Citations

Abstract INTRODUCTION Associations of arterial stiffness, measured through pulse wave velocity (PWV), with incident dementia may be driven by age‐related structural changes to the arterial wall or by elevated blood pressure. METHODS Dementia‐free White or Black participants in the community‐based Atherosclerosis Risk in Communities (ARIC) cohort study with measures of PWV were examined. The associations of carotid‐femoral PWV (cfPWV) and total, structural, and load‐dependent PWV with dementia were estimated using Poisson regression models and Cox proportional hazards models. Dementia cases were defined by physician‐adjudicated review, telephone interviews, hospitalization records, and death certificates. RESULTS Of 4818 participants included in the study population (mean age: 75 years; 41% male, 21% Black), 1067 (22%) developed dementia over a median follow‐up of 9.0 years. Higher cfPWV, total PWV, structural PWV, and load‐dependent PWV were associated with greater dementia risk. DISCUSSION Both structural and pressure‐related arterial stiffness mechanisms may underlie the link between PWV and dementia.

Abstract Rationale The impacts of COVID-19 vaccination and SAR-CoV-2 infection on brain tissues and structures remain controversial. This study examines whether COVID-19-related exposures are associated with measurable changes in structural magnetic resonance imaging (MRI) using data from the US general population-based Collaborative Cohort of Cohorts for COVID-19 Research (C4R) Study. Methods The C4R study is an observational meta-cohort study of 14 NIH-funded population-based cohorts, with directly measured data on COVID-19-related exposures, including vaccination and infection. For this analysis, we included participants with C4R data and paired brain MRI scans from both before and after the onset of the COVID-19 pandemic (defined as March 1, 2020) from two cohorts: the Atherosclerosis Risk in Communities study (ARIC) and Framingham Heart Study (FHS). MRI features examined as outcomes were white matter volume (WMV), gray matter volume (GMV), total brain volume (BV), hippocampal volume (HV), and white matter hyperintensity volume (WMH), a marker of microvascular disease. Exposures included SARS-CoV-2 infections identified via questionnaires, serosurveys, and medical record reviews from 2020-2025. Infections resulting in hospitalization were classified as severe. Time-to-recovery, symptoms of long COVID, and vaccination status were self-reported by questionnaire. Analysis of covariance (ANCOVA) estimated associations between COVID-19-related exposures and pandemic MRI-measured outcomes, with adjustment for: the corresponding pre-pandemic MRI measure, the time between the two MRI scans, age, sex, systolic blood pressure, diabetes, and cardiovascular disease. Results Of 270 participants with available data, mean (SD) age was 80.6 years (10.6); 43.0% were male; and the mean (SD) interval between paired MRI scans was 4.2 (2.0) years. Most (90%) were vaccinated (of whom 6.7% vaccinated before infection) and 7.9% reported SARS-CoV-2 infection (of which 13.6% were severe infections) prior to their pandemic MRI (conducted March 2020 - June 2022). In fully adjusted models, there was no statistically significant association for change in WMV, GMV, BV, HV, or WMH with SAR-CoV2 infection status, infection severity, vaccination status, or vaccination timing (Table, P > 0.05 for all comparisons). Self-reported symptoms of long COVID and vaccine manufacturer were also not associated with MRI outcomes. Conclusions Based on repeated (pre-pandemic and pandemic era) structural MRI scans, we found no evidence that SARS-CoV-2 infection or COVID-19 vaccination were associated with changes in brain structure or brain microvascular disease. These findings are consistent with prior data supporting COVID-19 vaccine safety and suggest resilience of brain structures following SARS-CoV-2 exposures. Nonetheless, further research is warranted using more sensitive measures and assessing longer term effects. This abstract is funded by: OT2HL156812

