Association between reproductive factors in women and risk of brain ageing and dementia

AbstractBackgroundWomen have a higher prevalence of dementia than men. We determined the association between female reproductive factors and risk of cognitive outcomes, including incident dementia, in a community‐based sample of cognitively healthy individuals.MethodLifetime reproductive factors including age of menarche, age of menopause, reproductive lifespan (age of menopause minus age of menarche), number of live births, post‐menopausal hormone replacement therapy use, and serum estradiol and estrone concentrations were measured in 796 dementia‐free women [mean age 68.4 (SD 5.7) yr] from the Framingham Heart Study Offspring cohort at examination cycle seven (1998‐2001). We related reproductive factors to subsequent risk of incident dementia. Structural MRI brain measures and neurocognitive test performance were included as secondary outcomes.ResultDuring a median 10 [Q1‐Q3, 8.04‐10.0] year follow‐up, 138 participants developed dementia. On Cox proportional‐hazards analysis adjusting for age and education, a longer reproductive lifespan was associated with a reduced risk of incident dementia (HR 0.94, 95% CI 0.91‐0.98, p = 0.004) while earlier age of menopause of ≤49 vs 50‐51 years was associated with an increased dementia risk (HR 2.56, 95% CI 1.12‐5.88, p = 0.027). Earlier menopause (≤49 versus 50‐51 years) was cross‐sectionally associated with lower hippocampal volume (β±SE, ‐0.123±0.057, p = 0.03). Compared to no live births, 1‐2 live births (5.85±2.03, p = 0.004) and ≥3 live births (5.17±2.06, p = 0.01) were associated with greater total cerebral brain volume. Use of post‐menopausal HRT (0.15±0.055, p = 0.007) and elevated serum estradiol (0.058±0.027, p = 0.03) and estrone concentrations (0.078±0.029, p = 0.006) were cross‐sectionally associated with improved abstract reasoning (Similarities test). Compared to no live births, 1‐2 live births (0.20±0.08, p = 0.018) and ≥3 live births (0.25±0.08, p = 0.003) were also associated with superior visuospatial performance.ConclusionGreater exposure to estrogen throughout a woman’s reproductive life was associated with a lower risk of incident dementia and cross‐sectionally associated with larger brain volumes and enhanced cognitive performance. Our results suggest positive cognitive benefits of greater lifetime estrogen exposure and highlight the potential role of estrogen exposure in modifying the risk of dementia.