Vascular-related biological stress, DNA methylation, allostatic load and domain-specific cognition: an integrated machine learning and causal inference approach.

Background: Vascular disease in aging populations spans a wide range of disorders including strokes, circulation disorders and hypertension. As individuals age, vascular disorders co-occur and hence exert combined effects. In the present study we introduce vascular-related biological stress as a novel biomarker to capture the combined effects of vascular disease burden for more precision in early detection of cognitive changes in aging.

Objective: to determine the role of vascular-related biological Stress, DNA methylation-based biological aging and Allostatic Load in the relationship between vascular disorders and major cognitive domains including global cognition, episodic memory and executive function in a representative sample of adults across the age span.

Methods: The present study included participants from MIDUS refresher sample. Vascular-related biological stress included: BMI, Average blood pressure, sitting, Waist-hip ratio, Blood hemoglobin A1c percent, Blood dehydroepiandrosterone (ng/mL), Blood fasting insulin levels uIU/mL, Blood serum interleukin-8 (pg/mL), Blood serum interleukin-6 (pg/mL), Blood fasting glucose levels mg/dL and Blood fibrinogen (mg/dL). DNA methylation-based biological age measures included GrimAge2 that was constructed based on DNA methylation surrogate markers for select plasma proteins and smoking-pack years. Allostatic load scores were calculated based on biomarkers commonly used in allostatic load calculations: cortisol (urine), norepinephrine (urine), epinephrine (urine), dopamine (urine), glycosylated hemoglobin (HBA1C, blood), low density lipoprotein (LDL, blood), C-reactive protein (CRP, blood) dehydroepiandrosterone sulfate (DHEAS, blood), high-density lipoprotein (HDL, blood) and systolic blood pressure (average, sitting). Least Absolute Shrinkage and Selection Operator (LASSO) and response models (item and continuous) were used to calculate vascular-related biological stress and theta scores. Four-way decomposition modeling approach was used to calculate the natural direct and indirect effects in the relationship between vascular disease and major cognitive domains.

Results: 550 individuals with data on biomarkers, DNA methylation and cognition assessments were included in the present study. Median age was 54 (range = 26, 78) with females representing 48% of the sample. In the relationship between vascular disease and cognition, the overall proportions mediated through vascular-related biological stress (item-response scale) were 0.60 (P = 0.01); 1.1 (P = 0.308); 0.53 (P = 0.002) for global cognition, episodic memory and executive function respectively. The overall proportions mediated through DNA methylation (GrimAge2) were 0.27 (P = 0.002); 0.39 (P = 0.102); 0.20, (P = 0.002) for global cognition, episodic memory and executive function respectively and 0.10 (P = 0.08); 0.09 (P = 0.5); 0.07 (P = 0.18) through allostatic load (sum scores).

Conclusions: Our findings suggest that vascular-related biological stress, DNA methylation and to some extent allostatic load mediate the effects of vascular disease on global cognition and executive function.