associations with cognitive function in African American adults, a population disproportionately impacted by both chronic kidney disease and dementia. We conducted a cross-temporal analysis of 368 participants (Age: 66.4 ± 7.4y, 75% Female) in the Genetic Epidemiology Network of Arteriopathy study with eGFR (CKD-EPI 2021 Creatinine Race-Free Equation) and mGFR assessed. eGFR was assessed using the CKD-EPI 2021 Creatinine Race-Free Equation and mGFR (urinary clearance of non-radiolabeled iothalamate). Memory (Rey Auditory Verbal Learning Test; RAVLT) and executive function (Digit Symbol Substitution Test; DSST) were assessed. Linear regression models were used to relate eGFR, mGFR, and serum creatinine to cognitive function with and without adjustment for age and sex. In unadjusted models, eGFR was positively associated with DSST scores (β = 0.19, 95%CI:0.11, 0.27) and RAVLT scores (β = 0.10, 95%CI:0.04, 0.16). mGFR was marginally associated with DSST scores (β = 0.07, 95%CI:-0.00, 0.14), but not RAVLT scores (β = 0.03, 95%CI:-0.01, 0.07). Associations of serum creatinine with cognitive function were mostly null to marginal. Age and sex adjustment greatly attenuated all associations. The observed differential renal function associations with cognition suggest age may largely explain prior reported associations.

BACKGROUND AND OBJECTIVES:Chronic kidney disease (CKD) is known to be associated with increased plasma phosphorylated tau217 (p-tau217) concentrations, potentially confounding the utility of plasma p-tau217 measurements as a marker of amyloid pathology in individuals with suspected Alzheimer disease (AD). In this study, we quantitatively investigate the relationship of plasma p-tau217 concentrations vs estimated glomerular filtration rate (eGFR) in individuals with CKD with and without amyloid pathology. METHODS:This was a retrospective examination of data from 2 observational cohorts from either the Mayo Clinic Study of Aging or the Alzheimer's Disease Research Center cohorts. p-Tau217 was determined using the ALZpath Simoa p-tau217 immunoassay and an immunoprecipitation mass spectrometry assay that simultaneously measures p-tau217 and nonphosphorylated-tau217 (np-tau217) to determine %p-tau217 ([p-tau217/nonphosphorylated-tau217]) × 100%) (C2N Diagnostics). Amyloid positivity was defined by amyloid-PET and a centiloid of ≥25. Log-log linear regression fits were used to quantitatively predict increases in plasma p-tau217 associated with decreasing eGFR. RESULTS:Participants (n = 202, mean age of 78 years, 38% female) with diagnoses of cognitive unimpairment (n = 109), mild cognitive impairment (n = 71), and dementia (n = 22) were included. In all, 114 (56%) of all participants were amyloid-PET positive (A+). In addition, 86 (43%) of all participants were classified as having CKD (CKD stages 3-4). p-Tau217 concentrations were significantly higher in A- participants with an eGFR of <60 (mL/min/1.73 m2), as compared with those with eGFR >60 A- participants. For an eGFR of 45 vs 60 in the A- cohort, the calculated percentage changes were +31%, +55%, and +19%, for ALZpath p-tau217, C2N p-tau217, and C2N %p-tau217, respectively. For the A+ cohort, the corresponding calculated percentage changes were +17%, +15%, and -5%, respectively. DISCUSSION:CKD was associated with increased p-tau217 concentrations when measuring p-tau217 by ALZpath and C2N methodologies, but the effect was mitigated by the use of %p-tau217. These results indicate limitations for the utility of plasma p-tau217 measurements in individuals with significant renal impairment (eGFR <45 or CKD stage 3b or greater). Determination of eGFR should be considered to avoid inaccurate classification of the presence of AD-related pathology by plasma p-tau217 in individuals with CKD. CLASSIFICATION OF EVIDENCE:This study provides Class II evidence that in individuals with CKD stage 3 (especially stage 3b) or higher, p-tau217 concentrations are increased, with a greater increase in amyloid-PET-negative individuals.

