We found no evidence to support the theory that natural variation in cumulative exposure to endogenous estrogens across the reproductive period influences the incidence of dementia in late life. Any beneficial effect on cognitive reserve is likely to be very small, and may arise from confounding by shared developmental antecedents. The case for post-menopausal hormone replacement is currently controversial, with conflicting evidence, and some clear risks associated with longer-term use. Nevertheless, the concept of a ‘critical window’ in the immediate post-menopausal period has been widely discussed, during which estrogen replacement therapy may be both less risky, and more beneficial to cognition. Our study provides only indirect evidence to inform this debate, since our focus was upon pre-menopausal endogenous exposure. However, associations with indicators of endogenous exposure are routinely presented as ‘proof of concept’ for the estrogen hypothesis, and this evidence is significantly weakened by the current study.