Lutsey, Pamela L.

Abstract The Atherosclerosis Risk in Communities (ARIC) study started in 1987‐1989 (visit 1), when participants from four U.S. communities were 45‐64yo. Participants have been seen at up to 10 additional in‐person visits with annual/semi‐annual telephone calls to ascertain clinical events, hospitalizations, and other health outcomes. In 2011‐2013, at ARIC visit 5, the ARIC Neurocognitive Study (ARIC‐NCS) was initiated for surviving participants, incorporating neuropsychological assessments at multiple in‐person visits and informant interviews to support cognitive adjudication. A subset of participants have undergone brain MRI with measurement of brain volumes, cortical thickness, arterial disease and vascular lesions, with a smaller subset having brain florbetapir PET. Blood‐based Alzheimer's disease (AD) biomarkers are available at multiple visits along with extensive measurement of vascular risk factors, vascular markers, and ‐omic (e.g.genomic and proteomic) data. This presentation will focus on the available data in ARIC, the methods underlying its collection and subsequent analysis, and some of the primary contributions of this study to the field. With 37 years of follow‐up, a great strength of ARIC is the ability to evaluate risk factors in midlife; ARIC studies have supported an association of midlife hypertension, diabetes, physical inactivity, and other vascular risk factors with reduced dementia risk, even among those with increased genetic risk for dementia. ARIC studies have demonstrated associations between stroke and dementia, and have linked vascular risk factors with blood‐based and imaging biomarkers of AD‐related dementias. ARIC has demonstrated the importance of hearing loss in dementia risk, and a subset of ARIC participants were recruited into (and were those who most benefited from the intervention of) the ACHIEVE study of hearing aid use for reduction of dementia. Proteomic studies have identified markers of dementia risk when evaluated in midlife. Recently, ARIC data informed updated estimates on lifetime risk of dementia, where it was estimated that among individuals surviving beyond age 55, 42% would develop dementia over their lifetime through age 95. ARIC studies continue to focus on risk factors for dementia, particularly now in the oldest old, and on contributors to cognitive reserve and resilience. ARIC follows a model of data sharing and broad collaboration.

Importance SARS-CoV-2 infection has been linked to neurotoxic effects and cognitive deficits. Objective To determine whether decreases in cognitive function were accelerated after SARS-CoV-2 infection compared with individuals not infected. Design, Setting, and Participants Multicenter, prospective cohort study from 2016 to 2022 among 3525 participants alive on March 1, 2020, and enrolled in The Atherosclerosis Risk in Communities (ARIC) study and the Collaborative Cohort of Cohorts for COVID-19 Research study who completed a prepandemic cognitive assessment and a pandemic-era assessment of SARS-CoV-2 infection. Final analyses performed in November 2024. Exposure SARS-CoV-2 infection determined via self-report of a positive SARS-CoV-2 test or health care professional diagnosis of COVID-19, a positive SARS-CoV-2 antinucleocapsid antibody response, or presence of an administrative code for COVID-19 on medical records. Main outcomes and measures A neuropsychological battery assessed multiple cognitive domains, and a cocalibrated confirmatory factor analysis generated factor scores for global cognitive function. The primary outcome was the rate of excess change in cognitive function. Results The 3525 eligible participants had a mean (SD) age of 80.8 (4.7) years, 2085 (59.1%) were female, 752 (21.4%) were Black, and 2773 (78.6%) were White. SARS-CoV-2 infection was detected among 307 participants (8.7%), 103 of whom (33.6%) were hospitalized. Among uninfected participants, the mean annualized change in cognitive function was −0.09 (95% CI, −0.13 to −0.04). Compared with this rate, change was faster (β = −0.06; 95% CI, −0.09 to −0.02) among participants hospitalized for infection, but not different from participants who were infected but not hospitalized (β = 0.00; 95% CI, −0.02 to 0.03). The association among participants hospitalized for infection was evident in the cognitive domains of memory and executive function, but not language. Conclusions and relevance This cohort study of older participants found accelerated decreases in cognition among individuals hospitalized for SARS-CoV-2 infection, but not nonhospitalized infection, in comparison with individuals not yet infected.