Blood-based biomarkers show promise as a noninvasive, inexpensive method for measuring Alzheimer’s disease pathology throughout the lifecourse. However, the predictive and classification accuracy of these biomarkers at different stages of the lifecourse and among diverse, community-dwelling populations requires further investigation. Between 2014 and 2015, 329 dementia-free participants from the Atherosclerosis Risk in Communities Study underwent brain magnetic resonance imaging (MRI) and florbetapir positron emission tomography (PET). Amyloid positivity was defined as a global cortex standardized uptake value ratio greater than 1.2. Stored plasma samples collected in midlife (1993-95, mean age 58.5 years) and late-life (2011-13, mean age 76.2 years) from a subsample of 259 participants were assayed in 2022 using Quanterix SiMoA. The assay quantified amyloid-β (Aβ)42/40, phosphorylated tau at threonine 181 (p-Tau181), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP). Unadjusted and covariate-adjusted logistic regression models estimated the association between plasma biomarkers from midlife and late-life and amyloid positivity in late-life. Unadjusted receiver operating characteristic curves documented the classification accuracy of the plasma biomarkers separately and collectively. The sample (Table 1) included 151 women (58.1%), 105 Black participants (40.4%), and 136 (52.3%) participants with amyloid positivity. In models adjusted for demographics, lifestyle factors, cardiovascular factors, and the presence of APOE ε4 alleles, assays measured in midlife were not associated with amyloid positivity in late-life (Table 2). However, late-life measurements of Aβ42/40, p-Tau181, and GFAP and change per decade from midlife to late-life in p-Tau181 and GFAP were associated with greater odds of amyloid positivity. The greatest classification accuracy (Figure 1) was achieved by using all assays measured in midlife and late-life (AUC = 0.754), although the accuracy when using only late-life measures was comparable (AUC = 0.737). Late-life plasma biomarkers of Alzheimer's disease neuropathology and astrogliosis were associated with late-life amyloid positivity, but midlife plasma biomarkers obtained 16 to 20 years earlier did not exhibit a statistically significant association. Additional longitudinal research is needed to determine whether changes in plasma biomarkers measured before an individual is classified as amyloid positive can be used to identify individuals at risk of developing Alzheimer's disease.

BACKGROUND AND OBJECTIVES:Midlife obesity is a risk factor of dementia, but late-life obesity has been associated with lower dementia risk. We investigated this paradox by exploring the relationship between late-life body mass index (BMI) category and dementia, with and without considering midlife to late-life BMI change. METHODS:This observational cohort study included participants of the community-based Atherosclerosis Risk in Communities (ARIC) study who were dementia-free at visit 5 (2011-2013). Dementia was ascertained by expert-adjudicated, algorithmic classification from an in-person neuropsychological battery, as well as telephone interviews and International Classification of Diseases codes from medical records. We first assessed the association of incident dementia with visit 5 BMI categories (normal weight, overweight, obese). Next, we used a cross-classification of visit 5 BMI categories with visit 4-visit 5 BMI change (decrease [loss of ≥2 kg/m2], increase [gain of ≥2 kg/m2], or stable [loss or gain of <2 kg/m2]) occurring during the 15 years before baseline. Cox regression was used. RESULTS:A total of 5,129 participants were included in the study (59% female; 22% identified as Black; mean (standard deviation) age at visit 5 of 75 (5) years). Over 8 years of follow-up, 20% of the sample developed dementia (n = 1,026). After covariate adjustment, participants with high late-life BMI had a lower risk of dementia; the hazard ratio (95% CI) was 0.86 (0.73-1.00) for overweight and 0.81 (0.68-0.96) for obesity. In stratified models, elevated dementia risk was observed only for participants of each late-life BMI category whose BMI had decreased from midlife to late life. Compared with normal-weight individuals who had maintained BMI from midlife to late life, the hazard ratio (95% CI) for those with BMI loss was 2.08 (1.62-2.67) for normal-weight individuals, 1.62 (1.25-2.10) for those with overweight, and 1.36 (1.00-1.85) for those with obesity. DISCUSSION:Our results provide insight into the dementia obesity paradox at older ages, tempering a causal interpretation of high late-life BMI as protective against dementia. Instead, they highlight the importance of considering weight loss from midlife to late life in conjunction with late-life BMI in dementia risk stratification.

