<p> Aging adults experience increased health vulnerability and compromised abilities to cope with stressors, which are the clinical manifestations of frailty. Frailty is complex, and efforts to identify biomarkers to detect frailty and pre‐frailty in the clinical setting are rarely reproduced across cohorts. We developed a predictive model incorporating biological and clinical frailty measures to identify robust biomarkers across data sets. Data were from two large cohorts of older adults: “ <italic>Invecchiare in Chianti</italic> (Aging in Chianti, InCHIANTI Study”) ( <italic>n</italic>  = 1453) from two small towns in Tuscany, Italy, and replicated in the Atherosclerosis Risk in Communities Study (ARIC) ( <italic>n</italic>  = 6508) from four U.S. communities. A complex systems approach to biomarker selection with a tree‐boosting machine learning (ML) technique for supervised learning analysis was used to examine biomarker population differences across both datasets. Our approach compared predictors with robust, pre‐frail, and frail participants and examined the ability to detect frailty status by race. Unique biomarker features identified in the InCHIANTI study allowed us to predict frailty with a model accuracy of 0.72 (95% confidence interval (CI) 0.66–0.80). Replication models in ARIC maintained a model accuracy of 0.64 (95% CI 0.66–0.72). Frail and pre‐frail Black participant models maintained a lower model accuracy. The predictive panel of biomarkers identified in this study may improve the ability to detect frailty as a complex aging syndrome in the clinical setting. We propose several concrete next steps to keep research moving toward detecting frailty with biomarker‐based detection methods. </p>

Diabetes Care 2023;46(4):1-9 | https://doi.org/10.2337/dc22-1830 ARTICLE HIGHLIGHTS • Plasma protein signatures preceding diabetes can improve our understanding of diabetes pathogenesis. • The aims of this study were to discover and validate (internally and externally) associations for nearly 5,000 ap-tamer measurements of the plasma proteome in midlife with incident diabetes. We also conducted a pathway analysis and examined causality using genetic instruments. • We identified 47 plasma proteins predictive of incident diabetes, established causal effects for 3 proteins (SHBG, ATP1B2, and GSTA1), and identified diabetes-associated inflammation and lipid pathways with potential implications for diagnosis and therapy.

<p>Background: Reduced kidney function is related to brain atrophy and higher risk of dementia. It is not known whether kidney impairment is associated with higher levels of circulating amyloid-β and brain amyloid-β deposition, which could contribute to elevated risk of dementia. Objective: To investigate whether kidney impairment is associated with higher levels of circulating amyloid-β and brain amyloid-β deposition. Methods: This cross-sectional study was performed within the community–based Atherosclerosis Risk in Communities (ARIC) Study cohort. We used estimated glomerular filtration rate (eGFR) based on serum creatinine and cystatin C levels and urine albumin-to-creatinine ratio (ACR) to assess kidney function. Amyloid positivity was defined as a standardized uptake value ratios &gt;  1.2 measured with florbetapir positron emission tomography (PET) (n = 340). Plasma amyloid-β 1 - 40 and amyloid-β 1 - 42 were measured using a fluorimetric bead-based immunoassay (n = 2,569). Results: Independent of demographic and cardiovascular risk factors, a doubling of ACR was associated with 1.10 (95% CI: 1.01,1.20) higher odds of brain amyloid positivity, but not eGFR (odds ratio per 15 ml/min/1.73 m2 lower eGFR: 1.08; 95% CI: 0.95,1.23). A doubling of ACR was associated with a higher level of plasma amyloid-β 1 - 40 (standardized difference: 0.12; 95% CI: 0.09,0.14) and higher plasma amyloid-β 1 - 42 (0.08; 95% CI: 0.05,0.10). Lower eGFR was associated with higher plasma amyloid-β 1 - 40 (0.36; 95% CI: 0.33,0.39) and higher amyloid-β 1 - 42 (0.32; 95% CI: 0.29,0.35). Conclusion: Low clearance of amyloid-β and elevated brain amyloid positivity may link impaired kidney function with elevated risk of dementia. kidney function should be considered in interpreting amyloid biomarker results in clinical and research setting.</p>

