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OBJECTIVE: The impact of age of diabetes diagnosis on dementia risk across the life course is poorly characterized. We estimated the lifetime risk of dementia by age of diabetes diagnosis. RESEARCH DESIGN AND METHODS: We included 13,087 participants from the Atherosclerosis Risk in Communities Study who were free from dementia at age 60 years. We categorized participants as having middle age–onset diabetes (diagnosis <60 years), older-onset diabetes (diagnosis 60–69 years), or no diabetes. Incident dementia was ascertained via adjudication and active surveillance. We used the cumulative incidence function estimator to characterize the lifetime risk of dementia by age of diabetes diagnosis while accounting for the competing risk of mortality. We used restricted mean survival time to calculate years lived without and with dementia. RESULTS: Among 13,087 participants, there were 2,982 individuals with dementia and 4,662 deaths without dementia during a median follow-up of 24.1 (percentile 25–percentile 75, 17.4–28.3) years. Individuals with middle age–onset diabetes had a significantly higher lifetime risk of dementia than those with older-onset diabetes (36.0% vs. 31.0%). Compared with those with no diabetes, participants with middle age–onset diabetes also had a higher cumulative incidence of dementia by age 80 years (16.1% vs. 9.4%) but a lower lifetime risk (36.0% vs. 45.6%) due to shorter survival. Individuals with middle age–onset diabetes developed dementia 4 and 1 years earlier than those without diabetes and those with older-onset diabetes, respectively. CONCLUSIONS: Preventing or delaying diabetes may be an important approach for reducing dementia risk throughout the life course. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Psychosocial factors are modifiable risk factors for Alzheimer's disease (AD). One mechanism linking psychosocial factors to AD risk may be through biological measures of brain amyloid; however, this association has not been widely studied. Objective: To determine if mid-life measures of social support and social isolation in the Atherosclerosis Risk in Communities (ARIC) Study cohort are associated with late life brain amyloid burden, measured using florbetapir positron emission tomography (PET). Methods: Measures of social support and social isolation were assessed in ARIC participants (visit 2: 1990–1992). Brain amyloid was evaluated with florbetapir PET standardized uptake value ratios (SUVRs; visit 5: 2012–2014). Results: Among 316 participants without dementia, participants with intermediate (odds ratio (OR), 0.47; 95% CI, 0.25–0.88), or low social support (OR, 0.43; 95% CI, 0.22–0.83) in mid-life were less likely to have elevated amyloid SUVRs, relative to participants with high social support. Participants with moderate risk for social isolation in mid-life (OR, 0.32; 95% CI, 0.14–0.74) were less likely to have elevated amyloid burden than participants at low risk for social isolation. These associations were not significantly modified by sex or race. Conclusions: Lower social support and moderate risk of social isolation in mid-life were associated with lower odds of elevated amyloid SUVR in late life, compared to participants with greater mid-life psychosocial measures. Future longitudinal studies evaluating mid-life psychosocial factors, in relation to brain amyloid as well as other health outcomes, will strengthen our understanding of the role of these factors throughout the lifetime. [ABSTRACT FROM AUTHOR]

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 < 1.01 × 10−5), and 40 remained significant in replication (P < 5.43 × 10−4). Eighteen of these proteins were independently associated with incident T2D (P < 1.25 × 10−3), including neuronal growth regulator 1 (NeGR1; hazard ratio per SD 0.85; P = 7.5 × 10−11). Two-sample Mendelian randomization (MR) inverse variance weighted analysis indicated that higher NeGR1 reduces T2D risk (odds ratio [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 = 6.3 × 10−5). 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. Article Highlights: Physical activity alters tissue and plasma proteomes, which have been shown to have roles in type 2 diabetes development. We aimed to identify protein signatures through which physical activity may influence type 2 diabetes pathogenesis. Of 40 proteins associated with physical activity, 18 of these were further related to incident type 2 diabetes over an ∼24-year follow-up. Two-sample Mendelian randomization analysis indicated that circulating neuronal growth regulator 1 reduces risk of type 2 diabetes. These findings suggest that plasma neuronal growth regulator 1 may link physical activity to reduced risk of type 2 diabetes. [ABSTRACT FROM AUTHOR]

The article focuses on examining the potential of 1,5-anhydroglucitol (1,5-AG) as a biomarker for sodium-glucose cotransporter 2 inhibitor (SGLT2i) adherence in adults with type 2 diabetes. Topics include how 1,5-AG reflects hyperglycemia episodes, the mechanism of action of SGLT2i medications, and the comparison of serum 1,5-AG concentrations between SGLT2i users and nonusers, suggesting significantly lower levels among SGLT2i users.

