npj Aging

Biological aging is heterogeneous across organ systems, yet whether CT-derived abdominal aging provides prognostic value beyond routine clinical data and whether organ decomposition adds beyond a unified estimate remains untested. We developed and evaluated organ-specific and ensemble biological age models from radiomic features across five abdominal organs in 68,675 CT scans from 32,883 subjects, evaluated on alignment with chronological age of healthy subjects (nested cross validation: MAE=3.68 years, R^2=0.90). In sequential analyses restricted to adults aged 20-60 years which is the stratum of strongest BAG-disease association, ensemble biological age gaps provided incremental prognostic value beyond demographic covariates for all-cause disease and mortality (Delta C-index=0.141, 0.051) and beyond routine blood biomarkers (Delta C-index=0.048), confirming CT-derived aging captures structural information beyond laboratory markers. Organ-specific biological age added incremental prognostic value beyond ensemble selectively for focal diseases: cardiovascular (aorta, Delta C-index=0.091) and hepato-pancreatic (pancreas, Delta C-index=0.096). These findings establish a hierarchical organization of CT-derived biological aging, positioning routine CT as a source that adds prognostic value to existing clinical biomarkers.

We trained a self-configuring nnU-Net model for CMB segmentation in a heterogeneous multicenter sample (n=264), including 1.5T and 3T field strengths, SWI and T2*-GRE sequences, and community and clinical cohorts. Model performance was evaluated using 5-fold cross-validation with a focus on object-level detection metrics. Real-world performance was evaluated on scans from an unseen dataset of people with cerebrovascular disease (n=20). The model achieved 0.82 cluster Dice, 0.88 precision, and 0.77 sensitivity on hold-out test data. Notably, the model demonstrated a low false-positive rate, averaging 0.58 false positives (FPs) per scan, an improvement on existing publicly available models. The model achieved high performance in dataset of those with Alzheimer's disease and mild cognitive impairment (0.89 cluster Dice, 0.94 sensitivity), supporting its utility in clinical settings where ARIA-H monitoring is critical. In external validation, the model maintained high robustness with 0.79 sensitivity and 0.95 FPs per scan. By leveraging a heterogenous training strategy and a self-adapting architecture, we demonstrate that deep learning can achieve high-precision CMB detection that is robust to domain shifts. The low FP rate suggests this publicly available pipeline is suitable for automated screening and lesion counting in heterogenous large-scale clinical trials, reducing the burden of manual quantification.

Background: Regular exercise is a highly effective yet underutilized strategy to reduce cardiometabolic disease burden. Whether brief structured exercise programs confer lasting cardiometabolic benefits remains unclear. The STRRIDE-Prediabetes Reunion study examined legacy effects of exercise training on cardiorespiratory fitness, body composition, and cardiometabolic health. Methods: Seventy-three participants (71.3 {+/-} 7.2 years; 64% women; 77% White) completed Reunion assessments ~11 years after completing one of four 6-month interventions differing in exercise amount, intensity, and inclusion of diet-induced weight loss. Linear mixed effects models evaluated longitudinal trajectories; secondary analyses examined baseline-adjusted associations among short-term intervention response and Reunion outcomes. Results: Abdominal adiposity improved across all groups from baseline to Reunion, with waist circumference decreasing ~3 cm over the follow-up period. In contrast, cardiorespiratory fitness and fat-free mass declined significantly. A significant group by time interaction was observed for total fat mass (p=0.01), with continued fat mass reductions observed in women randomized to high amount exercise. After baseline adjustment, greater short-term intervention response was associated with more favorable Reunion outcomes across fitness, body composition, and cardiometabolic domains; fat-free mass showed the strongest association ({beta}=0.84, p<0.0001). Conclusions: In older adults with prediabetes, the STRRIDE-Prediabetes interventions produced several legacy health effects persisting more than a decade later. Legacy effects differed by sex and exercise dose, and short-term intervention response relative to baseline was associated with long-term outcomes, supporting targeted exercise strategies to preserve cardiometabolic health and functional independence with aging.

