Gross, Alden L.

Abstract Background Even among cognitively unimpaired (CU) older adults, specific patterns of neuropsychological performance impart differential risk for progression to Alzheimer's disease and related dementias (ADRD). Early identification in the prodromal phase may inform early intervention efforts. We used a data‐driven approach to classify neuropsychological phenotypes within CU older adults from the Atherosclerosis Risk in Communities (ARIC) study and tested for differences in ADRD and cerebrovascular outcomes. Method Participants included 4737 CU (via a previously published algorithm plus consensus diagnosis protocol) older adults (mean age=75.1 years, 60.8% female, 23.1% Black) with neuropsychological data from Visit 5 (2011‐2013) of the ARIC study. Latent profile analysis was leveraged to identify unique cognitive phenotypes using 10 demographically adjusted (age, sex/gender, education, race‐center, WRAT Reading) neuropsychological z‐scores. Cognitive phenotypes were then compared on demographics, depressive symptoms, and vascular risk factors (VRFs). In a subset with available neuroimaging and biofluid data ( n range=1102‐1678), white matter hyperintensity (WMH) and bilateral hippocampal (HV) volumes normalized for intracranial volume and plasma biomarkers (i.e., Aβ42/40, ptau181, NfL, and GFAP) were examined by phenotype. Phenotype comparisons adjusted for demographic variables, VRFs, and an indicator of kidney function (i.e., eGFR‐creatinine) for plasma biomarkers. We applied Tukey adjustment for pairwise comparisons. Result A 6‐class solution of cognitive phenotypes emerged as the best fitting model: Average Overall (28%), Low Overall/Very Low Memory (7%), Average Overall/Super Memory (11%), Subtle Low Overall/Low Executive (22%), Subtle Low Executive/High Memory (13%), and Average Overall/Low Memory (19%; Figure 1). Phenotypes differed on education, race, and word reading, despite prior adjustments for these variables when creating the neuropsychological z‐scores (Table 1). Additionally, phenotypes differed on depressive symptoms, VRFs, WMH, HV, Aβ42/40, and ptau181 (all p s < .05). The Subtle Low Overall/Low Executive group had the highest WMH volumes, the Subtle Low Executive/High Memory group had the lowest Aβ42/40, and the Low Overall/Very Low Memory group had the lowest HV and highest levels of plasma ptau181 (Table 2). Conclusion Cognitive heterogeneity is observed even among CU older adults, with lower executive performance associated with cerebrovascular changes and lower memory associated with certain AD‐related changes, possibly indicating risk for cognitive progression through distinct pathways.

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: 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.

Background: Cognitive change is an important factor in understanding dementia. Estimating effects of exposures on cognitive change requires choosing an analytical timescale, typically time on study or current age. There is limited consensus regarding timescale choice in epidemiologic cognitive aging research. Methods: Using a coordinated analytic approach in 10 cohorts of older adults, we evaluated whether estimated effects of two exposures on memory change differed depending on timescale (time on study or current age). We modeled effects of apolipoprotein-E (APOE) ε4 genotype (a time-invariant exposure) and diabetes (a potentially time-varying/acquired exposure evaluated at baseline) using mixed-effects models with linear and nonlinear time specifications for both timescales. Results: Among APOE ε4 carriers, model-estimated memory scores at baseline (time on study timescale) or at each cohort’s median baseline age (current age timescale) were lower, and the average rate of decline was faster than among APOE ε4 noncarriers. Model-estimated memory scores at baseline or at median baseline age were generally similar across baseline diabetes status, with variability across cohorts in the diabetes-memory change association. In some cohorts, trends in diabetes-memory change associations differed in direction across timescales. Conclusions: Timescale was largely inconsequential for estimated effects of APOE genotype, but yielded differences in estimated diabetes effects, raising questions about the appropriate scale. The current age scale may be problematic because diabetes was measured heterogeneously in age across individuals, a common issue in aging cohorts. Our work demonstrates approaches to evaluate alternative timescales, including in multicohort analyses, and highlights potential implications for estimated exposure effects on cognitive change.