Background: Associations between magnetic resonance imaging markers of cerebral small vessel disease (CSVD) and dementia risk in older adults have been established, but it remains unclear how lifestyle factors, including psychosocial health, may modify this association., Methods: Social support and social isolation were assessed among participants of the community-based ARIC (Atherosclerosis Risk in Communities) Study, via self-reported questionnaires (1990-1992). Following categorization of both factors, participants were classified as having strong or poor mid-life social relationships. At visit 5 (2011-2013), participants underwent 3T brain magnetic resonance imaging quantifying CSVD measures: white matter hyperintensity volume, microbleeds (subcortical), infarcts (lacunar), and white matter integrity (diffusion tensor imaging). Incident dementia cases were identified from the time of imaging through December 31, 2020 with ongoing surveillance. Associations between CSVD magnetic resonance imaging markers and incident dementia were evaluated using Cox proportional-hazard regressions adjusted for demographic and additional risk factors (from visit 2). Effect modification by mid-life social relationships was evaluated., Results: Of the 1977 participants with magnetic resonance imaging, 1617 participants (60.7% women; 26.5% Black participants; mean age at visit 2, 55.4 years) were examined. In this sample, mid-life social relationships significantly modified the association between white matter hyperintensity volume and dementia risk ( P interaction=0.001). Greater white matter hyperintensity volume was significantly associated with risk of dementia in all participants, yet, more substantially in those with poor (hazard ratio, 1.84 [95% CI, 1.49-2.27]) versus strong (hazard ratio, 1.26 [95% CI, 1.08-1.47]) mid-life social relationships. Although not statistically significant, subcortical microbleeds in participants with poor mid-life social relationships were associated with a greater risk of dementia, relative to those with strong social relationships, in whom subcortical microbleeds were no longer associated with elevated dementia risk., Conclusions: The elevated risk of dementia associated with CSVD may be reduced in participants with strong mid-life social relationships. Future studies evaluating psychosocial health through the life course and the mechanisms by which they modify the relationship between CSVD and dementia are needed.

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., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Numerous studies have shown inverse associations between serum magnesium (Mg) and risk of cardiovascular disease (CVD), but studies of dietary Mg have not been consistent., Aim: To examine the association of a Mg-rich diet score with risks of CVD, coronary heart disease (CHD), and ischemic stroke in the Atherosclerosis Risk in Communities (ARIC) study., Methods: There were 15,022 Black and White adults without prevalent CVD at baseline (1987-89) included in this analysis. Diet was assessed at two visits 6 years apart using an interviewer-administered 66-item food frequency questionnaire. A Mg-rich diet score was created that included servings of whole grain products, nuts, vegetables, fruit, legumes, coffee, and tea. Cox proportional hazard regression evaluated associations of incident CVD, CHD and stroke across quintiles of Mg-rich diet score, adjusting for demographics, lifestyle factors, and clinical characteristics., Results: Over >30 years of follow-up, there were 3,531 incident CVD events (2,562 CHD, 1,332 ischemic stroke). Participants who consumed more Mg-rich foods were older, female, White, had lower blood pressure, fewer were not current smokers, and more reported being physically active. A Mg-rich diet was inversely associated with incident CVD (HRQ5 vs Q1=0.87, 95%CI: 0.77-0.98, ptrend=0.02) CHD (HRQ5 vs Q1=0.82, 95%CI: 0.71-0.95, ptrend=0.01); however, the diet-stroke association was null (HRQ5 vs Q1=1.00, 95%CI: 0.82-1.22, ptrend=0.97)., Conclusions: Consuming a diet including Mg-rich foods, such as whole grains, nuts, vegetables, fruits, legumes, coffee and tea, is associated with lower risk of CVD and CHD, but not ischemic stroke., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Importance: 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., Objective: To assess temporal plasma biomarker changes and their association with all-cause dementia, overall and among subgroups of community-dwelling adults., Design, Setting, and Participants: 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., Exposure: 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., Main Outcomes and Measures: 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., Results: 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 (APOEε4) 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)., Conclusions and Relevance: 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.

Introduction: Anemia is a risk factor for all-cause mortality in older adults. Iron deficiency may also be associated with adverse outcomes, independent of its role in causing anemia. This study tested the hypotheses that anemia, and low ferritin among non-anemic participants, were associated with all-cause and cause-specific mortality in a community-based cohort of older adults., Methods: Fasting blood was obtained from 5,070 ARIC participants (median age: 75 years) in 2011-2013. Anemia was defined by hemoglobin concentrations &lt;12 g/dL in women and &lt;13 g/dL in men. We classified 4,020 non-anemic participants by quartiles of plasma ferritin, measured by the SomaScan proteomics platform. Cox proportional hazards regression was used. Mortality was ascertained via phone calls with proxies as part of twice-yearly cohort follow-up, surveillance of local hospital discharge indexes, state death records, and linkage to the National Death Index., Results: Of the total participants, 21% had anemia at baseline. Over a median of 7.5 years, there were 1,147 deaths, including 357 due to cardiovascular disease (CVD), 302 to cancer, and 132 to respiratory disease. Compared to those with normal hemoglobin, participants with anemia had a higher risk of all-cause mortality (hazard ratio 1.81 [95% CI: 1.60-2.06]), and mortality due to CVD (1.77 [1.41-2.22]), cancer (1.81 [1.41-2.33]), and respiratory disease (1.72 [1.18-2.52]) in demographics-adjusted models. In fully adjusted models, associations with all-cause mortality (1.37 [1.19-1.58]) and cause-specific mortality were attenuated. In non-anemic participants, lower ferritin levels were not associated with all-cause or cause-specific mortality, though associations were observed among participants with lesser evidence of inflammation (CRP below the median level of 1.9 mg/L) and for cancer mortality in men only., Conclusion: Anemia is common among older adults and is associated with all-cause mortality, as well as mortality due to CVD, cancer, and respiratory disease. Our results do not provide evidence that iron deficiency, independent of anemia, is associated with mortality in this population., (© 2024 S. Karger AG, Basel.)

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., Competing Interests: Competing interests: SPB has had consultancy agreements with Boehringer Ingelheim, Sanofi/Regeneron and IntegrityCE. He has participated in research with Nuvaira Sanofi for which his institution has been remunerated. RK has had consultancy agreements with CVS Caremark, AstraZeneca, GlaxoSmithKline and Boehringer Ingelheim. He has participated in research with AstraZeneca, PneumRx/BTG and Spiration, for which his institution has been remunerated., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

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., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)