Abstract INTRODUCTION Understanding comorbidities’ combined impacts on dementia risk may offer a more comprehensive understanding of individuals’ risk. Using machine‐learning, we grouped individuals with similar midlife risk profiles into clusters and explored associations with dementia risk. METHODS Participants without dementia at baseline (1987–1989) from the prospective Atherosclerosis Risk in Communities (ARIC) study were included (ages 45–64 years; N = 15,250). Using unsupervised hierarchical cluster analysis, nine clusters were created and defined based on 14 midlife morbidities. The associations with incident dementia ( N = 3272 cases, median follow‐up 25 years) and deaths ( N = 9099) were evaluated using time‐to‐event regression models. RESULTS Compared with the healthiest cluster (Cluster 1), Clusters 2 (smoking) (hazard ratio [HR](95% confidence interval [CI]) = 1.62 (1.08, 2.43)), 5 (obesity, diabetes, hypertension, and hypertriglyceridemia) (HR(95%CI) = 1.91 (1.35,2.70)), and 7/8 (atrial fibrillation/heart failure) (HR(95%CI) = 2.69 (1.59,4.57)) were associated with dementia. Accounting for competing risk of death in the Fine‐Gray subdistribution model negated the cluster‐dementia association. DISCUSSION Midlife morbidity clusters are important for dementia and mortality risk.

Abstract There is an urgent need to improve dementia ascertainment robustness in real-world studies assessing drug effects on dementia risk. We developed algorithms to dementia identification algorithms using Medicare claims (inpatient/outpatient/prescription) from 3318 Visit 5 (2011-2013) and 1828 Visit 6 (2016-2017) participants of the Atherosclerosis Risk in Communities (ARIC) Study, validated against ARIC's rigorous syndromic dementia classification. Algorithm performance was compared to existing algorithms (Jain, Bynum, Lee). We further evaluated algorithms effectiveness in a 20% random Medicare sample aged ≥70 years who initiating liraglutide or dipeptidyl peptidase 4 inhibitors (DPP4i) to assess 3-year adjusted risk difference (aRD) for dementia. Our incident dementia algorithm required two dementia diagnostic codes within 1-year, or one dementia code plus a new dementia prescription within 90 days. It achieved a positive predictive value (PPV) of 69.2%, specificity of 99.0%, and sensitivity of 34.6% (population prevalence: 8.8%), comparable to extant algorithms (PPV, 58.7–68.6%; sensitivity 25.5–40.4%). Prevalent dementia algorithm (without requiring incident diagnoses/prescriptions) demonstrated similar performance. In the Medicare sample, dementia risk ranged from 3.0% to 12.5%, aRD comparing liraglutide to DPP4i varied −1.2% to −3.6%, with our algorithm closely matching the Bynum algorithm. Algorithm selection significantly impacts treatment effect estimates, highlighting its importance in in pharmacoepidemiologic research.

ImportanceIdentifying factors associated with resilience during the COVID-19 pandemic can inform targeted interventions and resource allocation for groups disproportionately affected by systemic inequities.ObjectiveTo examine factors associated with self-reported resilience during the COVID-19 pandemic in racially and ethnically diverse, community-dwelling US adults.Design, Setting, and ParticipantsThis cross-sectional study was conducted as part of the Collaborative Cohort of Cohorts for COVID-19 Research (C4R) study, which assessed the associations of the pandemic with self-reported resilience of participants from 14 established US prospective cohorts since January 2021. This report includes participants who responded to the self-reported resilience question on C4R questionnaires. Data was initially analyzed from October 2023 to May 2024, with updated analyses performed from August 2024 to April 2025.ExposureRace and ethnicity, behavior factors, health conditions, and social determinants of health measurements accessed before and during the COVID-19 pandemic through cohort visits and C4R questionnaires.Main Outcomes and MeasuresSelf-reported resilience was collected via 1 question (from the Brief Resilience Scale) in C4R questionnaires, “I tend to bounce back quickly after hard times.” Participants who answered agree or strongly agree were classified as resilient, and those who reported neutral, disagree, or strongly disagree were classified as not resilient. Modified Poisson regression was performed to estimate prevalence ratios (PRs) and access multivariable-adjusted associations with resilience.ResultsOf 31 045 participants (18 672 [60%] women; 10 746 [34.6%] aged <65 years), 1185 (3.8%) identified as American Indian, 6728 (21.7%) as Black, 293 (0.9%) as East Asian, 6311 (20.3%) as Hispanic, 565 (1.8%) as South Asian, and 15 961 (51.3%) as White; a total of 23 103 participants (74.4%) self-identified as resilient. Compared with White participants, Black and Hispanic participants had higher prevalence of self-reported resilience (adjusted PR [aPR], 1.04; 95% CI, 1.02-1.06; aPR, 1.08; 95% CI, 1.06-1.11; respectively) and American Indian and East Asian participants had lower prevalence (aPR, 0.90; 95% CI, 0.86-0.94; aPR, 0.76; 95% CI, 0.68-0.84; respectively). Higher education, being married or living as married, higher income, and overweight were also associated with higher prevalence of resilience. Being female, having diabetes, and being unemployed were associated with lower prevalence of self-reported resilience. Compared with participants with public insurance only, participants with private insurance had higher prevalence of resilience (aPR, 1.07; 95% CI, 1.03-1.10). COVID-19 vaccination and infection statuses were not significantly associated with resilience. Modification analyses showed important racial and ethnic differences in how factors such as hypertension, marital status, and insurance status were associated with resilience.Conclusions and RelevanceIn this cross-sectional study of 31 045 adults, self-reported resilience varied by race, ethnicity, and sociodemographic factors. These findings highlight the complex interplay of individual and social factors in shaping the perception of resilience.

