Sample demographics of menopausal hormone therapy (MHT) never-, current, and past-users in the whole sample.

Sample demographics of menopausal hormone therapy (MHT) users with and without a history of hysterectomy +/-bilateral oophorectomy in the whole sample.

Sample demographics of menopausal hormone therapy (MHT) users with prescription data, stratified by estrogen only MHT or combined MHT use.

Correlations (Pearson’s r) between white matter (WM) and grey matter (GM) brain age gap (BAG) as well as left and right hippocampal volumes and total white matter hyperintensity (WMH) volume.

BAG measures are adjusted for age63. WM BAG, GM BAG and hippocampal volumes were available for 20,360 individuals, and 19,538 had data on WMH volume.

Associations between brain MRI measures and MHT user status.

Point plot of estimated marginal means with standard errors from separate regression models with brain measure as dependent variable and MHT user status as independent (categorical) variable, with never-users as a reference group. Brain measures include white matter (WM) and grey matter (GM) brain age gap (BAG) as well as left and right hippocampal volumes and total white matter hyperintensity (WMH) volume. The models were adjusted for age, education, body mass index, lifestyle score, and menopausal status. All variables were standardized prior to performing the regression analysis (subtracting the mean and dividing by the standard deviation). Stars indicate significant associations. Significance codes: 0 ‘***’ 0.001 ‘**’ 0.01 ‘*’.

Associations between brain MRI measures and history of hysterectomy and/or bilateral oophorectomy in MHT users.

Point plot of estimated marginal means with standard errors from separate regression analysis with MRI measure as dependent variable and history of hysterectomy and/or bilateral oophorectomy as independent (categorical) variable. MHT users without such surgical history served as a reference group. Brain measures include white matter (WM) and grey matter (GM) brain age gap (BAG) as well as left and right hippocampal volumes and total white matter hyperintensity (WMH) volume. The models were adjusted for age, education, body mass index, lifestyle score, and menopausal status. All variables were standardized prior to performing the regression analysis (subtracting the mean and dividing by the standard deviation). Stars indicate significant associations. Significance codes: 0 ‘***’ 0.001 ‘**’ 0.01 ‘*’.

Associations between APOE ε4 genotype and brain MRI measures.

Point plot of standardized beta-values with standard errors from separate multiple regression analysis with MRI measure as dependent variable and APOE ε4 genotype as independent variable. Non-carrier served as a reference group (n = 10,787). APOE ε4 (all, n = 3935) represents the ε3/ε4 (n = 3572) and ε4/ε4 carriers (n = 363) grouped together. For WMH, the sample sizes were as follows: non-carrier (n = 10,377), APOE ε4 (all, n = 3410), ε3/ε4 (n = 3410) and ε4/ε4 carriers (n = 349). Brain measures include white matter (WM) and grey matter (GM) brain age gap (BAG) as well as left and right hippocampal volumes and total white matter hyperintensity (WMH) volume. The models were adjusted for age, education, body mass index, lifestyle score, and menopausal status. All variables were standardized prior to performing the regression analysis (subtracting the mean and dividing by the standard deviation). Stars indicate significant associations. Significance codes: 0 ‘***’ 0.001 ‘**’ 0.01 ‘*’.