<p>Stroke is a leading cause of death in the United States across all race/ethnicity and sex groups, though disparities exist. We investigated the potential for primary prevention of total first stroke for Americans aged 20 and older, stratified by sex and race/ethnicity. Specifically, we calculated population attributable fractions (PAF) of first stroke for 7 potentially modifiable risk factors: smoking, physical inactivity, poor diet, obesity, hypertension, diabetes, and atrial fibrillation. PAFs are a function of (1) the relative risk of first stroke for people with the exposure and (2) the prevalence of the risk factor in the population. Relative risks came from recent meta-analyses and sex-race/ethnicity-specific prevalence estimates came from the 2015-2018 NHANES or Multi-Ethnic Study of Atherosclerosis (for atrial fibrillation only). Approximately 1/3 (35.7% [CI: 21.6%-49.0%]) for women, 32.7% [CI: 19.2%-45.1%] for men) of strokes were attributable to the 7 risk factors we considered. A 20% proportional reduction in stroke risk factors would result in approximately 37,000 fewer strokes annually in the United States. The estimated PAF was highest for non-Hispanic Black women (39.3% [CI: 24.8%-52.3%]) and lowest for non-Hispanic Asian men (25.5% [CI: 14.6%-36.2%]). For most groups, obesity and hypertension were the largest contributors to stroke rates.</p>

Diabetes Care 2024;47(9):1-8 | https://doi.org/10.2337/dc24-0203 ARTICLE HIGHLIGHTS Why did we undertake this study? The association of diabetes with dementia is age dependent and is only characterized in relative risk scale. It is important to estimate the absolute dementia risk by diabetes age of diagnosis across the late life course, to inform dementia prevention strategies. What is the specific question(s) we wanted to answer? Does the lifetime risk of dementia differ by age of diabetes diagnosis? What did we find? Individuals who were diagnosed with diabetes before age 60 had earlier dementia onset and a higher risk of dementia than those diagnosed after age 60 and those with no diabetes.

Introduction Cigarette smoking leads to altered DNA methylation at the aryl-hydrocarbon receptor repressor (AHRR) gene. However, it remains unknown whether pipe or cigar smoking is associated with AHRR methylation. We evaluated associations of non-cigarette tobacco use with AHRR methylation and determined if AHRR methylation was associated with smoking-related health outcomes. Methods Data were pooled across four population-based cohorts that enrolled participants from 1985 to 2002. Tobacco exposures were evaluated using smoking questionnaires. AHRR cg05575921 methylation was measured in peripheral blood leucocyte DNA. Spirometry and respiratory symptoms were evaluated at the time of methylation measurements and in subsequent visits. Vital status was monitored using the National Death Index. Results Among 8252 adults (mean age 56.7±10.3 years, 58.1% women, 40.6% black), 4857 (58.9%) participants used cigarettes and 634 (7.7%) used non-cigarette tobacco products. Exclusive use of non-cigarette tobacco products was independently associated with lower AHRR methylation (−2.44 units, 95% CI −4.42 to −0.45), though to a lesser extent than exclusive use of cigarettes (−6.01 units, 95% CI −6.01 to −4.10). Among participants who exclusively used non-cigarette tobacco products, reduced AHRR methylation was associated with increased respiratory symptom burden (OR 1.60, 95% CI 1.03 to 2.68) and higher all-cause mortality (log-rank p=0.02). Conclusion Pipe and cigar smoking were independently associated with lower AHRR methylation in a multiethnic cohort of US adults. Among users of non-cigarette tobacco products, lower AHRR methylation was associated with poor respiratory health outcomes and increased mortality. AHRR methylation may identify non-cigarette tobacco users with an increased risk of adverse smoking-related health outcomes. Data are available on reasonable request.

