Sex Differences in the Association Between Metabolic Dysregulation and Cognitive Aging: The Health and Retirement Study

Abstract

Background: Dysregulation of some metabolic factors increases the risk of dementia. It remains unclear if overall metabolic dysregulation, or only certain components, contribute to cognitive aging and if these associations are sex specific.

Methods: Data from the 2006-2016 waves of the Health and Retirement Study (HRS) was used to analyze 7 103 participants aged 65 and older at baseline (58% women). We created a metabolic-dysregulation risk score (MDRS) composed of blood pressure/hypertension status, glycosylated hemoglobin (HbA1c)/diabetes status, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and waist circumference, and assessed cognitive trajectories from repeated measures of the HRS-Telephone Interview for Cognitive Status (HRS-TICS) over 10 years of follow-up. Linear mixed-effects models estimated associations between MDRS or individual metabolic factors (biomarkers) with mean and change in HRS-TICS scores and assessed sex-modification of these associations.

Results: Participants with higher MDRSs had lower mean HRS-TICS scores, but there were no statistically significant differences in rate of decline. Sex stratification showed this association was present for women only. MDRS biomarkers revealed heterogeneity in the strength and direction of associations with HRS-TICS. Lower HRS-TICS levels were associated with hypertension, higher HbA1c/diabetes, and lower HDL-C and TC, whereas faster rate of cognitive decline was associated with hypertension, higher HbA1c/diabetes, and higher TC. Participants with higher HbA1c/diabetes presented worse cognitive trajectories. Sex differences indicated that women with higher HbA1c/diabetes to have lower HRS-TICS levels, whereas hypertensive males presented better cognitive trajectory.

Conclusions: Our results demonstrate that metabolic dysregulation is more strongly associated with cognition in women compared with men, though sex differences vary by individual biomarker.

Keywords: Biomarkers; Brain aging; Diabetes; Epidemiology.

Figure 1.

Study flow chart with final study sample, n = 7 103.

Figure 2.

Association between biomarkers and cognitive trajectories. This figure demonstrates the relationship between metabolic dysregulation biomarkers (or diagnosed health conditions) included in the MDRS and population mean (standardized) HRS-TICS score (red) units and rate of change in HRS-TICS score over 5 yr (blue). Output are beta estimates and 95% CIs for the respective variable terms in linear mixed-effects models with standardized biomarker values as the exposure. All shown estimates come from final, fully adjusted overall and sex-stratified regression models. DBP = diastolic blood pressure; HbA1c = hemoglobin A1C (percentage); HDL-C = high-density lipoprotein cholesterol (mg/dL); HRS = Health and Retirement Study; HRS-TICS = Telephone Interview Cognitive Screening from Health and Retirement Study; MDRS = Metabolic Dysfunction Risk Score; SBP = systolic blood pressure (mmHg); TC = total cholesterol (mmHg); WC = waist circumference (cm).

Figure 3.

Predicted cognitive trajectories per MDRS point for all and stratified by sex. Output represents predicted HRS-TICS scores for each participant and observation from fully adjusted model by MDRS points. We calculated the predicted value for HRS-TICS based on the model estimates as follows: Level 1: Y_ij = β _0i time + β _2i time 2; Level 2: For the intercept: β _0i = γ 00 + γ 01 MDRS + γ 02 age+ γ 03 age 2 + γ 04 race + γ 05 education + γ 06 cohort + u 0i, and for linear growth rate: β _1i = γ 10 + γ 11 MDRS + γ 12 age + u 1i, which indicates the predicted HRS-TICS score for each participant’s covariate values. MDRS scores of 4 and 5 were merged for data figure only. X-axis shows SD from the mean cognitive score, and y-axis shows age in years. MDRS = Metabolic Dysfunction Risk Score.

Figure 4.

Predicted cognitive trajectories for individual biomarkers for all and stratified by sex for those biomarkers where the sex stratification was significant. This figure demonstrates the relationship between biomarkers (dichotomized at MDRS cut point values) and predicted HRS-TICS score. Outputs are predicted HRS-TICS scores for each participant and observation from fully adjusted overall and sex-stratified linear mixed-effects models. X-axis shows SD from the mean cognitive score, and y-axis shows age in years. DBP = diastolic blood pressure; HbA1c = hemoglobin A1C (percentage); HDL-C = high-density lipoprotein cholesterol (mg/dL); HRS = Health and Retirement Study; HRS-TICS = Telephone Interview Cognitive Screening from Health and Retirement Study; MDRS = Metabolic Dysfunction Risk Score; SBP = systolic blood pressure (mmHg); TC = total cholesterol (mmHg); WC = waist circumference (cm).