Importance SARS-CoV-2 infection has been linked to neurotoxic effects and cognitive deficits. Objective To determine whether decreases in cognitive function were accelerated after SARS-CoV-2 infection compared with individuals not infected. Design, Setting, and Participants Multicenter, prospective cohort study from 2016 to 2022 among 3525 participants alive on March 1, 2020, and enrolled in The Atherosclerosis Risk in Communities (ARIC) study and the Collaborative Cohort of Cohorts for COVID-19 Research study who completed a prepandemic cognitive assessment and a pandemic-era assessment of SARS-CoV-2 infection. Final analyses performed in November 2024. Exposure SARS-CoV-2 infection determined via self-report of a positive SARS-CoV-2 test or health care professional diagnosis of COVID-19, a positive SARS-CoV-2 antinucleocapsid antibody response, or presence of an administrative code for COVID-19 on medical records. Main outcomes and measures A neuropsychological battery assessed multiple cognitive domains, and a cocalibrated confirmatory factor analysis generated factor scores for global cognitive function. The primary outcome was the rate of excess change in cognitive function. Results The 3525 eligible participants had a mean (SD) age of 80.8 (4.7) years, 2085 (59.1%) were female, 752 (21.4%) were Black, and 2773 (78.6%) were White. SARS-CoV-2 infection was detected among 307 participants (8.7%), 103 of whom (33.6%) were hospitalized. Among uninfected participants, the mean annualized change in cognitive function was −0.09 (95% CI, −0.13 to −0.04). Compared with this rate, change was faster (β = −0.06; 95% CI, −0.09 to −0.02) among participants hospitalized for infection, but not different from participants who were infected but not hospitalized (β = 0.00; 95% CI, −0.02 to 0.03). The association among participants hospitalized for infection was evident in the cognitive domains of memory and executive function, but not language. Conclusions and relevance This cohort study of older participants found accelerated decreases in cognition among individuals hospitalized for SARS-CoV-2 infection, but not nonhospitalized infection, in comparison with individuals not yet infected.

Abstract RATIONALE: Chronic lower respiratory diseases (CLRD) confer higher risks from respiratory viral infections, hence CLRD patients are prioritized for influenza, pneumococcal, and COVID-19 vaccination. Nonetheless, vaccine deferral and declination remain common. Given that COVID-19 vaccination is particularly polarizing, and attitudes toward it may differ from other vaccines, we assessed COVID-19 vaccination behaviors and attitudes in adults with versus without CLRD and/or smoking history, which is strongly associated with CLRD risk. METHODS: We pooled data from 10 cohorts participating in the Collaborative Cohort of Cohorts for COVID-19 Research (C4R) that collected pre-pandemic data on self-reported physician diagnosis of asthma or COPD. C4R assessed COVID-19 vaccination status through three waves of standardized questionnaires (2020-2022, 2021-2023, 2023-2024). Prompt COVID-19 vaccination was defined as self-report of receiving at least one COVID-19 vaccine by May 1, 2021. Cumulative COVID-19 vaccine count was self-reported on the Wave 3 Questionnaire. Vaccine attitudes and receipt of influenza and/or pneumococcal vaccines were self-reported on the Wave 1 or 2 Questionnaire. Age-adjusted Poisson regression was used to test associations of vaccination behaviors with CLRD and smoking status at the most recent pre-pandemic exam. RESULTS: Of 20,034 participants (pre-pandemic COPD, 9.3%; asthma, 11.7%; current smoking, 13.4%; former smoking, 36.3%), 64.2% reported prompt COVID-19 vaccination. Among the subset of 10,626 participants completing the Wave 3 Questionnaire in 2023-24, the median COVID-19 vaccine count was 3 (Q1:2, Q3:4). Compared to participants without CLRD, prompt vaccination was more likely in those with asthma (RR=1.04, 95%CI:1.01-1.07, p=0.008) and less likely with COPD (RR=0.94, 95%CI:0.91-0.98, p=0.001), but there were no differences in doses for asthma and COPD. Compared to never smokers, former smoking participants were more likely to receive prompt vaccination (RR=1.11, 95%CI:1.08-1.13, p<0.0001) and more vaccine doses (RR=1.03, 95%CI:1.01-1.05, p=0.015); conversely, current smoking was inversely associated with prompt vaccination (RR=0.94, 95%CI:0.91-0.97, p=0.001) and was associated with fewer doses (RR=0.93, 95%CI:0.89-0.96, p<0.0001). Participants with CLRD versus without CLRD were more likely to report receiving influenza and pneumococcal vaccines, but they were more likely to believe that vaccines are unsafe or ineffective (figure). CONCLUSIONS: COPD was associated with lower likelihood of prompt COVID-19 vaccination. Current smoking was associated with both lower likelihood of prompt COVID-19 vaccination and a lower number of COVID-19 vaccine doses by 2023-24. These associations may be partly attributed to negative vaccine attitudes and beliefs. How the COVID-19 pandemic may have influenced vaccine behaviors and attitudes merits additional study.