The VACS 2.0 Frailty Index was developed using the VA health records system to identify frailty and predict mortality in older Veterans that were living with HIV. Systemic inflammatory indices have been associated with frailty, but little is known about the association between frailty and immunosenescence. We aim to investigate the potential link between soluble inflammatory indices, T cell expression of exhaustion and senescence markers, and frailty as measured by the VACS 2.0 index. We analyzed a one-time blood draw for plasma levels of inflammatory indices, T cell subsets and expression of exhaustion and senescence markers, and calculated VACS 2.0 index scores in a cohort of 30 older (>65 years) Veteran participants. We found that VACS 2.0 scores correlated with the number of prescribed medications in the older Veterans. Soluble TNF receptor levels strongly correlated with VACS 2.0 frailty scores. How these soluble TNF receptors are generated and whether they mechanistically contribute to frailty warrants further investigation.

Background The study aimed to estimate healthcare costs associated with malnutrition in Swedish older adults. Methods We conducted a cohort study using data from the population-based Swedish National Study on Aging and Care in Kungsholmen (SNAC-K, N = 2982), a geriatric inpatient cohort of complex patients (N = 7680), and a cohort of individuals with cognitive impairment from the Swedish Register of Cognitive/Dementia Disorders (SveDem, N = 64192). At risk of malnutrition and malnutrition were ascertained by the Mini-Nutritional Assessment in SNAC-K and the geriatric inpatient cohort. In SveDem, body mass index was used for identifying malnutrition. Healthcare resource use was derived from regional and national registers. Associations between malnutrition and healthcare costs in 2024 Swedish kronor (SEK) were analyzed using two-part models and generalized linear regression models, adjusting for demographic and clinical factors. Findings In the community, at risk of malnutrition and malnutrition were associated with an increase in annual healthcare costs of 2267 SEK (95% CI: 64,4469) and 1846 SEK (95% CI: -6802,10493), respectively. In geriatric patients, healthcare costs over 6 months in individuals at risk of malnutrition and individuals with malnutrition were 60205 SEK (45613,74798) and 86619 SEK (68362,104875) higher than those without malnutrition. In people with cognitive impairment, malnutrition was associated with higher annual healthcare costs (22170 SEK, 95% CI: 15152,29188). Interpretation Both at risk of malnutrition and malnutrition are associated with higher healthcare costs in Swedish older adults. The study findings are important for informing future economic evaluations of malnutrition interventions in Swedish older adults.

Background: It is well-established that males have a higher mortality risk than females. Immune cells and their function are known to undergo characteristic changes during aging, and immune cells are known to have sex differences. Immune cells and their function have been linked to mortality risk, but no studies have investigated to what degree, if at all, Immune Cell Biomarkers (ICBs) contribute to the known differences in mortality risk by sex. Methods: Using participant data from the Health and Retirement Study (n = 8,822), we applied multivariable linear regressions adjusting for age, cytomegalovirus (CMV) serostatus, sex, and race/ethnicity to identify differences by sex in 48 immune cell biomarker (ICB, e.g. T cells, B cells, Monocytes, etc.) percentages and counts (measured in 2016). We studied how the associations between ICBs and mortality risk differ by sex using stratified Cox Proportional Hazard (CPH) models. We estimated how inclusion of sex explained the relationship between ICBs and all-cause mortality, and conversely, how inclusion of individual and all ICBs combined explain the relationship between sex and all-cause mortality using multivariable modeling approaches. Results: Differences in ICBs by sex range between 2-38% (39/48 statistically significant). 9 ICBs were significantly associated with mortality risk in the entire sample. While different ICBs were significantly associated with mortality risk in the stratified analyses, particularly with respect to monocyte, B cell, and NK cell populations, adjusting for sex modestly influenced the hazard ratios of the ICBs (sex: 8 ICBs, percent change <5.4%). Furthermore, individual and cumulative contributions of ICBs in explaining the differences in mortality risk by sex were not significant.

