Investigating links between white matter hyperintensities and menopausal status using robust age-correction methods...

White matter hyperintensities (WMHs) are radiological abnormalities indicative of cerebrovascular dysfunction associated with increased risk for cognitive decline. WMHs increase in prevalence with older age, and there are known sex differences as older women harbour higher WMH burden than men. Some have hypothesized that the increase in this dementia-related risk factor is related to the menopausal transition. To untangle the effects of age and menopause, we leveraged a large cross-sectional sample of women from the UK Biobank (n = 9560) to investigate differences in WMH volumes across menopausal status using a strict age-matching procedure. Surprisingly, we find higher WMH volumes in premenopausal women compared to postmenopausal women in certain analysis schemes, especially as compared to surgically postmenopausal women. These results reached significance mostly in analyses where the postmenopausal groups had a longer time since menopause. Our results pertaining to menopause-related characteristics, such as age at menopause or menopause hormonal therapy, did not replicate the literature reporting an association with WMH volumes. Cardiometabolic factors, such as smoking and blood pressure, were significant predictors of WMH volume in the full sample without age-matching. These effects were not significantly different across menopausal status, with the exception of blood pressure medication use, which was associated with higher WMH volumes to a larger extent in premenopausal women relative to postmenopausal women. Our findings are in the opposite direction of reported effects of higher WMH volumes following the menopausal transition, which could be due to variations in age correction techniques or idiosyncrasies in the UK Biobank sample, especially as it relates to the lack of data on perimenopause. We further show that the effects of positive cardiometabolic and lifestyle factors on brain health, as indexed with WMH volumes, generally do not change after menopause. Factors other than the menopausal status may be at play in explaining the difference in WMH burden between men and women in later life.