Palta, Priya

Abstract There is an urgent need to improve dementia ascertainment robustness in real-world studies assessing drug effects on dementia risk. We developed algorithms to dementia identification algorithms using Medicare claims (inpatient/outpatient/prescription) from 3318 Visit 5 (2011-2013) and 1828 Visit 6 (2016-2017) participants of the Atherosclerosis Risk in Communities (ARIC) Study, validated against ARIC's rigorous syndromic dementia classification. Algorithm performance was compared to existing algorithms (Jain, Bynum, Lee). We further evaluated algorithms effectiveness in a 20% random Medicare sample aged ≥70 years who initiating liraglutide or dipeptidyl peptidase 4 inhibitors (DPP4i) to assess 3-year adjusted risk difference (aRD) for dementia. Our incident dementia algorithm required two dementia diagnostic codes within 1-year, or one dementia code plus a new dementia prescription within 90 days. It achieved a positive predictive value (PPV) of 69.2%, specificity of 99.0%, and sensitivity of 34.6% (population prevalence: 8.8%), comparable to extant algorithms (PPV, 58.7–68.6%; sensitivity 25.5–40.4%). Prevalent dementia algorithm (without requiring incident diagnoses/prescriptions) demonstrated similar performance. In the Medicare sample, dementia risk ranged from 3.0% to 12.5%, aRD comparing liraglutide to DPP4i varied −1.2% to −3.6%, with our algorithm closely matching the Bynum algorithm. Algorithm selection significantly impacts treatment effect estimates, highlighting its importance in in pharmacoepidemiologic research.

ImportanceMidlife vascular risk factors are associated with an elevated risk of dementia. However, the total contribution of vascular risk factors in midlife and late life with incident dementia is uncertain.ObjectiveTo quantify the proportion of incident dementia attributable to modifiable vascular risk factors measured in midlife and late life and to examine differences by apolipoprotein ε4 genotype, self-reported race, and sex.Design, Setting, and ParticipantsThis was a prospective cohort analysis of the Atherosclerosis Risk in Communities (ARIC) study using 33 years of follow-up (1987-2020). The setting included ARIC field centers (Jackson, Mississippi; Forsyth County, North Carolina; Minneapolis suburbs, Minnesota; Washington County, Maryland). Study baseline in Black and White participants with complete exposure and covariate data was set by age at risk factor measurement (45-54 years, 55-64 years, and 65-74 years). Data were analyzed from August 2023 to December 2024.ExposuresHypertension (systolic blood pressure [BP] ≥130 mm Hg, diastolic BP ≥80 mm Hg, or use of medication for BP), diabetes (fasting glucose ≥126 mg/dL, nonfasting glucose ≥200 mg/dL, self-reported physician’s diagnosis, or use of any diabetes medication), and current smoking (self-reported).Main Outcomes and MeasuresIncident dementia. Population attributable fractions were estimated by age 80 years, and separately after 80 years, from having at least 1 vascular risk factor by age at risk factor measurement.ResultsA total of 7731 participants were included in analysis of risk factors measured at age 45 to 54 years (4494 female [58%]; 2207 Black [29%]; 5524 White [71%]), 12 274 contributed to analysis of risk factors measured at age 55 to 64 years (6698 female [55%]; 2886 Black [24%]; 9388 White [76%]), and 6787 contributed to analysis of risk factors measured at age 65 to 74 years (3764 female [56%], 1375 Black [20%]; 5412 White [80%]). There were 801, 995, and 422 dementia cases by 80 years, respectively. The fraction of dementia by 80 years attributable to at least 1 vascular factor at age 45 to 54 years was 21.8% (95% CI, 14.3%-29.3%), at 55 to 64 years was 26.4% (95% CI, 19.1%-33.6%), and at 65 to 74 years was 44.0% (95% CI, 30.9%-57.2%). Attributable fractions for these factors were higher in apolipoprotein ε4 noncarriers at age 55 years and older (range, 33.3%-61.4%), Black individuals at age 45 years and older (range, 25.5%-52.9%), and female individuals at age 55 years and older (range, 29.2%-51.3%). Only 2% to 8% of dementia cases after 80 years were attributable to these factors.Conclusions and RelevanceResults of this cohort study suggest that between 22% and 44% of incident dementia cases by 80 years in the ARIC study were attributed to midlife and late-life vascular risk factors. Assuming causal relationships, maintaining optimal vascular health across the life course could mitigate a sizeable proportion of dementia risk by 80 years.

Introduction: Physical activity (PA) has been identified as a modifiable factor inversely associated with cognitive decline and dementia risk. However, most longitudinal studies to date have short follow-up and report inconsistent results on the benefit of PA to support brain health among older adults. In this study, we hypothesized that higher levels of PA measured in late life would be associated with slower rates of global and domain-specific cognitive decline and a lower risk of dementia over ~10 years in late life. Methods: Dementia-free participants (n=5,982; mean age: 76 years; 42% male, 23% Black) who completed the interviewer-administered Modified Baecke PA Questionnaire at ARIC visit 5 (2011-2013) were included. Using the PA component of the American Heart Association’s Life’s Simple 7, participants’ PA levels were categorized as ideal, intermediate, or poor. Cognitive tests were administered at ARIC visits 5 (2011-13), 6 (2016-17), 7 (2018-19), 8 (2020), and 9 (2021-22), and were used to calculate factor scores for global cognitive function and the domains of memory, language, and executive function. Linear mixed models estimated the association of PA with change in cognitive function. Dementia cases were defined by adjudicated review, telephone interviews, informant interviews, hospitalization records, and death certificates. Dementia risk was estimated using Cox proportional hazards regression models. All models adjusted for age, sex, race-center, education, APOE-ε4 allele, smoking, hypertension, body mass index, and diabetes. Results: Participants with ideal or intermediate PA, compared to poor PA, had slower rates of decline in global cognition, but no significant differences in rates of decline across individual cognitive domains. Over a median follow-up of 7.8 years, participants with ideal (adjusted hazard ratio [HR] = 0.62, 95% CI: 0.60, 0.67) or intermediate (adjusted HR = 0.87, 95% CI: 0.80, 0.91) PA had a reduced risk of dementia compared to participants with poor PA. Conclusions: Higher PA levels in late life demonstrated a protective association with long-term global cognitive decline and incident dementia. Although further research with more frequent and objective measures of PA is needed to determine the duration, frequency, and intensity of PA recommended to promote brain health in older adults, our findings suggest that promoting PA among aging populations offers a non-invasive and accessible approach to support brain health.