The choroid is critical for maintaining vision and implicated in several ocular diseases, being the sole source of nutrients and waste removal for the outer retina. Genetic discovery can help elucidate the pathways through which choroidal features influence disease risk. Our meta-analysis of genome-wide association studies (n= 78,682 participants) identified 30 genomic regions, including 20 novel loci, associated with choroidal thickness. Findings suggest inflammatory and vascular processes drive choroidal thickness, with overlapping mechanisms shared with refractive error. Genome-wide independently significant SNPs accounted for 18.7% of the genetic variance in choroidal thickness. Mendelian randomisation analyses showed a causal effect of age-related macular degeneration on choroidal thickness, and suggest a bidirectional causal effect between choroidal thickness and primary angle-closure glaucoma. These findings provide insight into the shared genetic architecture and biological pathways linking choroidal thickness and related diseases.

INTRODUCTION: Cognitive trajectories may clarify how type 2 diabetes (T2D) and impaired fasting glucose (IFG) relate to dementia risk, but longitudinal associations remain unclear, particularly in the context of stroke. METHODS: Data from 5,631 dementia- and stroke-free older adults (mean age 75 years) from 7 international population-based cohorts were analyzed. Linear mixed-effects models estimated cognitive trajectories during stroke-free and post-stroke follow-up. Glucose status was defined by fasting glucose and prior T2D diagnosis. RESULTS: Over 6.6 years of follow-up (4.5% with incident stroke), T2D was associated with lower baseline cognitive performance compared with normal fasting glucose (-0.14 SD, 95% CI -0.21 to -0.07), but not with faster cognitive decline during stroke-free or post-stroke follow-up. IFG was not associated with lower cognitive performance or faster decline. DISCUSSION: In older adults, T2D was associated with persistently lower cognitive performance but not faster decline, suggesting adverse cognitive effects may be established before late life.

Clonal hematopoiesis of indeterminate potential (CHIP) represents the age-related expansion of hematopoietic stem cells with preleukemic mutations. However, its association with all-cause and cause-specific mortality has not been well characterized in older adults. We aimed to evaluate whether CHIP is associated with all-cause and cause-specific mortality in a population of older women in the United States. Our study included 6,704 participants in the Women?s Health Initiative Long Life Study (WHI-LLS) without hematologic malignancy. The co-primary exposures were any CHIP (variant allele frequency [VAF] [&ge;] 2%) and large CHIP (VAF [&ge;] 10%), and the primary outcome was all-cause mortality. Multivariable-adjusted Cox proportional hazards models tested the associations of CHIP and CHIP subtypes with all-cause and cause-specific mortality. Any CHIP and large CHIP were independently associated with all-cause mortality, with multivariable-adjusted hazard ratios (aHRs) of 1.12 (95% confidence interval [CI] 1.04-1.21; P = 0.003) and 1.28 (95% CI 1.15-1.43; P < 0.001), respectively. In gene-specific analyses, non-DNMT3A CHIP was associated with all-cause mortality (aHR: 1.22 [95% CI: 1.12-1.34], P < 0.001), while DNMT3A CHIP was not (aHR: 1.07 [95% CI: 0.98-1.18], P = 0.13). Furthermore, large CHIP was associated with cardiovascular (aHR: 1.29 [95% CI: 1.08-1.55], P = 0.006), cancer (aHR: 1.49 [95% CI: 1.11-2.02], P = 0.009), and neurologic (aHR: 1.40 [95% CI: 1.07-1.84], P = 0.02) death. In this cohort of older women, CHIP, particularly large clones and non-DNMT3A CHIP, was associated with all-cause and cause-specific mortality. These findings suggest that clonal size and subtype may differentially influence mortality risk.