AbstractBackgroundMidlife vascular risk factors are associated with an increased risk of dementia. However, the overall contribution of modifiable vascular risk factors in midlife and late‐life to dementia remains unclear. In this study, we quantified population attributable fractions, which account for risk factor prevalence and strength of relative risks, of incident dementia from vascular risk factors measured in midlife and early late‐life.MethodWe used 33 years of prospective cohort data in the Atherosclerosis Risk in Communities Study. Incident dementia (community surveillance and algorithmic diagnosis with expert clinical adjudication) was ascertained from baseline (1987‐1989) through December 31, 2020. We quantified population attributable fractions of incident dementia by age 80 from the combination of hypertension (systolic blood pressure ≥130, diastolic blood pressure ≥80, or use of medication), diabetes (fasting glucose ≥126, non‐fasting glucose ≥200, self‐reported physician diagnosis of diabetes, or use of medication for diabetes/insulin), and self‐reported current cigarette smoking (at least one risk factor versus none) measured at different ages (45‐54 [n = 7,731], 55‐64 [n = 12,273]; 65‐74 [n = 6,660]). We also computed attributable fractions stratified by sex, apolipoprotein ε4 genotype, and self‐reported race.ResultThe prevalence of having one or more of the vascular risk factors was 61.6% (95% CI: 60.5, 62.7%) at age 45‐54 and increased to 77.5% (95% CI: 76.5, 78.5%) by age 65‐74. Population attributable fractions of dementia increased from 22.7% (95% CI: 15.3, 30.1%) for vascular risk factors measured at age 45‐54 to 45.4% (95% CI: 32.5, 58.3%) for vascular risk factors assessed at age 65‐74 (see Figure). Attributable fractions were larger in females, participants without apolipoprotein ε4 alleles, and Black participants (Figure).ConclusionBetween 23% to 45% of incident dementia cases by age 80 were attributed to a combination of hypertension, diabetes, or current smoking up through age 74. Attributable fractions for the combined impact of vascular risk varied by key demographics. Public health strategies targeting modifiable vascular risk factors could reduce dementia risk and increase healthy lifespan.

AbstractBackgroundThe Uniform Data Set (UDS) neuropsychological battery, administered across Alzheimer’s Disease Centers (ADC), includes memory tests but lacks a list‐learning paradigm. ADCs often supplement the UDS with their own preferred list‐learning task. Given the importance of list‐learning for characterizing memory, we aimed to develop a harmonized memory score that incorporates UDS memory tests while allowing centers to contribute differing list‐learning tasks.MethodWe applied item‐banking confirmatory factor analysis to develop a composite memory score in 5,287 participants (mean age 67.1; SD = 12.2) recruited through 18 ADCs and four consortia (DiverseVCID, MarkVCID, ALLFTD, LEADS) who completed UDS memory tasks (used as linking‐items) and one of five list‐learning tasks. All analyses used linear regression. We tested whether memory scores were affected by which list‐learning task was administered. To assess construct validity, we tested associations of memory scores with demographics, disease severity (CDR Box Score), an independent memory task (TabCAT Favorites, n = 675), and hippocampal volume (n = 811). We compared performances between cognitively unimpaired (n = 279), AD‐biomarker+ MCI (n = 26), and AD‐biomarker+ dementia (n = 98). In a subsample with amyloid‐ and tau‐PET (n = 49), we compared memory scores from participants with positive vs negative scans determined using established quantitative cutoffs.ResultModel fit indices were excellent (e.g., CFI = 0.998) and factor loadings were strong (0.43‐0.93). Differences in list‐learning task had a negligible effect on scores (average Cohen’s d = 0.11). Higher memory scores were significantly (p’s<.001) correlated with younger age (β = ‐0.18), lower CDR Box Scores (β = ‐0.63), female sex (β = 0.12), higher education (β = 0.19), larger hippocampal volume (β = 0.42), and an independent memory task (β = 0.71, p<0.001). The memory composite declined in a stepwise fashion by diagnosis (cognitively unimpaired>MCI>AD dementia, p<0.001). On average, amyloid‐PET positivity was associated with lower composite scores, but was not statistically significant (β = ‐0.34; p = 0.25; d = 0.40). Tau‐PET positivity was associated with worse performance, demonstrating a large effect size (β = ‐0.75; p<0.002; d = 0.91).ConclusionThe harmonized memory score developed in a large national sample was stable regardless of contributing list‐learning task and its validity for cross‐cohort ADRD research is supported by expected associations with demographics, clinical measures, and Alzheimer’s biomarkers. A processing script will be made available to enhance cross‐cohort ADRD research.

AbstractINTRODUCTIONThe contribution of neuropsychological assessments to risk assessment for incident dementia is underappreciated.METHODSWe analyzed neuropsychological testing results in dementia‐free participants in the Atherosclerosis Risk in Communities (ARIC) study. We examined associations of index domain–specific neuropsychological test performance with incident dementia using cumulative incidence curves and Cox proportional hazards models.RESULTSAmong 5296 initially dementia‐free participants (mean [standard deviation] age of 75.8 [5.1] years; 60.1% women, 22.2% Black) over a median follow‐up of 7.9 years, the covariate‐adjusted hazard ratio varied substantially depending on the pattern of domain‐specific performance and age, in an orderly manner from single domain language abnormalities (lowest risk) to single domain executive or memory abnormalities, to multidomain abnormalities including memory (highest risk).DISCUSSIONBy identifying normatively defined cognitive abnormalities by domains based on neuropsychological test performance, there is a conceptually orderly and age‐sensitive spectrum of risk for incident dementia that provides valuable information about the likelihood of progression.Highlights Domain‐specific cognitive profiles carry enhanced prognostic value compared to mild cognitive impairment. Single‐domain non‐amnestic cognitive abnormalities have the most favorable prognosis. Multidomain amnestic abnormalities have the greatest risk for incident dementia. Patterns of domain‐specific risks are similar by sex and race.