Abstract RATIONALE: Deferral and declination of the COVID-19 vaccine is correlated with many factors, including different health guidelines and difficulties accessing the vaccine. In the US, COVID-19 vaccines were made available in tranches of clinical risk starting in December 2020 and were available to all adults on April 19, 2021. In the post-pandemic period, repeating COVID-19 vaccination with updated formulations is broadly recommended. Given that the public health impact of vaccine allocation strategies depends on public acceptance of vaccination, we aimed to evaluate demographic, clinical and social correlates of (1) receiving at least one COVID-19 vaccine by May 1, 2021 (prompt vaccination) and (2) the total number of vaccine doses received (vaccine count) through 2023-2024. METHODS: The Collaborative Cohort of Cohorts for COVID-19 Research (C4R) is a prospective observational meta-cohort study comprising 14 extant NIH-funded population-based cohorts. C4R assessed COVID-19 vaccination using three waves of standardized questionnaires (2020-2021, 2021-2023, 2023-2024). Prompt vaccination was defined by participant self-report of vaccination before May 1, 2021; participants vaccinated after May1, 2021 were classified as non-prompt; participants with missing vaccination information were excluded. Vaccine count was defined by self-report on the 2023-2024 wave Questionnaire. Demographic, clinical and social factors were classified by self-report and/or objective measures from the most recent pre-pandemic cohort exam. Poisson models regressed either prompt vaccination or vaccine count on pre-pandemic factors. RESULTS: Of 17,866 participants (mean age, 6713 years; 60.1% female; 42.1% non-Hispanic White, 22.0% Black, 28.9% Hispanic/Latino, 3.4% American Indian, 2.3% South Asian, 1.4% East Asian), 11,481 (64.3%) reported prompt vaccination. Of the subset of 14,529 participants completing the Wave 3 questionnaire, the median vaccine count in 2023-24 was 3 (Q1, 2; Q3 4). Likelihood of prompt vaccination was higher with greater age, income, and education and with history of diabetes and hypertension; prompt vaccination was less likely with male sex, current smoking, and non-White race and ethnicity (table). Similar associations were observed with respect to vaccine count (table). CONCLUSIONS: In a diverse C4R cohort community-based sample, earlier and greater COVID-19 vaccination was associated with older age and several clinical comorbidities; in contrast, later and lesser vaccine uptake was observed among historically marginalized groups. Whether disparities in COVID-19 vaccination could contribute to disparities in post-COVID-19 conditions merits further investigation.

