Josef Coresh

Plasma biomarkers of Alzheimer disease (AD) neuropathology (amyloid-β42 to amyloid β40 [Aβ42/40] ratio, phosphorylated tau at threonine [p-tau181]), neurodegeneration (neurofilament light [NfL]), and neuroinflammation (glial fibrillary acidic protein [GFAP]) in late-life are associated with cognitive decline. Whether these biomarkers in midlife are predictive of subsequent cognitive decline, and whether they are associated with different cognitive domains, is uncertain. In this study, we investigated associations of midlife and late-life plasma Aβ42/40, p-tau181, NfL, and GFAP with late-life change in domain-specific (memory, language, and executive function) and global cognitive function. We performed a prospective cohort analysis of the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS). Outcome follow-up was from ARIC visit 5 (2011-2013) to visit 9 (2021-2022). We included all individuals from ARIC field centers (Jackson, Mississippi; Forsyth County, North Carolina; Washington County, Maryland; and Minneapolis suburbs, Minnesota) with biomarkers measured from stored specimens in midlife (visit 3, 1993-1995, mean age 59.0 years) and late-life (visit 5, 2011-2013, mean age 76.8 years). Aβ42/40, p-tau181, NfL, and GFAP were measured with the Quanterix Simoa platform and standardized to visit 3 to facilitate cross-biomarker comparisons of their rate of change from midlife to late-life. We estimated change in memory, language, executive function, and global cognition factor scores from visit 5 to visit 9 with linear mixed-effect models. In 1,515 included participants, 60.7% (n = 920) were female and 25.5% (n = 387) were Black. Each SD increase in p-tau181 in midlife was significantly associated with faster late-life memory decline (β = -0.030 [95% CI -0.059 to -0.001] SD. Midlife Aβ42/40, NfL, and GFAP were not associated with subsequent decline in any cognitive domain. In late-life, p-tau181, NfL, and GFAP were significantly associated with faster decline in different cognitive domains, with the strongest associations seen with memory (β = -0.091 [95% CI -0.123 to -0.058] SD; β = -0.064 [95% CI -0.106 to -0.023] SD; and β = -0.048 [95% CI -0.082 to -0.013] SD, respectively). Midlife p-tau181 was associated with faster 11-year memory decline beginning 20 years later in the ARIC cohort, which underscores a potentially long prodromal phase of cognitive decline that could precede dementia onset. In late-life, biomarkers for AD, neurodegeneration, and neuroinflammation were associated with faster decline across different cognitive domains, but associations remained strongest for p-tau181 and memory.

Background: The impact of mild/trace valvular abnormalities on cardiac remodeling is not well understood, despite their association with poor cardiovascular outcomes. Methods: Using data from 4684 participants in the ARIC (Atherosclerosis Risk in Communities) Study (2011–2013), aged 66 to 90 years, we examined cross‐sectional associations of mild/trace valvular abnormalities (aortic stenosis, aortic regurgitation, and mitral regurgitation) with cardiac parameters using multivariable linear regression models. Cardiac parameters included cardiac structure (eg, left ventricular mass index), systolic function (eg, ejection fraction), diastolic function, and biomarkers (eg, high‐sensitivity cardiac troponin T). Results: The prevalence was 4.3% for mild aortic stenosis, 10.9% for mild/trace aortic regurgitation, and 44.7% for mild/trace mitral regurgitation. Mitral regurgitation showed the most consistent associations with cardiac measures (left ventricular mass index 5.48 g/m ² [95% CI, 4.38–6.57 g/m ² ]; ejection fraction –1.92% [95% CI, −2.29% to −1.54%]; high‐sensitivity cardiac troponin T 0.08 log ng/L [95% CI, 0.05–0.12 log ng/L]). Aortic stenosis was associated with impaired ventricular filling (Ratio of early transmitral flow velocity to early diastolic mitral annular velocity (E/e’) lateral ratio 2.00 [95% CI, 1.48–2.53]) and elevated biomarkers (high‐sensitivity cardiac troponin T 0.17 ng/L [95% CI, 0.09–0.25 ng/L]), whereas aortic regurgitation was associated with worsened cardiac structure (left ventricular mass index 3.52 [95% CI, 1.76–5.28] g/m ² ) and systolic dysfunction (ejection fraction −1.54% [95% CI, −2.14% to −0.94%]). A dose–response relationship was also observed between the number of total abnormalities and all cardiac parameters examined. Conclusions: Mild/trace mitral regurgitation was most consistently associated with all cardiac parameters examined. Aortic stenosis was associated with elevated E/e’ lateral ratio and high‐sensitivity cardiac troponin T, whereas aortic regurgitation was associated with worsening in cardiac structure and ejection fraction. Our study supports the possibility of pathophysiological contributions of these mild/trace valvular abnormalities.