The aim of this work was to evaluate whether the association of prediabetes with dementia is explained by the intervening onset of diabetes. Among participants of the Atherosclerosis Risk in Communities (ARIC) study we defined baseline prediabetes as HbA1c 39–46 mmol/mol (5.7–6.4%) and subsequent incident diabetes as a self-reported physician diagnosis or use of diabetes medication. Incident dementia was ascertained via active surveillance and adjudicated. We quantified the association of prediabetes with dementia risk before and after accounting for the subsequent development of diabetes among ARIC participants without diabetes at baseline (1990–1992; participants aged 46–70 years). We also evaluated whether age at diabetes diagnosis modified the risk of dementia. Among 11,656 participants without diabetes at baseline, 2330 (20.0%) had prediabetes. Before accounting for incident diabetes, prediabetes was significantly associated with the risk of dementia (HR 1.12 [95% CI 1.01, 1.24]). After accounting for incident diabetes, the association was attenuated and non-significant (HR 1.05 [95% CI 0.94, 1.16]). Earlier age of onset of diabetes had the strongest association with dementia: HR 2.92 (95% CI 2.06, 4.14) for onset before 60 years; HR 1.73 (95% CI 1.47, 2.04) for onset at 60–69 years; and HR 1.23 (95% CI 1.08, 1.40) for onset at 70–79 years. Prediabetes is associated with dementia risk but this risk is explained by the subsequent development of diabetes. Earlier age of onset of diabetes substantially increases dementia risk. Preventing or delaying progression of prediabetes to diabetes will reduce dementia burden.

Comparative effectiveness evaluation of newer P2Y12 inhibitors (prasugrel and ticagrelor) compared with clopidogrel after acute coronary syndrome (ACS) is limited in real-world US populations. The objective of this study was to evaluate cardiovascular events based on ticagrelor, prasugrel, and clopidogrel use in a real-world patient setting. This retrospective cohort study used the IBM MarketScan database (January 1, 2013, to December 31, 2018) to create three propensity score-matched pairs: ticagrelor vs. clopidogrel (N = 21,719), prasugrel vs. clopidogrel (N = 11,513), and prasugrel vs. ticagrelor (N = 11,065). The primary outcome was a composite of myocardial ischemia, unstable angina, stroke, and heart failure hospitalization. These groups were compared in a time-to-event analysis for the primary outcome at 30, 90, and 180 days following P2Y12 inhibitors initiation after percutaneous coronary intervention. Compared with clopidogrel, ticagrelor use suggested a 10% reduction in the primary outcome at 90 days (hazard ratio (HR): 0.90, 95% confidence interval (CI): 0.82–0.99). There were no differences for all other matched pairs or follow-up combinations. In the subgroup analysis of females, the results suggested a risk reduction of 27% for prasugrel at 30 days (HR: 0.73, 95% CI: 0.53–1.00) and 17% for ticagrelor at 90 days (HR: 0.83, 95% CI: 0.70–0.98) when compared with clopidogrel. Among patients treated with bare-metal stents, the results suggested that prasugrel vs. ticagrelor was associated with a 55% and 33% reduced risk for the primary outcome at 30 days and 180 days, respectively. With limited evidence in the United States comparing these drugs, this study helps inform clinicians when choosing P2Y12 inhibitors after ACS.

<p>We examined the associations between lung function and incident dementia and cognitive decline in 12,688 participants of the ARIC study who provided lung function measurements in 1990-1992. Cognitive tests were administered up to seven times, and dementia was ascertained through 2019. We used shared parameter models to jointly model proportional hazard models and linear mixed-effect models to estimate lung function-associated dementia rate and cognitive change, respectively. Higher forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) were associated with reduced dementia rate (n=2452 developed dementia); hazard ratios per 1L higher FEV1 and FVC were 0.79 (95%CI: 0.71-0.89) and 0.81 (95%CI: 0.74-0.89), respectively. Each 1L higher FEV1 and FVC was associated with 0.08 (95%CI: 0.05-0.12) SD and 0.05 (95%CI: 0.02-0.07) SD attenuation of 30-year cognitive decline, respectively. One percent higher FEV1/FVC was associated with 0.008 (95% CI: 0.004-0.012) SD less cognitive decline. We observed statistical interaction between FEV1 and FVC, suggesting that cognitive declines depended on values of specific FEV1 and FVC (as compared to FEV1, FVC, or FEV1/FVC% models that suggested linear incremental associations). Our findings may have important implications for reducing burden of cognitive decline that is attributable to environmental exposures and associated lung function impairment.</p>

Venous thromboembolism (VTE) affects 1.2 million people per year in the United States. With several clinical changes in diagnosis and treatment approaches in the past decade, we evaluated contemporary post-VTE mortality risk profiles and trends. Incident VTE cases were identified from the 2011–2019 Medicare 20% Sample, which is representative of nearly all Americans aged 65 and older. The social deprivation index was linked from public data; race/ethnicity and sex were self-reported. The all-cause mortality risk 30 days and 1 year after incident VTE was calculated in demographic subgroups and by prevalent cancer diagnosis status using model-based standardization. Risks for major cancer types, risk differences by age, sex, race/ethnicity, and socio-economic status (SES), and trends over time are also reported. The all-cause mortality risk among older US adults following incident VTE was 3.1% (95% CI 3.0–3.2) at 30 days and 19.6% (95% CI 19.2–20.1) at 1 year. For cancer-related VTE events, the age-sex-race-standardized risk was 6.0% at 30 days and 34.7% at 1 year. The standardized 30-day and 1-year risks were higher among non-White beneficiaries and among those with low SES. One-year mortality risk decreased 0.28 percentage points per year (95% CI 0.16–0.40) on average across the study period, with no trend observed for 30-day mortality risk. In sum, all-cause mortality risk following incident VTE has decreased slightly in the last decade, but racial and socio-economic disparities persist. Understanding patterns of mortality among demographic subgroups and in cancer-associated events is important for targeting efforts to improve VTE management.

