This study will investigate genetic risk factors for dementia in individuals with Down syndrome (DS) and their relatives. The brains of virtually all adults with Down syndrome show high densities of senile plaques and neurofibrillary tangles characteristic of the pathological changes of Alzheimer disease (AD), and individuals with DS are at increased risk for clinical dementia. A shared genetic susceptibility to DS and AD is supported by the findings of increased prevalence of DS births to women who themselves have AD or whose relatives have AD, by findings of increased frequency of AD in relatives of individuals with DS, and by linkage of early-onset familial AD to chromosome 21. The gene for beta-amyloid precursor protein (APP) has been localized to chromosome 21 and the early occurrence of AD pathology in adults with DS has been attributed to increased expression of beta-amyloid. However, not all individuals with DS and AD pathology dement. Mosaicism for trisomy 21 may be associated with reduced expression of beta-amyloid and later age of onset of AD. In addition, mutations in the gene for APP have been shown to cosegregate with AD in several families with early onset AD. We will determine if these or related mutations in the APP gene are associated with increased expression of clinical dementia in individuals with Down syndrome or with a history of early-onset AD in their families. Subjects for this study will be drawn from a larger ongoing study of the familial aggregation of Down syndrome and Alzheimer disease. We will study the first 150 individuals with DS and their parents. Data from the larger study will provide information on the occurrence of AD and related disorders in first- and second-degree relatives of DS probands, on the medical status and functional skills level of DS probands and on the occurrence of clinically significant regression in DS probands consistent with a diagnosis of dementia. We will determine DS karyotype (trisomy, translocation, mosaicism) and estimate the age-specific prevalence of mosaicism for trisomy 21. We will determine whether the risk for dementia and age of onset of dementia is correlated with the level of mosaicism. We will screen all individuals with DS and their parents for mutations in the coding region and promoter sequences of the APP gene and estimate the prevalence of APP mutations. We will determine whether increased risk for clinical dementia in adults with DS is associated with APP mutations by comparing DS cases with and without mutations in terms of the lifetime cumulative incidence of dementia. We will determine whether increased risk for AD in relatives of DS probands is associated with APP mutations by comparing DS cases with and without mutations in the APP gene in terms of the cumulative incidence of AD in their first- and second-degree relatives.
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