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.

Background Heart failure (HF) is a growing public health burden. Systemic inflammation is commonly observed in patients with HF and believed to be related to disease pathogenesis. Infection is a potential acute trigger of chronic inflammation. Our objective was to examine the relationship between infection‐related hospitalization (IRH) and HF. Methods and Results We studied beneficiaries with at least 15 months of continuous enrollment in the US‐based MarketScan databases during 2013 to 2019. We included n=152 008 patients with an inpatient or outpatient HF International Classification of Diseases, Ninth Revision/Tenth Revision ( ICD‐9/10 ) code in the primary position. Among patients with HF, IRH was identified using select ICD‐9/10 codes. We used a case‐crossover design to compare the frequency of IRH occurring within 3 months of the index HF event (case period) versus the frequency of IRH occurring 12 to 15 months before the index HF event (control period). Logistic models regressed the log‐odds of having an IRH during the case versus control periods; odds ratios (ORs; 95% CIs) are presented. Among 152 008 beneficiaries, 53% were male with a mean±SD age of 56(±11) years. The odds of having an IRH during the case (versus control) period was elevated for both the 3‐month case period (OR, 4.39 [95% CI, 4.18–4.60]), and 1‐month case period (OR, 7.39 [95% CI, 6.88–7.94]), after adjusting for the total number of hospitalizations. This relationship persisted across different types of infections. Conclusions IRH was associated with incident HF after both 1 and 3 months and may represent a modifiable risk factor for HF.

Introduction: Physical activity (PA) has been identified as a protective factor for dementia, but the mechanisms linking PA to brain health are unclear. To elucidate potential pathways linking PA to brain health, we tested the hypothesis that higher levels of late-life PA are associated with a lower burden of Alzheimer’s disease (AD) pathology, cerebrovascular disease, and neurodegeneration measured through brain imaging and plasma biomarkers. Methods: ARIC-NCS participants without dementia in 2011-13 and with measures of PA, 3T brain magnetic resonance imaging (MRI), and stored plasma samples were examined (n=1,771; mean age: 76.5 years; 40.5% male; 27.6% Black). Participants were classified as meeting or not meeting 2018 aerobic PA guidelines based on a standardized interviewer-administered questionnaire. MRI biomarkers included white matter hyperintensity (WMH) volume (cm 3 ), total brain volume (TBV) (cm 3 ), and cortical thickness (CT) (mm). Plasma biomarkers of the ratio of amyloid beta 42 to 40 (Aβ42/Aβ40), phosphorylated Tau-181 (p-Tau181), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) were measured using Quanterix Simoa immunoassays. All biomarkers were standardized to measures in 2011-13 to facilitate comparisons. Covariate-adjusted linear regression models estimated cross-sectional associations of PA with MRI or plasma biomarkers. Covariate-adjusted linear mixed effects models quantified associations of PA with the 5-year rate of change in a subset of participants with MRI (n=669) or plasma (n=651) biomarkers at both baseline and follow-up from 2011-19 (median follow-up: 5.4 years). Results: Meeting versus not meeting aerobic PA guidelines was cross-sectionally associated with lower volumes of WMH (β = -0.16, 95% CI: -0.25, -0.07), higher TBV (β = 0.09; 95% CI: 0.05, 0.13), and lower plasma NfL (β = -0.102, 95% CI: -0.184, -0.021) ( Figure ). Late-life PA was not associated with 5-year rates of change in MRI or plasma biomarkers. Conclusions: Late-life PA was cross-sectionally associated with less neurodegeneration and cerebrovascular disease. Associations with 5-year changes in imaging and plasma biomarkers of AD pathology, cerebrovascular disease, or neurodegeneration were not statistically supported. Longitudinal biomarker studies with wearable devices that quantify other daily intensity-based movement metrics (e.g., light PA) and larger sample sizes are needed to further examine mechanisms linking PA to brain health.

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.