BACKGROUND: Lower extremity peripheral artery disease (PAD) is a major contributor to cardiovascular morbidity and mortality; however, the metabolic pathways underlying disease development and progression are poorly understood. METHODS: We conducted a prospective cohort study of 3759 participants from the ARIC study (Atherosclerosis Risk in Communities; mean age, 53.5 years; 60% women; 62% Black participants) with untargeted metabolomic profiling at baseline (1987–1989). Incident PAD (458 cases) and its severe form with rest pain or tissue loss, critical limb ischemia (CLI; 135 cases), were identified through hospitalization codes over a median follow-up of 27 years. We used Cox regression with adjustment for traditional risk factors and accounted for multiple testing using a false discovery rate correction at a threshold of 0.05. Risk prediction improvement was evaluated using Harrell C statistics and the net reclassification improvement. RESULTS: Thirteen metabolites were significantly associated with incident PAD and primarily reflected dysregulated glycemic control, impaired redox balance, and altered lipid remodeling (eg, higher levels of mannose and lower levels of 1,5-anhydroglucitol, gamma-glutamyl dipeptides, and lysophospholipids). For CLI, 18 metabolites were identified, 11 of which were unique to CLI and reflected intensified oxidative and bioenergetic stress (eg, homocitrulline, arabonate, and 1-linoleoylglycerol). Metabolites significantly improved risk prediction for PAD beyond traditional risk factors (∆C statistic, 0.017 [95% CI, 0.008–0.025] from a base C statistic of 0.770; net reclassification improvement, 0.053 [95% CI, 0.018–0.083]) and particularly CLI (∆C statistic, 0.041 [95% CI, 0.018–0.064] from a base C statistic of 0.823; net reclassification improvement, 0.176 [95% CI, 0.085–0.268]). CONCLUSIONS: Distinct metabolomic profiles were associated with incident PAD and CLI years before clinical onset, highlighting dysregulated glycemic control, impaired redox balance, and altered lipid remodeling as key underlying pathways. These findings suggest that circulating metabolites may serve as early indicators of metabolic health relevant to PAD risk identification and progression to advanced disease.

Type 2 diabetes is a risk factor for cardiac arrhythmias, but it is unknown how specific aberrations in glucose (eg, episodes of high or low glucose) might contribute to the occurrence of heart rhythm abnormalities. The overarching goal of this study is to address research questions regarding how glucose patterns might contribute to the occurrence of arrhythmias, primarily atrial fibrillation, in adults with diabetes. To fulfill this goal, the Atherosclerosis Risk in Communities Generation 2 (ARIC Gen2) study recruited 507 community-dwelling adults aged 50-80 years with type 2 diabetes to wear continuous glucose monitoring (CGM) and electrocardiogram (ECG) “patch” monitoring sensors simultaneously for up to 14 days. Generation 2 study had high CGM and ECG completeness: The median wear time for sensors was 14 days and ~80% of participants wore both sensors for ≥10 days. By combining Gen2 and data from the original ongoing ARIC cohort (aged 80+), we have the capacity to conduct a comprehensive evaluation of the impact of CGM-defined glucose patterns on arrhythmias across a wide age spectrum from middle-aged to very old adults (aged 50-100) with type 2 diabetes. The findings from this study may help inform clinical strategies for the prevention and management of arrhythmias among adults with type 2 diabetes.

