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.