Aims. The risk of cognitive decline after losing a spouse remained mixed. This study aims to investigate the association between spousal loss and risk of cognitive decline, assess whether this association varies by sex and age, and identify modifiable factors. Methods. We conducted a prospective cohort study using harmonized data from six population-based aging surveys: the US Health and Retirement Study and its sister surveys in England, Mexico, China, India, and South Africa, incorporating their respective Harmonized Cognitive Assessment Protocol (HCAP) sub-studies. Spousal loss (yes vs no) was the exposure. Cognitive outcomes (i.e., orientation, memory, executive function, and language), were assessed using HCAP neuropsychological batteries. We conducted parallel analyses in six cohorts. Associations between spousal loss and cognitive outcomes were estimated using generalized linear models, and summarised estimates were derived via random-effects meta-analyses. Sex stratification and restricted cubic spines were used to examine how these associations vary by sex and age, respectively. Results. The analytical cohort consisted of 18,551 individuals aged 61.22 (SD 6.30) to 71.37 (SD 7.33) years. Widowhood prevalence ranged from 14.1% in CHARLS to 53.9% in HAALSI and was consistently higher in women. Spousal loss was associated with poorer memory (multivariable-adjusted {beta} = -0.07, 95% CI -0.12 to -0.01) and executive function (multivariable-adjusted {beta} = -0.08, 95% CI -0.13 to -0.03) in the meta-analysis, with no significant associations for orientation or language. While results were generally consistent in five cohorts, the ELSA showed divergent patterns (orientation: {beta} = 0.10, 95% CI 0.06 to 0.13; memory: {beta} = 0.05, 95% CI 0.02 to 0.08; language: {beta} = 0.16, 95% CI 0.12 to 0.19). Sex-stratified analyses indicated poorer executive function among men (multivariable-adjusted {beta} = -0.14, 95% CI -0.19 to -0.08) and poorer memory among women (multivariable-adjusted {beta} = -0.07, 95% CI -0.14 to -0.01) following widowhood. Nonlinear age-related effects on cognition were observed in ELSA, LASI, and HAALSI. Higher education, internet use, and BMI were negatively associated with the risk of cognitive decline among widowed participants. Conclusions. Spousal loss is associated with domain- and sex-specific differences in cognitive performance, with substantial heterogeneity across study populations. Future research should integrate biopsychosocial markers to develop context-sensitive interventions for widowed older adults.

Introduction Denosumab increases bone mineral density and reduces fracture risk in patients with osteoporosis. However, whether BMD response to denosumab differs by age, particularly during longer term treatment, remains unclear. This study investigated the association between baseline age and BMD gain during 3 years of denosumab treatment in patients with osteoporosis. Methods This retrospective study included patients with osteoporosis who were treated with denosumab. DXA-based BMD and bone turnover markers were followed for up to 3 years. Percent BMD gain from baseline, defined as %BMD gain, was evaluated. The longitudinal association between baseline age and %BMD gain was assessed using multivariable linear mixed-effects models for the lumbar spine and total hip. Analyses were performed in the treatment naive cohort and the overall cohort according to prior osteoporosis treatment status. Results A total of 255 patients were included in the analysis, of whom 110 had not received prior osteoporosis treatment. In multivariable linear mixed-effects models, older baseline age was associated with smaller lumbar spine %BMD gain in the treatment naive cohort at both 1 and 3 years. Each 1-year increase in age was associated with a 0.187 percentage-point lower lumbar spine %BMD gain at 1 year and a 0.293 percentage-point lower gain at 3 years (1 year: {beta} = -0.187, p = 0.006, 3 years: {beta} = -0.293, p = 0.031). In contrast, baseline age was not significantly associated with total hip %BMD gain in the treatment naive cohort (1 year: {beta} = -0.011, p = 0.826; 3 years: {beta} = 0.028, p = 0.727). In the overall cohort, baseline age was not significantly associated with %BMD gain at either the lumbar spine or total hip at 1 or 3 years (all p > 0.05). Conclusion Older baseline age was associated with a modestly smaller lumbar spine BMD gain in treatment naive patients, whereas no significant age-related association was observed at the total hip. In the overall cohort, age was not significantly associated with BMD gain at either site. These findings suggest that age may have a limited, site specific influence on BMD response to denosumab, particularly in treatment naive patients, and may support more individualized treatment planning in patients with osteoporosis.