Rationale: The autonomic nervous system extensively innervates the lungs but its role in COPD outcomes has not been well-studied. Objective: We assessed relationships between cardiovascular autonom...

In closely monitored randomized controlled trials (RCTs), newer P2Y12 agents (ticagrelor and prasugrel) reduced cardiovascular outcomes compared with clopidogrel following percutaneous coronary intervention (PCI) in acute coronary syndrome. However, these RCTs indicated a higher bleeding risk with these newer agents. This study evaluated the comparative safety of each P2Y12 inhibitor on hospitalizations due to major bleeding in a real-world population. This retrospective, propensity score-matched (PSM) cohort study utilized the IBM MarketScan database over 6 years (2013–2018) to identify incident users of P2Y12 inhibitors with age ≥18 years. The primary safety outcome was hospitalization due to any major bleeding event including gastrointestinal, intracranial, and other serious forms of bleeding. In pairwise comparisons using Cox-proportional hazards models, ticagrelor, prasugrel, and clopidogrel users were compared for the primary safety outcome at 30, 90, and 180 days following the first prescription of P2Y12 inhibitor after PCI. There were 21,719 (ticagrelor vs. clopidogrel), 11,513 (prasugrel vs. clopidogrel), and 11,065 (prasugrel vs. ticagrelor) PSM pairs. Overall, the risk of major bleeding was similar for all P2Y12 inhibitors. Hospitalization for major bleeding was generally lower among ticagrelor users vs. clopidogrel and higher among prasugrel users compared with clopidogrel. Importantly, a 66% higher risk of major bleeding at 90 days is suggested with prasugrel compared with clopidogrel (hazard ratio 1.66; 95% confidence interval, 1.11–2.48). This study indicated a higher short-term bleeding risk with prasugrel compared with clopidogrel, which concurs with the results of RCTs.

Objectives: We investigated the relationship between the cognitive status of participants’ spouses and participants’ own cognitive outcomes, controlling for mid-life factors. Methods: Participants (n = 1845; baseline age 66–90 years) from the prospective Atherosclerosis Risk in Communities Study were followed from 2011 to 2019. We used linear regression and Cox proportional hazard models to estimate whether spouses of people with MCI/dementia had lower cognitive functioning and elevated risk of incident dementia. Results: Having a spouse with MCI/dementia was associated with a deficit in cognitive function (b = −0.09 standard deviations; 95% CI = −0.18, 0.00). Adjustment for mid-life risk factors attenuated this association (b = −0.02 standard deviations; 95% CI = −0.10, 0.06). We observed no significant relationship between spousal MCI/dementia status and incident dementia (hazard ratio = 0.97; 95% CI = 0.69, 1.38). Discussion: Spousal cognitive status is not associated with poor cognitive outcomes independent of mid-life factors.

Background ACC/AHA guidelines caution against the use of antihypertensive therapy in the setting of

