Contributions of environmental versus genetic factors in Alzheimer's disease (AD) are not well understood. Our goal is to test two hypotheses regarding possible genetic etiologies. First, we will examine the role of mutations in the gene for the beta amyloid precursor protein (APP) in case of AD which appear to be sporadic. Our rationale is that this gene has previously been shown to be mutated in rare familial cases. Mutations with more subtle effects on biological activities of APP could convey a predisposition to AD without manifesting sufficient penetrance to produce a familial pattern. We will use polymerase chain reaction (PCR) amplification followed by single strand conformation polymorphism (SSCP) analysis to rapidly screen for base pair alterations in the APP coding region and promoter region in a large population study. The significance of mutations will be evaluated both by biological experiments in vitro and by a statistical analysis of the association of the specific types of mutations with AD in family members of the probands and in the study population as a whole. Second, we will test the possibility that mitotic nondisjunctions leading to low level mosaicism for trisomy 21 might play a role in AD. The frequency of trisomic cells in peripheral blood from living donors and brains from autopsies will be established by in situ hybridization with chromosome-specific probes. If measurable frequencies of trisomic cells are found, we will examine the correlation of the trisomy index (number of trisomic cells/number of disomic cells) with AD, both in terms of likelihood and age of onset of disease. We will also analyze cases of classical mosaic Down's syndrome to ask whether the trisomy index in these cases correlates with the age of onset of dementia.
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