Accumulating evidence supports a link between sleep disorders, disturbed sleep, and adverse brain health, ranging from stroke to subclinical cerebrovascular disease to cognitive outcomes, including the development of Alzheimer disease and Alzheimer disease-related dementias. Sleep disorders such as sleep-disordered breathing (eg, obstructive sleep apnea), and other sleep disturbances, as well, some of which are also considered sleep disorders (eg, insomnia, sleep fragmentation, circadian rhythm disorders, and extreme sleep duration), have been associated with adverse brain health. Understanding the causal role of sleep disorders and disturbances in the development of adverse brain health is complicated by the common development of sleep disorders among individuals with neurodegenerative disease. In addition to the role of sleep disorders in stroke and cerebrovascular injury, mechanistic hypotheses linking sleep with brain health and biomarker data (blood-based, cerebrospinal fluid-based, and imaging) suggest direct links to Alzheimer disease-specific pathology. These potential mechanisms and the increasing understanding of the "glymphatic system," and the recognition of the importance of sleep in poststroke recovery, as well, support a biological basis for the indirect (through the worsening of vascular disease) and direct (through specific effects on neuropathology) connections between sleep disorders and brain health. Given promising evidence for the benefits of treatment and prevention, sleep disorders and disturbances represent potential targets for early treatment that may improve brain health more broadly. In this scientific statement, we discuss the evidence supporting an association between sleep disorders and disturbances and poor brain health ranging from stroke to dementia and opportunities for prevention and early treatment.

<h3>Importance</h3><p>Plasma biomarkers show promise for identifying Alzheimer disease (AD) neuropathology and neurodegeneration, but additional examination among diverse populations and throughout the life course is needed.</p><h3>Objective</h3><p>To assess temporal plasma biomarker changes and their association with all-cause dementia, overall and among subgroups of community-dwelling adults.</p><h3>Design, Setting, and Participants</h3><p>In 1525 participants from the US-based Atherosclerosis Risk in Communities (ARIC) study, plasma biomarkers were measured using stored specimens collected in midlife (1993-1995, mean age 58.3 years) and late life (2011-2013, mean age 76.0 years; followed up to 2016-2019, mean age 80.7 years). Midlife risk factors (hypertension, diabetes, lipids, coronary heart disease, cigarette use, and physical activity) were assessed for their associations with change in plasma biomarkers over time. The associations of biomarkers with incident all-cause dementia were evaluated in a subpopulation (n = 1339) who were dementia-free in 2011-2013 and had biomarker measurements in 1993-1995 and 2011-2013.</p><h3>Exposure</h3><p>Plasma biomarkers of amyloid-β 42 to amyloid-β 40 (Aβ42:Aβ40) ratio, phosphorylated tau at threonine 181 (p-tau181), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP) were measured using the Quanterix Simoa platform.</p><h3>Main Outcomes and Measures</h3><p>Incident all-cause dementia was ascertained from January 1, 2012, through December 31, 2019, from neuropsychological assessments, semiannual participant or informant contact, and medical record surveillance.</p><h3>Results</h3><p>Among 1525 participants (mean age, 58.3 [SD, 5.1] years), 914 participants (59.9%) were women, and 394 participants (25.8%) were Black. A total of 252 participants (16.5%) developed dementia. Decreasing Aβ42:Aβ40 ratio and increasing p-tau181, NfL, and GFAP were observed from midlife to late life, with more rapid biomarker changes among participants carrying the apolipoprotein E epsilon 4 (<i>APOE</i>ε4) allele. Midlife hypertension was associated with a 0.15-SD faster NfL increase and a 0.08-SD faster GFAP increase per decade; estimates for midlife diabetes were a 0.11-SD faster for NfL and 0.15-SD faster for GFAP. Only AD-specific biomarkers in midlife demonstrated long-term associations with late-life dementia (hazard ratio per SD lower Aβ42:Aβ40 ratio, 1.11; 95% CI, 1.02-1.21; per SD higher p-tau181, 1.15; 95% CI, 1.06-1.25). All plasma biomarkers in late life had statistically significant associations with late-life dementia, with NfL demonstrating the largest association (1.92; 95% CI, 1.72-2.14).</p><h3>Conclusions and Relevance</h3><p>Plasma biomarkers of AD neuropathology, neuronal injury, and astrogliosis increase with age and are associated with known dementia risk factors. AD-specific biomarkers’ association with dementia starts in midlife whereas late-life measures of AD, neuronal injury, and astrogliosis biomarkers are all associated with dementia.</p>

