The association between reproductive factors and neurocognitive and neuroimaging markers of brain aging

Background Women have a higher risk of dementia than men. Reproductive factors may be implicated. Objective Determine the association between reproductive factors (earlier menarche, later menopause, longer reproductive lifespan (RLS), post-menopausal hormone replacement therapy [pmHRT] use, and serum estradiol/estrone) and neurocognitive and neuroimaging markers of brain aging and incident dementia in cognitively healthy women. Methods Lifetime reproductive factors were measured in dementia-free women [mean age 60.3 (SD 9.3) year] from the Framingham Heart Study Offspring cohort between 1998–2001 and related to concurrent neurocognitive (n = 1329) and MRI brain measures (n = 1165) using multivariable linear regression and risk of incident dementia (secondary outcome, n = 921) using Cox proportional hazards regression. Results Use of pmHRT (Beta (β, standardized regression coefficient)±standard error (SE), 0.14 ± 0.05, p = 0.009), elevated serum estradiol (0.06 ± 0.03, p = 0.02) and earlier menarche (≥14 years versus 12–13 years, −0.13 ± 0.06, p = 0.03) were associated with better abstract reasoning (Similarities). Older age at menopause (≥52 years versus the referent 50–51 years) (0.18 ± 0.09, p = 0.04), elevated serum estradiol (0.06 ± 0.03, p = 0.02), and 1–2 (0.17 ± 0.08, p = 0.03) or ≥3 (0.22 ± 0.08, p = 0.007) versus no live births were associated with superior visuospatial performance (Hooper's visual organization test). Earlier menopause age was associated with lower hippocampal volume (≤49 years versus 50–51 years, −0.11 ± 0.04, p = 0.02) while 1–2 (5.50 ± 1.95, p = 0.005) and ≥3 live births (β±SE, 4.94 ± 1.96, p = 0.01) were associated with greater total cerebral brain volume. Conclusions In general, greater exposure to estrogen throughout a woman's reproductive lifespan was associated with enhanced cognitive performance and larger brain volumes. Our results may suggest positive cognitive benefits of greater lifetime estrogen exposure, but require further validation.