Background: The inherent genetic effects were not established between type 2 diabetes (T2DM) and Alzheimer's disease and related dementia (ADRD). Objective: We aimed to investigate the association between T2DM and ADRD by integrating T2DM polygenic risk score (PRS) and applying matching in every subgroup. Methods: We utilized UK Biobank First-occurrences datasets. T2DM were 1:1 matched to non-T2DM using propensity scores generated by 8 covariates; age at diagnosis, sex, cerebrovascular disease, ischemic heart disease, hypertensive disorders, lipid disorders, obesity, and mood disorders. T2DM PRS was additionally matched in T2DM PRS matched analysis. Subgroup analyses by age at diagnosis, sex, and APOE4 genotype were performed with the same matching criteria within each subgroup. Cox proportional hazard and Fine & Gray competing risk model were utilized. Results: In T2DM PRS unmatched cohort, 24,583 T2DM were 1:1 matched to non-T2DM. The mean age at diagnosis was around 62 years old, with females constituting around 40%. Up to 25-year follow-up, ADRD rate/1000 person-years was 0.88 versus 1.52 (Non-T2DM versus T2DM); PRS unmatched (cHR: 1.72, 95% CI: 1.46–2.03) and matched (cHR:1.75, 95% CI: 1.47–2.09). Except for older age onset (≥75 years), the other subgroups demonstrated significantly increased ADRD risks in T2DM. T2DM PRS was higher in non-ADRD group across all subgroups. Contrarily, T2DM PRS was higher in ADRD in younger onset group (<55 years). Conclusions: T2DM is one of the strong risk factors of ADRD but genetic T2DM effect does not contribute to ADRD risk. However, a genetic link might be present in younger age onset group.

The epigenome likely interacts with traditional and genetic risk factors to influence blood pressure. We evaluated whether 13 previously reported DNA methylation sites (CpGs) are associated with systolic (SBP) or diastolic (DBP) blood pressure, both individually and aggregated into methylation risk scores (MRS), in 3070 participants (including 437 African ancestry (AA) and 2021 European ancestry (EA), mean age = 70.5 years) from the Health and Retirement Study. Nine CpGs were at least nominally associated with SBP and/or DBP after adjusting for traditional hypertension risk factors (p < 0.05). MRS_SBP was positively associated with SBP in the full sample (β = 1.7 mmHg per 1 standard deviation in MRS_SBP; p = 2.7 × 10⁻⁵) and in EA (β = 1.6; p = 0.001), and MRS_DBP with DBP in the full sample (β = 1.1; p = 1.8 × 10⁻⁶), EA (β = 1.1; p = 7.2 × 10⁻⁵), and AA (β = 1.4; p = 0.03). The MRS and BP-genetic risk scores were independently associated with blood pressure in EA. The effects of both MRSs were weaker with increased age (p_interaction < 0.01), and the effect of MRS_DBP was higher among individuals with at least some college education (p_interaction = 0.02). In AA, increasing MRS_SBP was associated with higher SBP in females only (p_interaction = 0.01). Our work shows that MRS is a potential biomarker of blood pressure that may be modified by traditional hypertension risk factors.

Poly-epigenetic scores (PEGS) are surrogate measures that help capture individual-level risk. Understanding how the associations between PEGS and cardiometabolic risk factors vary by demographics and health behaviors is crucial for lowering the burden of cardiometabolic diseases. We used results from established epigenome-wide association studies to construct trait-specific PEGS from whole blood DNA methylation for systolic and diastolic blood pressure (SBP, DBP), body mass index (BMI), C-reactive protein (CRP), high- and low-density lipoprotein cholesterol (HDL-C, LDL-C), triglycerides (TG), and fasting glucose. Overall and race-stratified associations between PEGS and corresponding traits were examined in adults >50 years from the Health and Retirement Study (n = 3,996, mean age = 79.5 years). We investigated how demographics (age, sex, educational attainment) and health behaviors (smoking, alcohol consumption, physical activity) modified these associations. All PEGS were positively associated with their corresponding cardiometabolic traits (p < 0.05), and most associations persisted across all racial/ethnic groups. Associations for BMI, HDL-C, and TG were stronger in younger participants, and BMI and HDL-C associations were stronger in females. The CRP association was stronger among those with a high school degree. Finally, the HDL-C association was stronger among current smokers. These findings support PEGS as robust surrogate measures and suggest the associations may differ among subgroups.