Aims Few studies investigate whether psychosocial factors (social isolation, social support, trait anger, and depressive symptoms) are associated with cardiovascular health, and none with the American Heart Association’s new definition of cardiovascular health, Life’s Essential 8 (LE8). Therefore, we assessed the cross-sectional associations of psychosocial factors with Life’s Essential 8 and individual components of Life’s Essential 8. Methods We included 11,311 Atherosclerosis Risk in Communities cohort participants (58% females; 23% Black; mean age 57 (standard deviation: 6) years) who attended Visit 2 (1990–1992) in this secondary data analysis using cross-sectional data from the ARIC cohort study. Life’s Essential 8 components included diet, physical activity, nicotine exposure, sleep quality, body mass index, blood lipids, blood glucose, and blood pressure. Life’s Essential 8 was scored per the American Heart Association definition (0–100 range); higher scores indicate better cardiovascular health. Associations of categories (high, moderate, and low) of each psychosocial factor with continuous Life’s Essential 8 score and individual Life’s Essential 8 components were assessed using multivariable linear regressions. Results 11% of participants had high Life’s Essential 8 scores (80–100), while 67% and 22% had moderate (50–79) and low Life’s Essential 8 scores (0–49) respectively. Poor scores on psychosocial factor assessments were associated with lower Life’s Essential 8 scores, with the largest magnitude of association for categories of depressive symptoms (low β = Ref.; moderate β = -3.1, (95% confidence interval: -3.7, -2.5; high β = -8.2 (95% confidence interval: -8.8, -7.5)). Most psychosocial factors were associated with Life’s Essential 8 scores for diet, physical activity, nicotine, and sleep, but psychosocial factors were not associated with body mass index, blood lipids, blood glucose, or blood pressure. Conclusion Less favorable measures of psychosocial health were associated with lower Life’s Essential 8 scores compared better measures of psychosocial health among middle-aged males and females.

<p>Direct oral anticoagulants (DOACs; rivaroxaban, apixaban) and warfarin are approved for venous thromboembolism (VTE) treatment. Few direct comparisons of DOACs on risk of mortality among VTE patients exist, and for patients with concomitant conditions (e.g., kidney and liver disease) clinical guidelines are unclear. We evaluated 6-month all-cause mortality by anticoagulant prescribed for primary treatment of VTE. Using Medicare 20% sample data, we created a propensity score matched analytic dataset of 47,860 beneficiaries with non-cancer incident VTE. We used Cox regression to estimate adjusted hazard ratios (HRs) of OACs with 6-month mortality, and tested interactions by liver/kidney disease. There were 3,422 deaths over 6 months of follow-up. In adjusted models, patients prescribed rivaroxaban [HR: 0.82 (95% CI: 0.76-0.90)] had lower rates of mortality versus warfarin. There was no association comparing apixaban to warfarin [HR: 0.96 (95% CI: 0.87-1.07)]. In head-to-head comparisons of apixaban versus rivaroxaban the HR was 1.14 (95% CI: 1.01-1.28)]. Findings were similar among patients with liver and kidney disease. Overall, risk of death was similar by OAC prescribed. Though it is possible residual confounding remained, there was some suggestion of lower risk with rivaroxaban than warfarin. DOACs appear safe among VTE patients with concomitant kidney or liver disease.</p>