<h3>Importance</h3><p>Good sleep is essential for health, yet associations between sleep and dementia risk remain incompletely understood. The Sleep and Dementia Consortium was established to study associations between polysomnography (PSG)–derived sleep and the risk of dementia and related cognitive and brain magnetic resonance imaging endophenotypes.</p><h3>Objective</h3><p>To investigate association of sleep architecture and obstructive sleep apnea (OSA) with cognitive function in the Sleep and Dementia Consortium.</p><h3>Design, Setting, and Participants</h3><p>The Sleep and Dementia Consortium curated data from 5 population-based cohorts across the US with methodologically consistent, overnight, home-based type II PSG and neuropsychological assessments over 5 years of follow-up: the Atherosclerosis Risk in Communities study, Cardiovascular Health Study, Framingham Heart Study (FHS), Osteoporotic Fractures in Men Study, and Study of Osteoporotic Fractures. Sleep metrics were harmonized centrally and then distributed to participating cohorts for cohort-specific analysis using linear regression; study-level estimates were pooled in random effects meta-analyses. Results were adjusted for demographic variables, the time between PSG and neuropsychological assessment (0-5 years), body mass index, antidepressant use, and sedative use. There were 5946 participants included in the pooled analyses without stroke or dementia. Data were analyzed from March 2020 to June 2023.</p><h3>Exposures</h3><p>Measures of sleep architecture and OSA derived from in-home PSG.</p><h3>Main Outcomes and Measures</h3><p>The main outcomes were global cognitive composite<i>z</i>scores derived from principal component analysis, with cognitive domains investigated as secondary outcomes. Higher scores indicated better performance.</p><h3>Results</h3><p>Across cohorts, 5946 adults (1875 females [31.5%]; mean age range, 58-89 years) were included. The median (IQR) wake after sleep onset time ranged from 44 (27-73) to 101 (66-147) minutes, and the prevalence of moderate to severe OSA ranged from 16.9% to 28.9%. Across cohorts, higher sleep maintenance efficiency (pooled β per 1% increase, 0.08; 95% CI, 0.03 to 0.14;<i>P</i> &lt; .01) and lower wake after sleep onset (pooled β per 1-min increase, −0.07; 95% CI, −0.13 to −0.01 per 1-min increase;<i>P</i> = .02) were associated with better global cognition. Mild to severe OSA (apnea-hypopnea index [AHI] ≥5) was associated with poorer global cognition (pooled β, −0.06; 95% CI, −0.11 to −0.01;<i>P</i> = .01) vs AHI less than 5; comparable results were found for moderate to severe OSA (pooled β, −0.06; 95% CI, −0.11 to −0.01;<i>P</i> = .02) vs AHI less than 5. Differences in sleep stages were not associated with cognition.</p><h3>Conclusions and Relevance</h3><p>This study found that better sleep consolidation and the absence of OSA were associated with better global cognition over 5 years of follow-up. These findings suggest that the role of interventions to improve sleep for maintaining cognitive function requires investigation.</p>

Aim: We investigate if periodontal disease is prospectively associated with cerebrovascular and neurodegenerative markers of dementia and Alzheimer's pathology. Materials and Methods: N = 1306 participants (Visit 5 mean age = 76.5 [standard deviation = 5.4] years) in the Atherosclerosis Risk in Communities study with completed dental exams at Visit 4 underwent brain magnetic resonance imaging scans at Visit 5 while N = 248 underwent positron emission tomography scans. Participants were classified as edentulous or, among the dentate, by the modified Periodontal Profile Class. Brain volumes were regressed on periodontal status in linear regressions. Cerebrovascular measures and β-amyloid positivity were regressed on periodontal status in logistic regressions. Results: Periodontal disease was not associated with brain volumes, microhaemorrhages, or elevated β-amyloid. Compared with periodontally healthy individuals, odds ratios [95% confidence interval] for all-type infarcts were 0.37 [0.20, 0.65] for severe tooth loss and 0.56 [0.31, 0.99] for edentulous participants. Conclusions: Within the limitations of this study, periodontal disease was not associated with altered brain volumes, microhaemorrhages, or β-amyloid positivity. Tooth loss was associated with lower odds of cerebral infarcts.

Introduction: Obstructive sleep apnea (OSA) is a common disorder associated with increased risk for cardiovascular disease, diabetes, and premature mortality. There is strong clinical and epi-demio...

Aims/hypothesis: Genetic predisposition to type 2 diabetes is well-established, and genetic risk scores (GRS) have been developed that capture heritable liabilities for type 2 diabetes phenotypes. However, the proteins through which these genetic variants influence risk have not been thoroughly investigated. This study aimed to identify proteins and pathways through which type 2 diabetes risk variants may influence pathophysiology. Methods: Using a proteomics data-driven approach in a discovery sample of 7241 White participants in the Atherosclerosis Risk in Communities Study (ARIC) cohort and a replication sample of 1674 Black ARIC participants, we interrogated plasma levels of 4870 proteins and four GRS of specific type 2 diabetes phenotypes related to beta cell function, insulin resistance, lipodystrophy, BMI/blood lipid abnormalities and a composite score of all variants combined. Results: Twenty-two plasma proteins were identified in White participants after Bonferroni correction. Of the 22 protein–GRS associations that were statistically significant, 10 were replicated in Black participants and all but one were directionally consistent. In a secondary analysis, 18 of the 22 proteins were found to be associated with prevalent type 2 diabetes and ten proteins were associated with incident type 2 diabetes. Two-sample Mendelian randomisation indicated that complement C2 may be causally related to greater type 2 diabetes risk (inverse variance weighted estimate: OR 1.65 per SD; p=7.0 × 10−3), while neuropilin-2 was inversely associated (OR 0.44 per SD; p=8.0 × 10−3). Conclusions/interpretation: Identified proteins may represent viable intervention or pharmacological targets to prevent, reverse or slow type 2 diabetes progression, and further research is needed to pursue these targets. Graphical abstract: [Figure not available: see fulltext.]

Background: Clinical management of orthostatic hypotension (OH) prioritizes the prevention of standing hypotension (HYP), sometimes at the expense of supine hypertension (HTN). It is unclear whethe...

Introduction: We evaluated whether better cardiovascular health at midlife and