Faster gait speed and better endurance have been cross-sectionally and jointly associated with a lower likelihood of dementia. However, gait speed associations plateau above 1m/s, suggesting gait speed may be less predictive at near normal speeds. This study examined prospective associations of gait speed, endurance, and moderating effects of endurance on gait speed associations with incident dementia among ARIC participants without dementia at Visit 6 (2016-2017) who completed assessments of endurance ( 2- Minute Walk (2MW), meters) and usual-pace 4-meter gait speed (m/s) (n = 2767, mean age 78+/- 4.3 years, 43% male, 18% Black). Dementia was adjudicated using neuropsychological tests, functional assessments, informant interviews, and medical/vital record surveillance over a median of 3.3 years follow-up. Cox regression models estimated the hazard ratio (HR, 95% CI) for dementia, incorporating gait speed, 2MW, gait speed-by-2MW interaction, demographic, and cardiovascular factors. In separate models, each standard deviation higher 2MW [HR = 0.62, (0.50,0.76)] and faster gait speed [HR = 0.63, (0.50,0.81)] were associated with lower incident dementia risk. However, when jointly adjusting for 2MW and gait speed, higher 2MW was associated with a 32% lower incident dementia risk [HR = 0.68,(0.51, 0.90)], but faster gait speed was not statistically associated with incident dementia [HR = 0.85, (0.62,1.16)]. Moderating effects were not supported (gait speed-x-2MW interaction, p = 0.14). Although both endurance and gait speed predict dementia, endurance may be more informative across the gait speed spectrum, whereas gait speed may be more feasible for clinical settings. Longer follow-up and more dementia events may better inform differential utilities of gait speed and endurance measures.

Lower cerebral perfusion is associated with adverse outcomes, but risk factors are poorly understood. This study examined associations of cumulative systolic blood pressure [SBP], diabetes, and BMI from mid- to late-life with late-life cerebral perfusion, using whole-brain MRI Arterial Spin Labeling (ASL). Cumulative exposures were defined as either average continuous SBP or BMI across visits or number of years with diabetes, hypertension, or obesity. Multiple regression, adjusted for age and gender, estimated ASL (β: 95% CI) among participants without prevalent conditions at baseline in participants with ASL data from the Atherosclerosis Risk in Communities Study (ARIC; Jackson, MS; n = 100; age=81±3 years; 65% Female; 100% Black participants; 34 years retrospective risk factor assessments (1987-2021); pulsed ASL, 8/2021-1/2024) and the Mayo Clinic Study of Aging (MCSA; Rochester, MN; n = 537; age=71±13 years; 36.3% Female, 100% White participants; 18 years retrospective risk factor assessments (2005-2023); pseudo-continuous ASL 2/2023-3/2024). A 10 mmHg higher cumulative SBP was associated with a 0.04 lower ASL (MCSA β=-0.04; -0.01, -0.07; ARIC β=-0.04; -0.09, 0.01). A 10 kg/m2 higher cumulative BMI was associated with a 0.30 lower ASL (-0.51, -0.08) in ARIC and 0.03 lower ASL (-0.16, 0.10) in MCSA participants. Every five additional years of diabetes exposure was associated with a 0.03 (-0.06, -0.01) lower ASL in ARIC and 0.11 (-0.27, 0.05) lower ASL in MCSA participants. High BP, obesity, and diabetes may contribute to poor cerebral perfusion over extended exposures from midlife. Longer risk factor assessment periods and different ASL techniques may explain differences in the cohorts.