<h3>Importance</h3><p>Familial hypercholesterolemia (FH) is a genetic disorder that often results in severely high low-density lipoprotein cholesterol (LDL-C) and high risk of premature coronary heart disease (CHD). However, the impact of FH variants on CHD risk among individuals with moderately elevated LDL-C is not well quantified.</p><h3>Objective</h3><p>To assess CHD risk associated with FH variants among individuals with moderately (130-189 mg/dL) and severely (≥190 mg/dL) elevated LDL-C and to quantify excess CHD deaths attributable to FH variants in US adults.</p><h3>Design, Setting, and Participants</h3><p>A total of 21 426 individuals without preexisting CHD from 6 US cohort studies (Atherosclerosis Risk in Communities study, Coronary Artery Risk Development in Young Adults study, Cardiovascular Health Study, Framingham Heart Study Offspring cohort, Jackson Heart Study, and Multi-Ethnic Study of Atherosclerosis) were included, 63 of whom had an FH variant. Data were collected from 1971 to 2018, and the median (IQR) follow-up was 18 (13-28) years. Data were analyzed from March to May 2023.</p><h3>Exposures</h3><p>LDL-C, cumulative past LDL-C, FH variant status.</p><h3>Main Outcomes and Measures</h3><p>Cox proportional hazards models estimated associations between FH variants and incident CHD. The Cardiovascular Disease Policy Model projected excess CHD deaths associated with FH variants in US adults.</p><h3>Results</h3><p>Of the 21 426 individuals without preexisting CHD (mean [SD] age 52.1 [15.5] years; 12 041 [56.2%] female), an FH variant was found in 22 individuals with moderately elevated LDL-C (0.3%) and in 33 individuals with severely elevated LDL-C (2.5%). The adjusted hazard ratios for incident CHD comparing those with and without FH variants were 2.9 (95% CI, 1.4-6.0) and 2.6 (95% CI, 1.4-4.9) among individuals with moderately and severely elevated LDL-C, respectively. The association between FH variants and CHD was slightly attenuated when further adjusting for baseline LDL-C level, whereas the association was no longer statistically significant after adjusting for cumulative past LDL-C exposure. Among US adults 20 years and older with no history of CHD and LDL-C 130 mg/dL or higher, more than 417 000 carry an FH variant and were projected to experience more than 12 000 excess CHD deaths in those with moderately elevated LDL-C and 15 000 in those with severely elevated LDL-C compared with individuals without an FH variant.</p><h3>Conclusions and Relevance</h3><p>In this pooled cohort study, the presence of FH variants was associated with a 2-fold higher CHD risk, even when LDL-C was only moderately elevated. The increased CHD risk appeared to be largely explained by the higher cumulative LDL-C exposure in individuals with an FH variant compared to those without. Further research is needed to assess the value of adding genetic testing to traditional phenotypic FH screening.</p>