Purpose. The choroid plexus (ChP) is the primary source of cerebrospinal fluid and an emerging marker of cerebral health, with enlargement and hypoperfusion reported in aging and neurodegeneration. However, frequent ChP calcifications can confound volumetric and perfusion measures. Although computed tomography (CT) is the gold standard for detecting calcification, it is rarely available in research MRI. Quantitative susceptibility mapping (QSM) offers an alternative sensitive to diamagnetic mineralization but lacks validated susceptibility thresholds. Method. Participants underwent CT and MRI within four weeks, including 3D T1-weighted and a multi-echo gradient echo QSM MRI. ChP calcifications were identified on CT using standard diagnostic criteria. Using the Bayes decision boundary framework, we identified optimal susceptibility thresholds for detecting diamagnetic signals consistent with calcification and compared these thresholds with multiple density levels measured on gold standard CT images. Results. Across all participants (n=20; age=62.2+-12.0 yrs), the optimal susceptibility threshold separating background ChP signal from calcifications was -0.10 ppm at 60 HU (low-density) and -0.15 ppm at 100 HU (high-density). Susceptibility values within calcified tissue exhibited a linear relationship with CT-derived tissue density. A significant positive association was observed between ChP volume and calcification volume among participants with detectable calcification (beta=2.26, p=0.047). Conclusion. This work should provide a practical framework for quantifying ChP calcifications routinely from MRI. The observed relationship between ChP volume and calcification volume highlights the importance of accounting for calcified tissue, particularly when calcification burden is substantial, when investigating ChP abnormalities in aging and neurodegenerative disease.

Understanding the regulatory consequences of genetic variation in the aging human brain requires molecular maps that span brain regions, cell types and regulatory modalities. We present the Alzheimer's Disease Sequencing Project Functional Genomics (FunGen-AD) xQTL Atlas, a harmonized resource of molecular quantitative trait loci from four postmortem brain studies, ROSMAP, MSBB, Knight-ADRC and MiGA. The atlas integrates histone acetylation, DNA methylation, gene expression, splicing and protein abundance QTLs across 14 brain regions, 7 major cell types and 17,566 samples, with standardized association, significance-filtered and fine-mapping outputs. To expand discovery beyond conventional 1-Mb cis windows, we include variants within Topologically Associating Domains (TAD) and their boundaries where appropriate, identifying on average 21% more variant-molecular-trait associations per dataset. Statistical fine-mapping reduced broad association sets by 95% into credible sets of candidate regulatory variants. Distributed through the NIAGADS xQTL portal and bulk-download services, the atlas provides a comprehensive functional-genomic foundation for interpreting genetic risk variants in Alzheimer's disease and aging-brain research.

Introduction Air pollution is a leading driver of cardiovascular disease with a growing body of literature implicating this in worse glucose homeostasis. Increases in fine particulate matter air pollution (PM2.5) are associated with increased blood glucose and hemoglobin A1c across the glycemic spectrum from normoglycemia to prediabetes to all forms of diabetes. Despite strong evidence for positive associations of PM2.5 with dysglycemia, it remains unknown if reducing air pollution exposure through air filtration can effect improvements in glucose. This study aims to test the hypothesis that short-term, in-home air pollution reduction using high efficiency particulate air (HEPA) filtration will improve blood sugar in adults with prediabetes. Methods and analysis This trial is a randomized, double-blind, sham-controlled trial of the effects of lowering air pollution exposure using HEPA filtration on cardiometabolic health in adults with prediabetes living in the New York City area. Participants will be randomly assigned to use bedroom air cleaners, or sham air cleaners, while measuring PM2.5 continuously for 1 month. The primary outcomes will be continuous glucose monitoring metrics measured before and after HEPA air filtration. Exploratory outcomes will include insulin resistance measures, serum biomarkers and transcriptomics measured before and after HEPA intervention. We will quantify effects of HEPA filtration with models using treatment arm (true versus sham filtration) as the independent variable. Secondary analyses will model continuous measures of PM2.5 as the independent variable. Ethics and Dissemination This study has undergone peer review; and the work was supported by Grant 2023-0214 from the Doris Duke Foundation, who had no other role in study design or implementation. The study was registered in ClinicalTrials.gov (NCT05994937) prior to recruitment. Clinical Trials Clinical Trials NCT05994937; https://clinicaltrials.gov/study/NCT05994937

