Untangling age and menopausal status reveals no effect of menopause on white matter hyperintensity volume

Background and objectives White matter hyperintensities (WMHs) are radiological abnormalities indicative of cerebrovascular dysfunction associated with increased risk for cognitive decline and increase in prevalence in older age. However, there are known sex-differences as older females harbour higher WMH burden than males. Some have hypothesized that the increase in this dementia-related risk factor is related to the menopausal transition. Methods To untangle the effects of age and menopause, we leveraged a large sample from the UK Biobank (n = 10,519) to investigate differences in WMH volumes across the menopausal transition using a strict age-matching procedure. Results Surprisingly, we find increased WMH volumes in premenopausal women compared to postmenopausal women when simply correcting for age with linear models, but we find no effect in the age-matched sample. Menopause-related characteristics, such as age at menopause or hormone replacement therapy, did not replicate previous literature reporting an association with WMH volumes. Cardiovascular lifestyle variables, such as smoking and blood pressure, were significant predictors of WMH volume in the full sample without age-matching. These effects varied by menopausal status only for days of moderate activity. Discussion In sum, our findings in a well-powered study suggest that previous reports of menopause-related differences in WMH burden are potentially confounded by age. We further show that the effect of positive lifestyle factors on brain health, as indexed with WMH burden, generally does not change after menopause. Factors other than the menopausal transition are likely at play in explaining the difference in WMH burden between males and females in later life.