Sex and sex hormones largely explain associations between glucose levels and brain atrophy in AD‐sensitive regions: Biomarkers (non‐neuroimaging)/Plasma/Serum/Urine biomarkers

Background High glucose levels are related to worse cognitive performance and brain health in AD‐sensitive regions. Sex hormones are thought to be a protective factor against hyperglycemia and many of its sequelae, where menopause and andropause in mid‐life lead to pronounced decreases in sex hormone secretion. It is unknown if sex and sex hormones modulate relationships between high glucose and regional brain atrophy or cognitive performance. Method The study consisted of 15,506 participants from the UK Biobank with complete brain volume, blood glucose measures, and demographic data. Multiple linear regression models tested relationships between fasting serum glucose and key brain regions of interest. Covariates included age, sex, intracranial volume, white matter hyperintensity load, and education in lieu of intracranial volume for cognition outcomes. To examine sex differences, moderation analyses were conducted. The sample was also separated by sex to test sex hormone by blood glucose interactions for the brain volume and fluid intelligence measures. Result For the overall sample, higher glucose or glycated hemoglobin (Hba1c) levels were associated with less total grey matter and regional grey matter in amygdala and parahippocampus. Higher Hba1c levels also predicted poorer fluid intelligence performance. Sex interactions indicated that higher HbA1c levels were related to relatively more brain atrophy among men in the hippocampus and amygdala. Due to these observations, testosterone and oestradiol levels were tested as moderators in a subset of participants with available data ( n =13,858). Hormone levels only among women impacted blood glucose and brain volume relationships. Higher oestradiol and testosterone levels led to more atrophy in hippocampus and amygdala per unit increase in glucose levels. Conclusion In general, higher glucose levels were associated with poorer neural and cognitive outcomes. Men showed this relationship more strongly, but not due to sex hormone levels. Comparatively, sex hormones in women largely accounted for detrimental glucose associations with AD‐sensitive brain regions. Future research should examine other mechanisms that may explain sex differences observed with glucoregulatory function and brain health.