Self-rated health (SRH) is an in-dividual's self-evaluation of well-being, as influenced by social and biological factors, that correlates with cardiovascular risk factors, car-diovascular disease (CVD), and cardiac and all-cause mortality. 1,2 Coronary artery calcium (CAC) scoring, which quantifies the burden of calcified coronary athero-sclerosis by cardiac computed to-mography, serves as a more exact and personalized measure of CVD risk than traditional 10-year athero-sclerotic CVD risk scores by capturing lifetime exposure to traditional risk factors, additional risk enhancers, and genetic predisposition. A study in middle-aged adults found that a general self-assessment rating of overall health correlated poorly with CAC 3 ; however , it is not clear whether these results would apply to older adults. Therefore, in a community-based sample of adults 73 to 95 years old without known CVD, we studied whether SRH including overall life satisfaction, perceived heart attack risk, and attitude toward CVD prevention is correlated with individual CAC burden. Methods The Atherosclerosis Risk in Communities Study (ARIC) is a large prospective cohort study of adults across 4 US communities. 4 Our cross-sectional analysis included a total of 2290 ARIC participants without coronary heart disease at visit 7 (years 2018 to 2019), aged 73 to 95 (female, 61%; Black, 22%); 92% of these participants had survey data reporting both their perceived cardiovascular health and their overall satisfaction with life. Data were analyzed in 2022. Three queries that were included as part of the ARIC CAC study questionnaire were investigated. The first question stated "Overall, how satisfied are you with life these days?" and was rated on a scale of 0 to 10, with 0 noted as not at all satisfied and 10 noted as completely satisfied. The second question stated "Compared to other people your age and sex, how would you rate your risk of a heart attack?" and was scored on a 5-point scale for which the options were much higher than average, higher than average, about average, lower than average, and much lower than average. The final question stated "Please rate how strongly you agree or disagree with the following statement: Taking medication helps prevent a heart attack in people your age" and was scored on a 5-point scale for which the options were strongly agree, agree, neither agree nor disagree, disagree, and strongly disagree. Data were stratified by sex. Mean CAC scores in Agatston units and standard deviation as well as median with interquartile interval were calculated for each category. Spearman rank correlation coefficients were calculated for the variables of SRH responses to each topic and CAC. A 2-tailed P value of .05 was set as the threshold for statistical significance. All analyses were conducted using Stata software , version 15 (StataCorp LLC).

Background: Self-rated health is a simple measure that may identify individuals who are at a higher risk for hospitalization or death. Objective: To quantify the association between a single measure of self-rated health and future risk of recurrent hospitalizations or death. Participants: Atherosclerosis Risk in Communities (ARIC) study, a community-based prospective cohort study of middle-aged men and women with follow-up beginning from 1987 to 1989. Main Measures: We quantified the associations between initial self-rated health with risk of recurrent hospitalizations and of death using a recurrent events survival model that allowed for dependency between the rates of hospitalization and hazards of death, adjusted for demographic and clinical factors. Key Results: Of the 14,937 ARIC cohort individuals with available self-rated health and covariate information, 34% of individuals reported “excellent” health, 47% “good,” 16% “fair,” and 3% “poor” at study baseline. After a median follow-up of 27.7 years, 1955 (39%), 3569 (51%), 1626 (67%), and 402 (83%) individuals with “excellent,” “good,” “fair,” and “poor” health, respectively, had died. After adjusting for demographic factors and medical history, a less favorable self-rated health status was associated with increased rates of hospitalization and death. As compared to those reporting “excellent” health, adults with “good,” “fair,” and “poor” health had 1.22 (1.07 to 1.40), 2.01 (1.63 to 2.47), and 3.13 (2.39 to 4.09) times the rate of hospitalizations, respectively. The hazards of death also increased with worsening categories of self-rated health, with “good,” “fair,” and “poor” health individuals experiencing 1.30 (1.12 to 1.51), 2.15 (1.71 to 2.69), and 3.40 (2.54 to 4.56) times the hazard of death compared to “excellent,” respectively. Conclusions: Even after adjusting for demographic and clinical factors, having a less favorable response on a single measure of self-rated health taken in middle age is a potent marker of future hospitalizations and death.

Personal health literacy (PHL) has recently been defined by the US Department of Health and Human Services in Healthy People 2030 as “the degree in which individuals have the ability to find, under...