Background and ObjectivesMidlife vascular risk factors are associated with both dementia and premature death; however, their combined association with dementia-free survival years remains unclear. ...

BACKGROUND: The American Heart Association Predicting Risk of Cardiovascular Disease EVENT (PREVENT) equations were developed from observational research cohorts and electronic health record data and provide sex-specific risk estimates for cardiovascular disease (CVD), atherosclerotic CVD (ASCVD), and heart failure (HF). External validation in large contemporary samples across multiple health systems in the United States is needed. METHODS: We assembled a national electronic health record-based cohort of US adults with individual-level patient data pooled from a collective of 30 health systems (Truveta) to externally validate the outcome-specific 10-year PREVENT equations (PREVENT-CVD, PREVENT-ASCVD, and PREVENT-HF). We included patients aged 30 to 79 years without a history of prior CVD and with an ambulatory encounter in the electronic health record between 2013 and 2018. The outcomes were defined as total CVD (composite of ASCVD and HF), ASCVD, and HF through December 2024 using diagnosis codes. Model performance of the outcome-specific PREVENT base equations was assessed with the Harrell C statistic and calibration slope, stratified by sex. RESULTS: Of the 680 864 adults included, the mean (SD) age was 55 (13) years, and 56% were women. Over a mean (SD) follow-up of 6.8 (2.3) years, there were 29 535 incident CVD events, 19 280 incident ASCVD events, and 16 824 incident HF events. The median (interquartile range) 10-year predicted risk of PREVENT-CVD among women was 3.6% (1.3%–8.8%), and among men was 5.8% (2.5%–11.7%). The C statistic (95% CI) was 0.788 (0.786–0.790), and the calibration slope (95% CI) was 0.98 (0.95–1.01) for PREVENT-CVD. PREVENT-ASCVD and PREVENT-HF demonstrated similar C statistics (0.774 [0.771–0.777] and 0.824 [0.820–0.828]) and calibration slopes (1.07 [1.04–1.10] and 1.01 [0.97–1.04]) for prediction of the 10-year risk of ASCVD and HF, respectively. CONCLUSIONS: The PREVENT equations accurately and precisely estimate the 10-year risk of CVD, ASCVD, and HF in a large sample of US adults. These findings support the generalizability of the PREVENT equations to inform guideline-recommended risk assessment and preventive efforts.

Adverse social determinants of health (SDOH) associate with greater heart failure (HF) risk. Among 9879 community-based participants of the Atherosclerosis Risk in Communities (ARIC) cohort study, we assessed 4955 plasma proteins using an aptamer-based platform (SomaLogic). We derived an SDOH factor comprising income, education, and area deprivation index (ADI) in Black and white participants. Proteins associated with this factor at Bonferroni significance were tested for associations with incident HF using multivariable Cox proportional hazard models. Among Black participants, 36 proteins were associated with both the SDOH factor and incident HF, 126 were among white participants, and 12 were shared between race strata. Eight of these demonstrated significant mediation effect in causal mediation models. Key results were replicated in 49,396 participants in UK Biobank. Mendelian randomization and colocalization suggested a potentially causal effect of C1q tumor necrosis factor–related protein 1 (C1QTNF1), an adiponectin paralog, on HF. We demonstrate protein biomarkers associated with SDOH burden and HF risk.