Background The immune response to infections may become dysregulated and promote myocardial damage contributing to heart failure (HF). We examined the relationship between infection‐related hospitalization (IRH) and HF, HF with preserved ejection fraction, and HF with reduced ejection fraction. Methods and Results We studied 14 468 adults aged 45 to 64 years in the ARIC (Atherosclerosis Risk in Communities) Study who were HF free at visit 1 (1987–1989). IRH was identified using select International Classification of Diseases ( ICD ) codes in hospital discharge records and was treated as a time‐varying exposure. HF incidence was defined as the first occurrence of either a hospitalization that included an ICD, Ninth Revision ( ICD‐9 ) discharge code of 428 (428.0–428.9) among the primary or secondary diagnoses or a death certificate with an ICD‐9 code of 428 or an ICD, Tenth Revision ( ICD‐10 ) code of I50 among any of the listed diagnoses or underlying causes of death. We used multivariable‐adjusted Cox proportional hazards models to assess the association between IRH and incident HF, HF with reduced ejection fraction, and HF with preserved ejection fraction. Median follow‐up time was 27 years, 55% were women, 26% were Black, mean age at baseline was 54±6 years, 46% had an IRH, and 3565 had incident HF. Hazard ratio (HR) for incident HF events among participants who had an IRH compared with those who did not was 2.35 (95% CI, 2.19–2.52). This relationship was consistent across different types of infections. Additionally, IRH was associated with both HF with reduced ejection fraction and HF with preserved ejection fraction: 1.77 (95% CI, 1.35–2.32) and 2.97 (95% CI, 2.36–3.75), respectively. Conclusions IRH was associated with incident HF, HF with reduced ejection fraction, and HF with preserved ejection fraction. IRH might represent a modifiable risk factor for HF pathophysiology.

AbstractBackgroundCerebral small vessel disease (cSVD), as defined by neuroimaging characteristics such as white matter hyperintensities (WMHs), cerebral microhemorrhages (CMHs), and lacunar infarcts, is highly prevalent and has been associated with dementia risk and other clinical sequelae. Although risk factors for cSVD have been identified, little is known about the biological processes and molecular mediators that influence cSVD development and progression.MethodsWithin the Atherosclerosis Risk in Communities (ARIC) study, we used SomaScan Multiplexed Proteomic technology to relate 4,877 plasma proteins to concurrently measured MRI‐defined cSVD characteristics, including WMHs, CMHs, and lacunar infarcts, in late‐life (n=1508; mean age: 76). Candidate protein associations with WMH volume were replicated in the Cardiovascular Health Study (n=765; mean age: 73) and Baltimore Longitudinal Study of Aging (n=902; mean age: 66). Cohort‐specific effect estimates were pooled using a fixed‐effect, inverse variance weighted meta‐analysis. Within 4228 non‐demented older adults in ARIC, we examined the association of WMH‐associated proteins with eight‐year dementia risk (641 incident dementia cases) using multivariate Cox proportional hazard models. All multivariate regression models were adjusted for demographic, kidney function, and cardiovascular risk variables.ResultsThis proteome‐wide analysis of older adults identified 13 WMH‐associated plasma proteins involved in synaptic function, endothelial integrity, and angiogenesis (Figures 1a, 2a). Nine of these proteins replicated in one or more external cohort (Figures 1b, 2b) and two proteins, oligodendrocyte myelin glycoprotein (OMG) and neuronal pentraxin receptor (NPTXR), remained associated with late‐life WMH volume when measured nearly two decades earlier during midlife (Figures 1c, 2c). Eight of the 13 WMH‐associated proteins were associated with lacunar infarcts, 6 with subcortical CMHs, and 4 with lobar CMHs (Figures 1d, 2d). Although none of the genes coding for WMH‐associated proteins have been nominated by WMH GWAS, 7 of these genes have been previously linked to cardiometabolic traits known to influence cSVD, such as blood pressure and cholesterol (Figures 1e, 2e). Finally, 11 candidate proteins were associated with incident dementia, underscoring their clinical relevance (Figures 1f, 2f).ConclusionsThis large‐scale proteomic analysis within longitudinal community‐based samples identified several plasma proteins, including OMG and NPTXR, as top candidate biomarkers for elevated WMH volume and its clinical manifestations.