Background: Recent food-based recommendations for flavan-3-ols highlight a growing need to understand the breadth of our dietary polyphenol exposure. However, estimation of dietary polyphenol intake remains challenging, requiring custom computational tools that are often difficult to implement or not fully reproducible. Objective: We aimed to an automated, user-friendly tool to estimate polyphenol intake from diet recalls and records. Methods: We developed Polyphenol Estimator, a tool that processes dietary data from the Automated Self-Administered 24-Hour (ASA24) Dietary Assessment Tool or the Automated Multiple-Pass Method from the National Health and Examination Survey (NHANES). Polyphenol Estimator disaggregates foods using the FDA Food Disaggregation Database into ingredients, matches these ingredients to FooDB, and estimates polyphenol intake at the total, class, and compound level. Optionally, these polyphenol estimates can be used to calculate the Dietary Inflammatory Index (DII). Polyphenol Estimator is freely available online (https://swi1.github.io/polyphenol_estimator) with a tutorial for users with limited programming experience. Results: To illustrate Polyphenol Estimator, we applied it to two days of diet recalls from adults ([&ge;] 20 years) in NHANES 2021-2023 (n = 2778). For 97.7% of participants, less than 2.5% of reported foods went unmapped, with 75.7% of participants having complete mappings. Total polyphenol intake was 517 +/- 439 (mean +/- SD) mg/1000 kcal, largely from green tea, coffee, black tea, apples, wine, oranges, and blueberries. At the class level, polyphenols classified as organooxygen compounds, flavonoids, and cinnamic acids and derivatives were top intake contributors. At the compound level, cyptochlorogenic acid, neocholorogenic acid, and caffeic acid were top contributors. Lastly, the DII was 1.4 +/- 1.9, indicating the average diet had proinflammatory potential. Conclusions: Polyphenol Estimator offers an automated method to obtain total, class, and compound-level polyphenol estimates from dietary data to aid future efforts to understand polyphenol intake exposures and their biological impact on health.

Abstract Importance: Irregular sleep-wake patterns have been associated with poor health and cognitive outcomes, yet evidence linking 24-hour sleep-wake regularity to cognitive decline or dementia remains inconsistent. Particularly, regularity can be measured as regularity of rest-wake, sleep-wake or overall 24-hour activity, but it is unclear which aspects are most relevant for cognitive aging. Objective: To assess associations of rest-wake, sleep-wake, and 24-hour activity regularity with cognitive decline and dementia risk. Design: Observational prospective study comprised of six US and European cohorts: MrOS (sleep study between 2003-2005, mean follow-up: 7.1 years), Rotterdam Study (2004-2007, 11.6 years), MESA (2010-2013, 8.2 years), MAP (2005-2018, 7.2 years), Whitehall II (2012-2013, 6.9 years), and UKB (2013-2015, 7.9 years). Setting: Cohort-specific estimates were pooled using random-effects meta-analysis. Analyses were done between June 2025 and March 2026. Participants 74,733 dementia-free adults with multi-day actigraphy were included across cohorts: MrOS (age: 67-96 years, female:0%), MESA (54-95y, female:54.6%), Rotterdam Study (46-98y, female:55.0%), MAP (56-100y, female:77.1%), Whitehall II (59-83y, female:25.9%), and UKB (55-78y, female:55.5%). Exposure: Day-to-day rest-wake regularity (Rest Regularity Index, RRI), day-to-day sleep-wake regularity (Sleep Regularity Index, SRI), and 24-hour activity regularity (Interdaily Stability, IS) were derived from multi-day actigraphy. Main Outcome: Outcomes were risk of dementia and changes in global cognition. Results: Across six cohorts, 1,906 dementia cases occurred among 74,733 participants. After adjusting for demographics, health behaviors, depressive symptoms and cardiovascular comorbidities, each 1-SD higher regularity score was associated with an 9-14% lower dementia risk (pooled hazard ratios: RRI 0.86 95%CI: [0.79-0.95]; SRI 0.87[0.79-0.97]; IS: 0.91[0.88-0.95]). Associations were approximately linear. Age-stratified analyses showed directionally stronger associations among adults aged < 65, although meta-regression did not support an interaction(p > 0.55). Greater regularity was associated with modestly slower decline in global cognition (pooled {beta} per 1-SD higher score of RRI per year: 0.003, 95%CI [0.001-0.006]). Conclusions & Relevance: Greater regularity of rest-wake, sleep-wake, and 24-hour activity rhythms was associated with lower dementia risk and modestly slower global cognitive decline. These findings suggest that 24-hour sleep-wake regularity is a relevant behavioral marker of cognitive aging and may inform future efforts to identify or intervene on early risk.