Olfactory impairment appears early in the course of Alzheimer’s Disease (AD) and may serve as a non-invasive early marker of AD. Few studies have examined the association between olfaction and blood biomarkers of AD neuropathology in large, diverse, community-based populations. Blood levels of amyloid-beta (Aβ 42 and Aβ 40 ), phosphorylated-tau (p-tau) forms, glial fibrillary acidic protein (GFAP), and neurofilament-light chain (NfL) appear to reliably reflect corresponding brain neuropathologies and neurodegeneration. Investigation of olfaction in relation to these biomarkers could provide insights into its utility in the early identification of individuals at high risk of progressing to AD. We investigated cross-sectional associations of olfaction (measured by a 12-item odor identification test) with blood Aβ 42 /Aβ 40 ratio, GFAP, NfL, p-tau 181 , and p-tau 181 /Aβ 42 ratio (measured using Quanterix ultrasensitive single-molecule array assays) in 1,565 Black and White participants from the community-based ARIC Study and whether these associations differed by race and APOE ε4 genotype. Both olfaction and blood biomarkers were obtained at ARIC visit 5 (2011-2013). Separate linear regression models were used to examine the association of continuous olfaction score and olfaction categories (anosmia: score ≤6; hyposmia: score 7-8; moderate olfaction: score 9-10, normal olfaction: score 11-12) with each biomarker (all biomarkers were log-transformed and measured in pg/mL), adjusting for relevant covariates (See Table). Among 1,565 participants (mean ± SD age:76±5 years, 60% women, 27% self-reported Black), the mean ± SD olfaction score was 9.2±2.3; 14% had anosmia. Consistent with our hypotheses, higher olfaction score (i.e., better olfactory function) was significantly associated with lower levels of NfL, GFAP, p-tau 181 , and p-tau 181 /Aβ 42 , and higher Aβ 42 /Aβ 40 ratio (See Table). Compared to normal olfaction, anosmia (i.e., poor olfaction) was significantly associated with higher NfL, GFAP, p-tau 181 , and p-tau 181 /Aβ 42 ratio and lower (although not statistically significant) Aβ 42 /Aβ 40 ratio. Associations of hyposmia and moderate olfaction with these biomarkers were not statistically significant. The associations did not differ by APOE ε4 status or race. Our findings suggest that poor olfaction is associated with concurrent blood biomarkers of AD and neurodegeneration. Future analyses will examine associations of olfaction with prospective changes in these biomarkers and if these associations are explained by relevant neuroimaging markers.

Although slower gait speed is associated with cognitive impairment, endurance may be more predictive in older adults with faster gait speed. We examined moderating effects of endurance on the relationship of gait speed with incident mild cognitive impairment (MCI) or dementia in cognitively normal ARIC participants (n = 2242, mean age=78.6 + 4.3, 58% female, 19% Black). At the sixth exam, endurance was assessed as distance walked at a fast pace (Two Minute Walk, 2MW); usual 4-meter gait speed was also assessed. Cognitive status was adjudicated during the 6th-9th exams (mean follow-up 5.1 years). Multinomial logistic regression models with a 2MW-x-gait speed interaction term estimated relative risk ratios (RRR) of MCI and dementia relative to normal cognition per SD higher gait speed or 2MW distance, adjusting for demographic and cardiovascular factors. Results used representative continuous gait speed and continuous 2MW distance values. Longer 2MW distance was associated with lower risk of MCI and dementia at gait speed <1m/s [e.g. gait speed=0.8: MCI RRR=0.59, 95%CI(0.42, 0.83); dementia RRR=0.29, (0.13, 0.63)] and with dementia at gait speed>1m/s [gait speed=1.2: RRR=0.28, (0.09, 0.81)], but not with MCI (RRR=0.85, (0.57, 1.26)]. Conversely, faster gait speed was associated with lower risk of MCI at low 2MW [100 m; RRR=0.84, (0.74, 0.94)], but was attenuated at high 2MW (150 m; RRR=0.91, (0.84, 1.00)]. A 2MW-x-gait speed interaction term was supported (p = 0.04), primarily driven by differential MCI associations. Combining endurance and gait speed may be especially helpful in identifying cognitively normal older adults at risk for impending early-stage cognitive impairment.