An epidemiologic study is proposed to test the hypothesis that reductions in estrogen, indicated by onset of menopause, are associated with onset of Alzheimer's disease (AD) in women with Down syndrome (DS). We further hypothesize that this association will be stronger in women who are genetically susceptible to AD because they carry the apolipoprotein E (apoE) epsilon4 allele. Prior studies in the general population suggest that declines in estrogen levels following menopause play an important role in the etiology AD and that the presence of the apoE epsilon4 allele is associated with earlier age at onset and increased risk of AD. The relationships between onset of menopause, apoE and onset of AD are difficult to study in women in the general population because of the extended time period between menopause and onset of AD. In contrast, women with DS have a very high risk of AD, with an average age at onset of AD between 50-55 years, 10-15 years earlier than in the general population. Thus, women with DS experience onset of AD more closely in time to onset of menopause than is typical in the general population, providing a unique cohort in which to study the relationship between menopause and AD. We hypothesize that earlier age at menopause will be associated with earlier age at onset of AD. We propose a 5-year longitudinal study of incident dementia in 350 women with DS, 45-52 years of age, followed at 18 month intervals. We will ascertain age a menopause by chart review, as menstrual cycles are regularly charted in nursing notes. We will supplement this measure with assays of reproductive hormones at each assessment. We will assess declines in cognitive and adaptive competence indicative of AD using a uniform neuropsychological test battery and neurological examination of those suspected to be affected and a sample of those not suspected, with ascertainment of other medical or psychiatric conditions that might cause dementia. We will use standardized criteria for dementia and the differential diagnosis of AD. We will determine DS karyotypes and apoE genotypes. The results of this study will provide important information about the role of estrogen in the etiology of AD and the optimal strategy for the development of clinical trials of hormone replacement therapy in women with DS.
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