Resuscitation in the oldest old at the end of life is associated with potential harm, raising concerns about misalignment with patients goals of care. This study aimed to elucidate changes in the use of resuscitation among the oldest old in Japan following the revision of the national guideline on end-of-life care which explicitly incorporates the concept of advance care planning. We conducted a repeated cross-sectional study using the National Database of Health Insurance Claims Open Data, including adults aged [&ge;]85 years, from April 2014 to March 2024. The annual number of resuscitation procedures per 100,000 individuals aged [&ge;]85 years was used as the measure of frequency. Resuscitation included closed-chest cardiopulmonary resuscitation (CPR) and endotracheal intubation. Interrupted time series analysis was used to examine changes following the 2018 revision of the national end-of-life care guideline. The frequencies of CPR and endotracheal intubation declined before 2018 (CPR: age 85-89, -68.4 [-87.9 to -48.8]; age [&ge;]90, -106.7 [-131.5 to -82.0]; intubation: age 85-89, -57.5 [-71.8 to -43.2]; age [&ge;]90, -69.5 [-80.7 to -58.3]), but the decline attenuated thereafter (CPR: age 85-89, +56.2 [28.0 to 84.5]; age [&ge;]90, +84.1 [50.7 to 117.6]; intubation: age 85-89, +36.6 [8.5 to 64.7]; age [&ge;]90, +38.3 [23.8 to 52.8]). These findings provide insight into the changes in resuscitation trends following policy interventions supporting end-of-life decision-making. Further studies are needed to better understand the mechanisms underlying this change.

Importance: Despite the benefits of statin therapy in individuals with diabetes, fewer than 70% of adults with diabetes meet contemporary guidelines for statin therapy and reducing low-density lipoprotein cholesterol (LDL) to <100 mg/dL. Evidence describing delays in statin initiation after diabetes diagnosis and associated clinical outcomes may motivate process of care interventions to improve guideline recommended care in individuals newly diagnosed with type 2 diabetes mellitus (T2D). Objective: To examine the timing of statin initiation and achievement of LDL <100 mg/dL after diabetes diagnosis, and to determine the association of early LDL reduction among statin initiators with incident atherosclerotic cardiovascular disease (ASCVD). Design: Retrospective observational cohort study using data from 2005-2021 Setting: Veterans Affairs Health Care System (VA) Participants: Individuals with newly diagnosed T2D Exposure: Primary exposure was ASCVD risk based on ACC/AHA Pooled Cohort Equations; secondary exposure was LDL <100 mg/dL in the first year after T2D diagnosis among statin initiators Main Outcomes and Measures: Co-primary outcomes were initiation of statin therapy and achievement of LDL <100 mg/dL within 5 years of diabetes diagnosis; incident 5-year ASCVD was a secondary outcome. Results: Among 100,406 individuals with newly diagnosed T2D, 59,615 were prescribed statin therapy within five years (59.4%), and 44,783 (57.5%) of those with LDL above goal achieved LDL <100 mg/dL within 5 years. Relative to those at low (<7.5%) 10-year ASCVD risk, individuals at intermediate (7.5-20%) and high (>20%) risk were more likely to be initiated on a statin (intermediate: Hazard Ratio [HR] 1.14 [95% CI 1.11, 1.17]; high: HR 1.16 [95% CI 1.13, 1.19]) and to achieve LDL <100 mg/dL (intermediate: HR 1.23 [95% CI 1.19, 1.26]; high: HR 1.34 [95% CI 1.30, 1.38]). Among those prescribed a statin within one year of diabetes diagnosis, achieving LDL <100 mg/dL in the first year after diabetes diagnosis was associated with lower risk of 5-year incident ASCVD (HR 0.84 [95% CI 0.77, 0.92]). Conclusions and Relevance: Gaps in guideline-directed primary prevention of ASCVD arise early following initial diabetes diagnosis. Guideline recommended early LDL lowering among statin initiators was associated with improved clinical outcomes.

