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Several lines of evidence suggest that loss of estrogen after menopause may play a role in the cognitive declines associated with Alzheimer's disease (AD). Women with Down syndrome (DS) experience early onset of both menopause and AD. This timing provides a model to examine the influence of endogenous estrogen deficiency on risk of AD. We hypothesized that low serum levels of bioavailable estradiol (E2) would be associated with increased risk of AD. One hundred and nineteen postmenopausal women with DS, 42-59 years of age, were ascertained through the New York State developmental disability service system and followed at 18-month intervals. Information from cognitive assessments, caregiver interviews, medical record review and neurological examination was used to establish the diagnosis of dementia. Women with DS who developed AD had lower levels of bioavailable E2, lower levels of total estradiol, higher levels of sex-hormone binding globulin, and lower levels of dehydroepiandrosterone sulfate at baseline than women who remained dementia free over the course of follow-up. Women who had low levels of bioavailable E2 at baseline were four times as likely to develop AD (HR=4.1, 95% CI: 1.2-13.9) and developed AD, on average, 3 years earlier, than those with high levels of bioavailable E2, after adjustment for age, level of mental retardation, ethnicity, body mass index, history of hypothyroidism or depression and the presence of the apolipoprotein varepsilon4 allele. Our findings support the hypothesis that reductions in estrogen following menopause can contribute to the cascade of pathological processes leading to AD.

Immunonephelometer investigation of specific proteins revealed a difference in levels of immunoglobulin G (IgG) found in the cytosol of estrogen receptor (ER) rich and estrogen receptor poor tumor tissue. Cytosols from estrogen receptor poor tumors had a significantly higher level of IgG than those from estrogen receptor rich tissues. The relationship between progesterone receptor levels and IgG was not as significant as that observed between ER levels and IgG. Other specific proteins did not correlate with either estrogen receptor levels or progesterone levels.