Endogenous and Exogenous Estrogen, Cognitive Function, and Dementia in Postmenopausal Women: Evidence from Epidemiologic Studies and Clinical Trials

Elizabeth Barrett-Connor, M.D.; Gail A. Laughlin, Ph.D.

Disclosures

Semin Reprod Med. 2009;27(3):275-282. 

In This Article

Sex Differences in Cognitive Decline and Dementia

Women passing through the menopause transition lose ~90% of their premenopausal estrogen level and typically have blood estrogen levels about one-fourth the usual levels observed in healthy men of the same age. If estrogen is neuroprotective, it might be expected that postmenopausal women would lose cognitive function more rapidly than do men and would have a higher prevalence of dementia than do men of similar age.

Evidence for sex differences in cognitive function decline and dementia is mixed. This is in part because population-based data comparing the cognitive function decline in men and women are mainly cross-sectional. For example, the Rancho Bernardo Study compared 12 tests of cognitive function in 551 men and 800 postmenopausal women, with women stratified by never, past, and current hormone use. In this early study, there was the expected sex difference in cognitive performance, most notably for better verbal test performance (Buschke recall) for women and better visuospatial test performance (Trails B) for men. The slope of decline, however, did not differ for men and women, and among women did not differ by hormone use status.[3]

Results are similar in prospective studies. In a 10-year population-based Norwegian study of 625 adults, sex differences in 11 cognitive function tests did not change over a 10-year follow-up interval.[4] In a 6-year follow-up Dutch study of 155 older adults, there was no sex difference in the decline of cognitive function tests.[5]

The prevalence of dementia is said to be higher in older women than in older men, but it is not clear whether this is due to a true sex difference, or differential survival with fewer men surviving to the ages when dementia is most common, or longer survival of women than men after they develop dementia. As reviewed elsewhere,[6] only 8 of 19 population-based studies of sex differences in dementia published before 2000 tested for statistical significance: four reported a higher prevalence in women and four reported no difference. Of 12 incidence studies, nine included fewer than 20 male cases, and only one study reported a significantly higher incidence among women.

In a study of community-dwelling older adults (aged 65+ years) from East Boston, who had a detailed clinical neurologic examination for dementia, there was no sex difference in the age-adjusted prevalence of dementia (men versus women odds ratio [OR], 1.29; 95% confidence interval [CI], 0.67 to 2.48), incidence of dementia (OR, 0.92; 95% CI, 0.51 to 1.67), or in the twofold increased risk of death in participants with prevalent dementia who were followed for 11 years.[6] The last result is the strongest available evidence that differences in dementia prevalence do not reflect longer survival in women than in men with dementia.

These results contrast with results from a pooled analysis of four European population-based prospective cohort studies of persons aged 65 years and older, with 528 incident cases (with excellent clinical diagnosis of dementia type) and 28,765 person-years of follow-up.[7] In this study, there was a statistically significant excess of Alzheimer's dementia in women compared with men (adjusted relative risk, 1.54; 95% CI, 1.21 to 1.96) but not for vascular dementia (adjusted relative risk, 0.72; 95% CI, 0.47 to 1.09). The authors note that more men than women aged 80 years and older were lost to follow-up (32.2% vs. 26.4%), and that there was an almost doubling of the incidence of Alzheimer's dementia in women between ages 80 and 90 years, not seen in men. It is therefore possible that the observed sex differences reflect sex differences in survival and loss to follow-up.

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