Sex-Dependent Effects of Cardiometabolic Health and <i>APOE4</i> on Brain Age: A Longitudinal Cohort Study.

Abstract

The aging population is growing faster than all other demographic strata. With older age comes a greater risk of health conditions such as obesity and high blood pressure (BP). These cardiometabolic risk factors (CMRs) exhibit prominent sex differences in midlife and aging, yet their influence on brain health in females vs males is largely unexplored. In this study, we investigated sex differences in relationships between BP, body mass index (BMI), and brain age over time and tested for interactions with <i>APOE</i> ε4 genotype (<i>APOE4</i>), a known genetic risk factor of Alzheimer disease. The sample included participants from 2 United Kingdom-based longitudinal birth cohorts, the Lothian Birth Cohort (1936) and Insight 46 (1946). Participants with MRI data from at least 1 time point were included to evaluate sex differences in associations between CMRs and brain age. The open-access software package brainageR 2.1 was used to estimate brain age for each participant. Linear mixed-effects models were used to assess the relationships between brain age, BMI, BP, and <i>APOE4</i> status (i.e., carrier vs noncarrier) in males and females over time. The combined sample comprised 1,120 participants (48% female) with a mean age (SD) of 73 (0.72) years in the Lothian Birth Cohort and 71 (0.68) years in Insight 46 at the time point 1 assessment. Approximately 30% of participants were <i>APOE4</i> carriers. Higher systolic and diastolic BP was significantly associated with older brain age in females only (β = 0.43-0.56, <i>p</i> < 0.05). Among males, higher BMI was associated with older brain age across time points and <i>APOE4</i> groups (β = 0.72-0.77, <i>p</i> < 0.05). In females, higher BMI was linked to older brain age among <i>APOE4</i> noncarriers (β = 0.68-0.99, <i>p</i> < 0.05), whereas higher BMI was linked to younger brain age among carriers, particularly at the last time point (β = -1.75, <i>p</i> < 0.05). This study indicates sex-dependent and time-dependent relationships between CMRs, <i>APOE4</i> status, and brain age. Our findings highlight the necessity of sex-stratified analyses to elucidate the role of CMRs in individual aging trajectories, providing a basis for developing personalized preventive interventions.