Nels C. Olson

Late-life dementia has a strong heritable component. While the APOE ε4 allele is the strongest genetic risk factor for Alzheimer’s disease (AD), polygenic risk factors also play a significant role. Cardiometabolic diseases (CMDs) and their risk factors predict dementia in many cohorts, but how genetic predictors of CMD influence dementia-related outcomes remain unclear. In this study, we examined the associations of polygenic risk scores (PRS) for major CMDs and the established APOE risk alleles with dementia-related outcomes in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, which is enriched for Black participants underrepresented in late-life dementia research. We constructed PRS for AD and related dementias (ADRD) and CMDs, including stroke, coronary artery disease, venous thromboembolism, type 2 diabetes (T2D), Atrial fibrillation (AFib), blood pressure [BP; systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure (PP)], and circulating lipid levels [high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), and triglycerides (TG)], using lead genome-wide significant genetic variants from the latest genome-wide association studies. We evaluated the predictive performance of each PRS on their primary endpoint and tested their associations with incident cognitive impairment (ICI), assessed via the six-item screener and enhanced cognitive battery, and dementia as a contributing cause of death (DCCD). Additionally, we explored the impact of APOE variants and, based on prior reports, local genetic ancestry at the APOE locus on these dementia-related outcomes. Up to 8,818 participants were analyzed (mean age, 63.7 years; 58.9% female, 83.3% Black). For CMD PRS, we identified a significant association between PRS for pulse pressure and DCCD [HR: 1.16 (1.06–1.28), p < 1.76×10⁻³]. We observed that the PRS for ADRD was associated nominally with DCCD [Hazard ratio (HR) (95% CI): 1.12 (1.00–1.25)], but not with ICI among REGARDS participants, suggesting heterogeneity in associations across different cognitive-related endpoints. Furthermore, we identified a nominally significant (p<0.1) attenuated effect of APOE risk alleles on ICI among those with African ancestry at the APOE locus, similar to prior reports. Higher PRS for pulse pressure was associated with increased DCCD risk, supporting shared genetic underpinnings between CMD and dementia.

The role of circulating monocytes in non-ischemic cardiac remodeling and heart failure (HF) is complex and unclear. We assessed monocyte gene expression profiles associated with cardiac imaging metrics and incident HF among participants of the Multi-Ethnic Study of Atherosclerosis free of ischemic heart disease. Circulating CD14+ monocytes were isolated, and RNA was quantified using an Illumina microarray. Contrast-enhanced cardiac magnetic resonance was performed concurrently. We studied 12,369 transcripts mapping to 9,430 genes among 1195 community-based participants (mean age 69 ± 9 years; 52% female; 22% Black; 32% Hispanic). We used multivariable linear regression to estimate cross-sectional associations between monocyte gene expression levels and cardiac structure and function, adjusting for key confounders and risk factors. Cox regression was used to assess time to incident HF (n = 45 events over a median follow-up of 7.7 years). Here we identify monocyte expression profiles associated with cardiac structure, function, and fibrosis that implicate lymphocyte activation, cytokine production, phagocytosis, wound healing, oxidative stress, and cell migration. Monocyte expression of PCCB was associated with left ventricular strain, left atrial size, myocardial fibrosis, and time to incident HF, and was validated using Mendelian randomization with peripheral monocyte-specific cis-eQTLs. In a community-based cohort, monocyte expression profiles reflecting both pro-inflammatory and pro-resolving activity, as well as tissue migration and homeostasis, are associated with subclinical cardiac remodeling and fibrosis. Monocyte expression of PCCB and related immunometabolism may be an especially strong candidate for future mechanistic investigation in non-ischemic HF.

We examined cross-sectional and longitudinal associations of urinary isoprostanes with carotid T-PWV, and its associated mechanisms (S-PWV and LD-PWV), in a multiethnic cohort of adults. Higher isoprostanes were cross-sectionally associated with carotid artery stiffness driven by structural remodeling in adults who self-reported taking angiotensin-II acting medications or self-identified as White. No associations were observed with isoprostanes and carotid stiffness a decade later in the entire analytic sample. Oxidative stress may augment the risk of structural remodeling in select populations.

Blood-based biomarkers offer a widely available, scalable, and noninvasive method to study neurodegeneration. However, the association between blood-based biomarkers of neurodegeneration and long-term risk of mortality, as well as dementia-specific mortality in a racially diverse cohort, remains understudied. The goal of this study was to determine whether baseline biomarkers of neurodegeneration are associated with long-term risk of all-cause and dementia-specific mortality in a biracial cohort. The REasons for Geographic and Racial Differences in Stroke cohort study enrolled 30,239 Black and White participants across the continental United States from 2003 to 2007, with ongoing follow-up. Plasma neurofilament light chain (NfL), total tau, glial fibrillary acidic protein (GFAP), and ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) were measured in baseline plasma from a random sample of participants. All-cause mortality, dementia-specific mortality, cardiovascular-specific mortality, and other causes of death were adjudicated and classified using medical records, the Social Security Death Index, and the National Death Index. Cause-specific Cox regression models accounting for competing risks were used to calculate hazard ratios (HRs) of outcomes for each biomarker separately. A total of 917 participants had a mean baseline age of 67.4 years (SD 12.1), 49.4% were female, and 48.6% self-identified as Black. With a mean follow-up of 11.1 (SD 5.7) years, 51.0% (477/935) of participants died and 9.2% experienced dementia-specific mortality (86/935). No associations were observed for total tau. In fully adjusted models for other biomarkers, HRs of all-cause mortality per standard deviation increments were 1.93 (95% CI 1.48-2.52) for GFAP, 1.90 (95% CI 1.55-2.32) for NfL, and 1.23 (95% CI 1.09-1.37) for UCH-L1. Furthermore, GFAP (HR 5.66, 95% CI 2.91-11.00) and NfL (HR 2.72, 95% CI 1.57-4.71) were associated with dementia-specific mortality in fully adjusted models. GFAP (HR 2.06, 95% CI 1.22-3.49) and NfL (HR 2.16, 95% CI 1.66-2.81) were also associated with cardiovascular-specific mortality in fully adjusted models. Plasma biomarkers of neurodegeneration, particularly GFAP and NfL, were associated with increased risk of all-cause, dementia-specific, and cardiovascular-specific mortality in a biracial cohort. These associations should be considered when assessing links between these biomarkers and other outcomes, as well as when used in clinical practice.