<p>Habitual physical activity (PA) impacts the plasma proteome and reduces the risk of developing type 2 diabetes (T2D). Using a large-scale proteome-wide approach in Atherosclerosis Risk in Communities Study participants, we aimed to identify plasma proteins associated with PA and determine which of these may be causally related to lower T2D risk. PA was associated with 92 plasma proteins in discovery (p&amp;lt;1.01x10−5), and 40 remained significant in replication (p&amp;lt;5.43x10−4). Eighteen of these proteins were independently associated with incident T2D (p&amp;lt;1.25x10−3) including neuronal growth regulator 1 (NeGR1) (HR per SD: 0.85; p-value=7.5x10−11). Two-sample Mendelian randomization inverse variance weighted analysis indicated that higher NeGR1 reduces T2D risk (OR per SD: 0.92; p=0.03) and was consistent with MR-Egger, weighted median, and weighted mode sensitivity analyses. A stronger association was observed for the single cis-acting NeGR1 genetic variant (OR per SD: 0.80; p=6.3x10−5). Coupled with previous evidence that low circulating NeGR1 levels promote adiposity, its association with PA and potential causal role in T2D shown here suggest that NeGR1 may link PA exposure with metabolic outcomes. Further research is warranted to confirm our findings and examine the interplay of PA, NeGR1, adiposity, and metabolic health.</p>

<h3>Importance</h3><p>Factors associated with the risk of dementia remain to be fully understood. Systemic infections are hypothesized to be such factors and may be targets for prevention and screening.</p><h3>Objective</h3><p>To investigate the association between hospitalization with infection and incident dementia.</p><h3>Design, Setting, and Participants</h3><p>Data from the community-based Atherosclerosis Risk in Communities (ARIC) study, a prospective cohort study, were used. Enrollment occurred at 4 research centers in the US, initiated in 1987 to 1989. The present study includes data up to 2019, for 32 years of follow-up. Data analysis was performed from April 2021 to June 2022.</p><h3>Exposures</h3><p>Hospitalizations with infections were identified via medical record review for selected<i>International Classification of Diseases, Ninth Revision</i>(<i>ICD-9</i>) and<i>International Statistical Classification of Diseases and Related Health Problems, Tenth Revision</i>(<i>ICD-10</i>) codes, from baseline until administrative censoring or dementia diagnosis. Participants were considered unexposed until first hospitalization with infection and exposed thereafter. Selected infection subtypes were also considered.</p><h3>Main Outcomes and Measures</h3><p>Incident dementia and time-to-event data were identified through surveillance of<i>ICD-9 </i>and<i>ICD-10</i>hospitalization and death certificate codes, in-person assessments, and telephone interviews. A sensitivity analysis was conducted excluding cases occurring within 3 years or beyond 20 years from exposure. Data were collected before study hypothesis formulation.</p><h3>Results</h3><p>Of the 15 792 ARIC study participants, an analytical cohort of 15 688 participants who were dementia free at baseline and of Black or White race were selected (8658 female [55.2%]; 4210 Black [26.8%]; mean [SD] baseline age, 54.7 [5.8] years). Hospitalization with infection occurred among 5999 participants (38.2%). Dementia was ascertained in 2975 participants (19.0%), at a median (IQR) of 25.1 (22.2-29.1) years after baseline. Dementia rates were 23.6 events per 1000 person-years (95% CI, 22.3-25.0 events per 1000 person-years) among the exposed and 5.7 events per 1000 person-years (95% CI, 5.4-6.0 events per 1000 person-years) among the unexposed. Patients hospitalized with infection were 2.02 (95% CI, 1.88-2.18;<i>P</i> &lt; .001) and 1.70 (95% CI, 1.55-1.86;<i>P</i> &lt; .001) times more likely to experience incident dementia according to unadjusted and fully adjusted Cox proportional hazards models compared with individuals who were unexposed. When excluding individuals who developed dementia less than 3 years or more than 20 years from baseline or the infection event, the adjusted hazard ratio was 5.77 (95% CI, 4.92-6.76;<i>P</i> &lt; .001). Rates of dementia were significantly higher among those hospitalized with respiratory, urinary tract, skin, blood and circulatory system, or hospital acquired infections. Multiplicative and additive interactions were observed by age and<i>APOE-ε</i>genotype.</p><h3>Conclusions and Relevance</h3><p>Higher rates of dementia were observed among participants who experienced hospitalization with infection. These findings support the hypothesis that infections are factors associated with higher risk of dementias.</p>