👤 Juan M Farina

Alzheimer's disease and related dementias (ADRD) are major public health concerns. DNA methylation (DNAm)-based biomarkers such as GrimAge and PhenoAge predict aging and health risk, but were not designed to optimize prediction of cognitive decline. We used data from the 2016 Venous Blood Study of the Health and Retirement Study (HRS), a nationally representative cohort of U.S. adults aged ≥51 years (N = 3575 with high-quality DNAm). Epigenetic g scores were computed using CpG weights from a BayesR+ model of general cognitive ability developed in Generation Scotland. Cognitive function was measured with a modified version of the Telephone Interview for Cognitive Status (TICS) at each interview wave; 6-year incident dementia was defined using the validated Langa-Weir algorithm. Linear regression estimated associations with cognitive scores; logistic regression estimated 4-year dementia risk. Models were adjusted sequentially for demographics, education, parental education, APOE ε4 status, and blood-based neurodegeneration markers (NfL, GFAP, Aβ42/40, pTau181). Higher epigenetic g was associated with better baseline cognition (β=2.55, 95% CI 1.92-3.17) and cognition at the time DNAm was measured (β=2.30, 95% CI 1.62-2.99) after demographic adjustment. Associations attenuated but remained significant with education and parental education (β=1.23-1.89). Each unit increase in epigenetic g predicted 29% lower 6-year risk of dementia (fully adjusted HR=0.71). Results were robust to adjustment for APOE ε4 and neurodegeneration biomarkers. Epigenetic g is a scalable, blood-based marker of cognitive function and dementia risk that adds predictive value beyond demographics, socioeconomic indicators, APOE, and neuropathology. Its validation in a diverse, nationally representative U.S. cohort underscores its potential for early risk profiling and for research on social determinants of cognitive aging in cross-national samples. Show less

Elevated lipoprotein(a) [Lp(a)] and low high-density lipoprotein-cholesterol (HDL-C) are established cardiovascular (CV) risk factors, but their combined impact on mortality and sex differences remains unclear. This retrospective study analyzed 97 396 patients with measured Lp(a) and HDL-C. Groups were stratified by Lp(a) (≥50 vs. <50 mg/dl) and HDL-C [low (<40), optimal (40-60), high (>60 mg/dl)]. Mortality was assessed using the Kaplan-Meier curve and Cox models. Over a median of 5.9 years, 7794 deaths occurred. Compared to optimal HDL-C/low Lp(a) (reference), high HDL-C/low Lp(a) had the lowest mortality [adjusted hazard ratio (aHR): 0.85; 95% confidence interval (CI): 0.80-0.91], while low HDL-C/high Lp(a) had the highest risk (aHR: 1.55; 1.41-1.71). High HDL-C protective effect was insignificant with elevated Lp(a) (aHR: 0.98; 0.89-1.08). Sex-stratified analyses revealed divergent effects: women with high HDL-C/high Lp(a) retained the HDL-C protective effect (aHR: 0.82; 0.72-0.93), whereas men faced increased risk (aHR: 1.22; 1.05-1.42). Elevated Lp(a) enhances mortality risk despite elevated HDL-C levels, with sex-specific differences: women retain mortality benefits from high HDL-C despite elevated Lp(a), whereas men with concurrent elevations in HDL-C and Lp(a) experienced mortality risks comparable to those with low HDL-C. Findings underscore sex-specific CV risk stratification incorporating HDL-C and Lp(a), challenging the HDL-C universal protective role. Show less

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiomyopathy. It follows an autosomal dominant inheritance pattern in most cases, with incomplete penetrance and heterogeneity. It is familial in 60% of cases and most of these are caused by pathogenic variants in the core sarcomeric genes ( Show less