Pre-clinical studies demonstrated lipids and lipoproteins influence T-cell phenotype. Several large cohort studies have also observed that plasma lipids and lipoproteins are associated with white blood cell and lymphocyte counts. However, there are little data on the relationships of lipids or lipoproteins with lymphocyte subsets in large, community-based, multi-ethnic cohorts. The purpose of this study was to evaluate associations of plasma lipid and lipoprotein fractions with circulating lymphocyte subsets in participants of the Multi-Ethnic Study of Atherosclerosis (MESA). MESA recruited 6,814 adults (aged 45–84 years) free of clinical cardiovascular disease at the baseline exam between 2000–2002. This study included 1,735 participants (49% male, 36% White) with lipoprotein and immune cell phenotyping data at baseline. Multivariable linear regression models evaluated associations between lipoprotein concentration (analyzed per 1-standard deviation (SD) increment) and lymphocyte subsets. Following correction for multiple hypothesis testing (p < 0.0006), higher high-density lipoprotein (HDL)-cholesterol was associated with higher proportions of memory B-cells, while HDL-lipoprotein concentration was associated with lower pan B-cells. In analyses not corrected for multiple hypothesis testing (p < 0.05), higher concentrations of total-cholesterol, low-density lipoprotein (LDL) cholesterol and LDL-lipoproteins, triglycerides and triglyceride-rich lipoproteins were associated with higher proportions of several T-cell subsets associated with inflammation and senescence. Conversely, a higher concentration of HDL-lipoproteins were associated with lower proportions of senescence-associated T-cells. These results indicate plasma lipids and lipoproteins may play a role in influencing circulating immune cells. If confirmed in longitudinal studies, these findings may have implications for the development of therapeutics targeting inflammation in patients with elevated lipids.

Background: Limited data exist on associations of immune cell subsets with longitudinal changes in subclinical coronary artery disease. Methods: In the MESA (Multi‐Ethnic Study of Atherosclerosis) study, we used a case‐cohort approach to explore associations of 28 immune cell subsets measured at baseline (2000–2002) with longitudinal changes in coronary artery calcium ( CAC ). We examined incident CAC from examination 2 (2002–2004) through examination 5 (2010–2012) in participants with 0 CAC at baseline using multivariable‐adjusted Cox regression. In participants with CAC >0 at baseline, we analyzed changes in CAC through examination 5 using multivariable‐adjusted linear mixed models. Because no studies have investigated immune cells and longitudinal CAC changes, analyses were considered exploratory, with P 0 at baseline (mean age, 65.7; 57.6% men). Natural killer cells were associated with higher incident CAC (hazard ratio [ HR], 1.26 per SD higher natural killer cell proportion; P =0.03), whereas T helper type cells were associated with lower incident CAC ( HR , 0.81; P =0.04). B cells were associated with CAC progression (β=53.1 Agatston units per SD higher B‐cell proportion, P =0.04), whereas CD14 + CD16 + monocytes (β=−71.6; P =0.03) and T regulatory cells (β=−61.9; P =0.03) were associated with lower CAC progression. Conclusions: Natural killer cells may be associated with incident CAC and T regulatory cells may be associated with attenuated CAC progression, among other findings. These warrant replication and experimental investigation.

We investigated whether peripheral T cells were associated with endothelial function in a multi-ethnic cohort. No significant associations were observed between Th1 or CD4⁺CD28-CD57⁺ T cells with endothelial function in the primarily analysis. A higher value of pan CD4⁺ T cells was associated with lower endothelial function, while a higher value of pan CD8⁺ T cells was associated with higher endothelial function in the secondary analysis. This study provides epidemiological data linking pan T cells to measures of endothelial function.

We investigated associations between T-cells and novel measures of structural and load-dependent arterial stiffness in a large multiethnic cohort. The primary analysis revealed that pro-inflammatory, senescence-associated CD4⁺CD28^–CD57⁺ T-cells were associated with higher load-dependent arterial stiffness. An exploratory analysis revealed that multiple pro-inflammatory CD4⁺ and CD8⁺ T-cell subpopulations were associated with both higher structural and load-dependent arterial stiffness. These results suggest that pro-inflammatory T-cells may contribute to arterial stiffness through both arterial remodeling and elevated blood pressure.