Introduction: Vascular risk factors of hypertension, diabetes, and smoking in midlife (45-64 years) and possibly early late-life (65-74 years) are associated with increased risk of dementia. Current estimates of population attributable risk for dementia assume vascular factors are independent and do not interact to increase risk of dementia, which may underestimate the combined impact of vascular risk reduction on dementia incidence. In this study, we evaluated the joint association and interaction of vascular risk factors on risk of dementia. Methods: We performed a prospective cohort analysis using the Atherosclerosis Risk in Communities Neurocognitive Study using up to 33 years of follow-up (1987-2020). We used age as baseline (45-54 years, n=7,731; 55-64 years, n=12,273; and 65-74 years, n=6,660). We defined hypertension as systolic blood pressure ≥130 mm Hg, diastolic blood pressure ≥80 mm Hg, or anti-hypertension medication use. We defined diabetes as fasting glucose level ≥126 mg/dL, non-fasting glucose ≥200 mg/dL, self-reported physician diagnosis, or use of any diabetes medication. Current smoking was self-reported. We investigated additive and multiplicative interactions for combinations of vascular risk factors on incident (adjudicated) dementia by age 80 using joint effect variables in Cox regression models stratified by age of risk factor measurement (45-54 years, 55-64 years, or 65-74 years). For interaction analyses, parameter values >1 indicate positive interaction (synergy) and values <1 indicate negative interaction (antagonism). Results: In participants with risk factors measured in these baseline age strata, there were 801 (10%), 995 (8%), and 422 (6%) cases of incident dementia by age 80, respectively. Hypertension and diabetes exhibited positive interactions on the additive and multiplicative scales in midlife (Figure 1). Diabetes and smoking in midlife had positive additive interaction (value >1, Figure 2). All vascular risk factor combinations in late-life had negative interactions on the multiplicative scale (values <1, Figures 1-3). Conclusions: Hypertension with diabetes and diabetes with smoking, all measured in midlife, interact to increase risk of dementia by age 80. The overall impact of reducing midlife vascular risk factors on incident dementia could be sizeable. These findings highlight the importance of multifactor interventions addressing combinations of vascular risk factors for dementia prevention strategies.

AbstractBackgroundBlood‐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.MethodBetween 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.ResultThe 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).ConclusionLate‐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.

AbstractBackgroundOlder adults with dual cognitive and mobility impairments have higher financial costs and poorer quality of life than adults with either impairment alone. Blood biomarkers of Alzheimer Disease (AD) pathology (Aβ42, Aβ40 and p‐tau181) and neurodegeneration (neurofilament light (NFL) and glial fibrillary acidic protein (GFAP)) may identify individuals at risk for both mobility and cognitive impairment and provide novel insights into mechanistic underpinnings.MethodBlood biomarkers (SiMoA Quanterix N4PE, p‐tau181 single‐plex) were available in a subsample of 1751 ARIC study participants at Visit 5 (V5, 2011‐13, mean age 76.2 years (5.3), 41% men, 28% Black); Aβ42 was reversed and adjusted for Aβ40 (‐Aβ42|40) for consistent directions of associations (higher=worse). Usual gait speed and cognitive status were assessed over 8 years at V5, V6 (2016‐17), and V7 (2017‐18). Participants were categorized by V5 impairment: mobility‐only (gait speed <0.8m/s, n=430), cognitive‐only (expert‐adjudicated dementia, n=38), dual (n=54), or neither (referent, n=1229). Multinomial regression models examined relative risk ratios (RRR) of V5 log‐transformed biomarkers with prevalent impairments and, among those with neither impairment at V5, incident impairments through V7. All models adjusted for V5 age, sex, self‐reported race (Black or White), renal function, and body mass index.ResultHigher levels of all biomarkers were associated with greater risk of prevalent impairment in mobility, cognitive, or dual domains (Figure A). Over 8‐years of follow‐up, incident impairments included 471 participants with only mobility impairments, 39 with only cognitive impairments, 55 with dual impairments, and 168 died without developing any impairment. All biomarkers were associated with incident dual impairment per IQR higher biomarker: p‐tau181 (RRR=2.54; 95% CI: 1.45, 4.44), ‐Aβ42|40 (RRR=1.66; 1.31, 2.09), NfL (RRR=2.69; 1.22, 5.91) and GFAP (RRR=2.13; 1.07, 4.25). P‐tau181, ‐Aβ42|40, and GFAP were also associated with incident cognitive‐only impairment, while P‐tau181, NFL and GFAP were associated with incident mobility‐only impairment. (Figure B).ConclusionBlood biomarkers of brain health may be useful tools for earlier identification of those at risk for cognitive, mobility, or dual declines, facilitating earlier targeted interventions. Potential differences in AD‐pathology versus neurodegeneration blood biomarker relationships with outcomes of mobility and cognition may help to identify more targeted interventions for both.