Age at natural menopause and memory function: Modification by education and genotype

Meta analyses show that positive effects of estrogen treatment on cognition are most apparent in women who have recently undergone surgical menopause. Observational data suggested that a) undergoing surgical menopause at an early age increases dementia risk; b) if surgically menopausal women are treated with hormones up to the natural age of menopause, risk for dementia is reduced; c) however, if estrogen treatment is continued up to a decade after induced menopause, there may be a risk of worse cognitive function when compared to not having had estrogen treatment.We analyzed the association between a natural early age at menopause and cognitive tests sensitive to dementia, including genetic risk factors which could mediate the association between age at menopause and cognition in 173 Indonesian postmenopausal women, who had not undergone ovariectomy and were not using hormone treatment.Age at menopause at 50 years or over was associated with better memory (beta=0.15, p=0.03) and better global cognition (beta=.22, p=0.002) in linear regression analyses, although education explained this association fully. However, worse memory was associated with an early age at menopause of 47 years or younger independent of confounds and mediators. ESR1 genotypes associated with age at menopause and dementia in other studies did not mediate these relationships. However, the P allele of the ESR1 PvuII polymorphism was associated with better memory function (p<0.05). Data suggested the converse may be the case for older (>65 years of age) women.These data link in with cell culture, treatment and observational studies suggesting that estrogen and estrogen sensitivity (ESR1 PvuII P allele) may confer protective effects on cognition in midlife, but not in elderly women. Whether and how long women who undergo an early natural or surgical menopause should be treated with hormones to maintain optimal cognitive function in old age needs further study (300 words).