Genetics represent a nonmodifiable risk factor for Alzheimer disease (AD), with 60%-80% heritability. Midlife hypertension is a modifiable risk factor for both dementia and death. Our primary objective was to determine how genetic risk for AD modifies the association between hypertension and dementia. The Atherosclerosis Risk in Communities Study is an ongoing community-based prospective cohort study of 4 US centers. We analyzed White and Black participants free of dementia at age 55 years with genotypes and blood pressure measured at visit 1 (1987-1989). Three genetic risk groups (low, medium, high) were defined based on tertiles of a race-specific AD polygenic risk score. Dementia was ascertained through cognitive testing, informant interviews, hospitalization, codes and death records. Death was ascertained through the National Death Index. We examined the association of midlife hypertension with incident dementia within 3 genetic risk groups using Cox proportional-hazards and cumulative incidence function estimations. We used age 55 years as the time origin, with left truncation to allow entry at ages older than 55 years; age on December 31, 2022, was the administrative censoring date. Among 8,931 White and 2,666 Black participants, the median follow up time was 26.6 and 23.8 years, the mean age was 54.0/53.5 years, and 53.0%/62.5% were female, respectively. After adjusting for demographics, midlife hypertension was significantly associated with dementia incidence across all genetic risk groups among White participants (low risk hazard ratio [HR] 1.29; 95% CI 1.07-1.55, medium risk HR 1.34; 95% CI 1.13-1.58, high risk HR 1.19; 95% CI 1.03-1.38) and among Black participants at high genetic risk (HR 1.31; 95% CI 1.04-1.66). Associations for low and medium genetic risk Black participants were consistent but not statistically significant. There were no significant differences in association of hypertension with dementia by AD genetic risk group. Individuals with hypertension had a 0%-2% higher probability of developing dementia by age 80 and a 6%-13% lower probability of dementia-free survival to age 80 years vs those without hypertension, across race and genetic risk groups. Genetic risk for AD does not modify the association between hypertension and dementia. These data support the fact that all individuals with hypertension are likely to benefit from antihypertensive treatment.

The contribution of late-life vascular risk factors to dementia risk remains controversial. Because low blood pressure (BP) has been associated with worse clinical outcomes in frail individuals, we hypothesized hypertension, but not diabetes or smoking, is associated with higher dementia risk in robust than in frail older adults. We performed a prospective cohort analysis of the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS) over 11 years (2011-2022). We included all community-living White and Black participants aged 67-89 years without dementia at baseline visit 5 (2011-2013) from ARIC-NCS field centers (Jackson, Mississippi; Forsyth County, North Carolina; Washington County, Maryland; Minneapolis suburbs, Minnesota). The primary vascular risk factors measured at baseline included elevated BP (systolic BP 120-129 mm Hg and diastolic BP < 80 mm Hg), hypertension (systolic 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 diabetes medication), and former and current smoking (self-reported). We defined frailty status using the Fried criteria (5 components that include low energy, low physical activity, slowness, weakness, and weight loss). We estimated cause-specific hazard ratios (HRs) of incident dementia (ascertained from in-person neuropsychological assessments, semiannual participant or informant report, or surveillance of claims from hospitalizations and death certificates) with Cox proportional hazards models including a multiplicative interaction between vascular factors and frailty. HRs of dementia were then stratified by frailty (robust [no frailty components present] vs prefrail/frail [at least 1 frailty component present]). There were 377 (15.8%) dementia cases in robust participants (n = 2,383; mean age, 74.2 years; 55.4% female) and 812 (30.0%) in prefrail/frail participants (n = 2,710; mean age 76.4 years; 61.3% female). There was a significant interaction between BP and frailty on dementia risk (p = 0.026). For robust participants, HRs were 1.03 (95% CI 0.65-1.64) for elevated BP and 1.39 (95% CI 1.00-1.94) for hypertension relative to normal BP. For prefrail/frail participants, HRs were 0.68 (95% CI 0.49-0.95) and 0.82 (95% CI 0.66-1.01), respectively. Diabetes and current smoking were associated with higher dementia risk in both robust and prefrail/frail individuals. Late-life hypertension was associated with a lower relative risk of dementia in prefrail/frail participants, but the association was positive in robust participants. BP interpretation and management to support brain health in older adults could consider age-related functional status.