Abstract Rationale: SARS-CoV-2 infection may be associated with new or worsening respiratory symptoms that, if persistent, may contribute to “Long COVID.” Research is needed on the prevalence and risk determinants of Long COVID and related respiratory symptoms in adults with and without pre-existing obstructive lung disease or smoking history. Methods: C4R is a prospective, observational study that collected information on SARS-CoV-2 infection using standardized methods across 14 NIH-funded cohorts. The third wave of C4R questionnaires, administered June 2023 to January 2025, assessed self-reported Long COVID via the question, “Do you think that you are experiencing, or have ever experienced, what has been called “long COVID,” or symptoms related to COVID at least a month after your infection?” Questionnaires also assessed the presence (vs absence) of 22 symptoms that have been linked to Long COVID, including cough, shortness of breath, and post-exertional malaise. Pre-pandemic obstructive lung disease (COPD or asthma) and smoking status (ever/never) were harmonized from self-reported data collected at the most recent pre-pandemic cohort exam. Poisson regression was used to assess prevalence ratios (PRs) adjusting for age, sex, BMI, education, and pre-pandemic hypertension, diabetes, cardiovascular disease, and depressive symptoms. PRs for respiratory symptoms were tested according to self-reported Long COVID and history of non-hospitalized or hospitalized infection; effect modification by pre-pandemic lung disease and smoking was assessed by multiplicative interaction terms and in fully stratified models. Results: Among 23,434 questionnaire respondents, 1,484 (6.3%) self-reported Long COVID, including 246/1,262 (19.5%) with pre-pandemic lung disease and 664/4,018 (16.5%) with smoking history. The adjusted PR for Long COVID was 1.17 (95%CI:0.99-1.39;P=0.06) comparing participants with/without lung disease and 1.17 (95%CI:1.04-1.32;P=0.01) comparing participants with/without smoking history. Respiratory symptoms were more prevalent in those with self-reported Long COVID, as well as in those with a history of hospitalized or non-hospitalized infection (Table). Associations were generally stronger in participants without pre-pandemic lung disease (p-interaction<0.05 for all comparisons). Respiratory symptoms were also more prevalent with a history of repeated, and pre-Omicron infections, and were less prevalent among participants vaccinated prior to their first infection; findings were similar even after excluding participants with self-reported Long COVID. Conclusions: Long COVID is common, particularly in adults with pre-existing COPD or asthma or smoking history. Long COVID and history of SARS-CoV-2 infection, including non-hospitalized infections, was associated with greater respiratory symptom burden. Whether SARS-CoV-2 infection or Long COVID are associated with development or progression of obstructive lung diseases warrants future studies.

AbstractBackgroundWeakened white matter (WM) integrity is highly associated with dementia risk. Still, not everyone with WM changes develops dementia, suggesting the important role modifiable lifestyle factors may have in reducing dementia risk. We investigated how social relationships in mid‐life may modify the association between WM integrity and incident dementia risk within race and sex subgroups.MethodIn 1,679 Atherosclerosis Risk in Community (ARIC) study participants who were dementia‐free in mid‐life, psychosocial health was assessed via self‐reported questionnaires and participants were classified as having strong or poor social relationships in mid‐life (visit 2: 1990‐1992). Through diffusion tensor imaging, WM integrity was evaluated with 3T brain MRI (visit 5: 2011 – 2013); fractional anisotropy (FA) and mean diffusivity (MD) were estimated. Incident dementia cases were identified from visit 5 through December 31, 2019, with ongoing surveillance. Relative contributions of social relationships and WM integrity to incident dementia were evaluated in Cox‐proportional hazard regression models with race and race‐sex as interaction terms, and in stratified models (White Females, Black Females, White Males, Black Males).ResultSignificant three‐way interactions were observed between race, WM integrity, and mid‐life social relationships (p‐interaction<0.01). In Black participants with strong mid‐life social relationships, higher MD (hazard ratio (HR): 0.93, 95% CI: 0.63 – 1.38) and lower FA (HR: 1.25, 95% CI: 0.84 – 1.86) were not associated with the risk of dementia, although in Black participants with poor social relationships, higher MD remained a significant risk factor for dementia. However, across all White participants, higher MD and lower FA were associated with the risk of dementia, regardless of mid‐life social relationships (Table 1; Figure 1). Analysis of three‐way interactions between race‐sex, WM integrity, and mid‐life social relationships suggested that effect modification by mid‐life social relationships was most evident in Black Females, respective to other groups (Table 2; Figure 1).ConclusionThe contribution of WM integrity to dementia risk may be lower in Black participants with strong social relationships in mid‐life, particularly in Black Females. Further understanding of how contextual social factors may influence brain health in diverse populations should be examined in future studies and intervention efforts.