Importance: Little is known about the impact of returning Alzheimer disease (AD) biomarkers to cognitively unimpaired (CU) research participants. Objective: Does return of research results (RoRR) negatively impact longitudinal symptoms of depression and cognition. Design: Randomized, noninferiority, delayed-start clinical trial, 2021-2025 Setting: AD biomarker research results offered to CU participants in a longitudinal study of aging Participants: CU participants age 65+ were offered research AD biomarker results (APOE genotype and either plasma AB42/40 or amyloid PET and MRI hippocampal volume) with an estimated 5-year risk of symptomatic AD. Intervention(s) (for clinical trials) or Exposure(s) (for observational studies): 147 participants were randomized to receive results either soon after consent (RoRR arm, N=73) or one year later (delayed-start arm, N=74). Main Outcome(s) and Measure(s): Longitudinal change in Geriatric Depression Scale (GDS), Clinical Dementia Rating sum of boxes (CDR-SB), and global cognitive composite. Outcomes were measured at annual assessments for a longitudinal study of aging. Results: 187 participants received results: 70 in RoRR arm (average age 75, 60% female), 66 in delayed-start arm (average age 73, 53% female). The observed changes in annual measures did not differ between arms in both those with elevated amyloid (AB+) and in those without elevated amyloid (AB-) for GDS (AB+ difference 0.7, 95% CI 0.0-1.3; AB- difference -0.1, 95% CI -0.7-0.5; clinically significant decline >4.0), CDR-SB (AB+ difference 0.0, 95% CI -0.1-0.1; AB difference 0.0, 95% CI 0.0-0.1; clinically significant decline >0.5), and cognitive composite (AB+ difference -0.10, 95% CI -0.25-0.06; AB- difference -0.05, 95% CI -0.17-0.07; clinically significant decline < -0.26). Secondary analyses found no evidence of association between RoRR and proximity to follow-up testing. Conclusions and Relevance: In the first randomized, delayed-start clinical trial of returning AD research results to CU older-adult participants, no effect was seen on longitudinal changes in symptoms of depression or cognition. This supports evidence that there are no harms to returning AD research results, although the results may not apply to more diverse populations not included in this study. Trial Registration: NCT04699786

Atherosclerosis is a systemic vascular process linked to cardiovascular, cognitive and renal outcomes. DNA methylation (DNAm)-based scores of atherosclerosis may capture cumulative biological processes underlying vascular aging. Here, we examined associations of DNAm scores for coronary artery calcification (DNAm-CAC) and carotid plaque (DNAm-cPlaque), derived from a large study of imaging-based subclinical atherosclerosis, with prevalent and incident outcomes in two population-based cohorts of older adults: the Health and Retirement Study (HRS; n = 3,875) and The Irish Longitudinal Study on Ageing (TILDA; n = 487). Higher DNAm scores were associated with adverse cardiometabolic profiles and socioeconomic indicators. In HRS, higher DNAm-CAC was associated with prevalent cardiovascular disease (odds ratio per SD, 1.16; 95% confidence interval (CI), 1.07-1.26), lower cognitive function ({beta} = -0.50, 95% CI -0.68 to -0.32) and lower estimated glomerular filtration rate (eGFR; -1.7 ml min-1 1.73 m-2, 95% CI -2.6 to -0.8) in unadjusted models. After adjustment for demographic and clinical risk factors, DNAm-CAC ({beta} = -0.29, 95% CI -0.46 to -0.13) and DNAm-cPlaque ({beta} = -0.24, 95% CI -0.42 to -0.06) remained associated with lower cognitive function, and DNAm-cPlaque was associated with incident cognitive impairment or dementia (hazard ratio per SD, 1.16; 95% CI, 1.01-1.32). Associations were attenuated after further adjustment for race/ethnicity and socioeconomic indicators. In TILDA, higher DNAm-cPlaque was associated with worse cognitive performance (incidence rate ratio, 1.11; 95% CI, 1.01-1.21), increased risk of incident cardiovascular disease (hazard ratio, 1.18; 95% CI, 1.00-1.42) and lower eGFR, with consistent associations observed for DNAm-CAC. These findings suggest that DNAm-based scores of atherosclerosis capture systemic vascular processes linked to multiple age-related outcomes across populations. Further work is needed to clarify the biological pathways reflected by these scores and their relation to cumulative and socially patterned vascular risk.