Dementia of the Alzheimer's type (DAT) is the most common form of dementia in the elderly. The etiology of DAT is a combination of genetic and environmental factors. Forty-five to fifty-five per cent of the total genetic risk. in DAT has been pegged to four genes (APP, PS1, PS2, APOE) with by far the greatest proportion explained by the APOE-4 allele. However, additional novel genes remain to be identified and would be most easily identified in large families having a low frequency of the APOE-4 allele. Large families are extremely valuable because they can provide identity-by-descent data across many affected individuals. Unfortunately the late-onset nature of DAT makes family histories difficult to trace and the geographic dispersion of families in the United States often results in lost contact between distant familial branches. While pervasive these problems are not universal, with certain cultural and religious isolates, such as the Amish, having large and stable families. The Amish present numerous advantages for study, including recent derivation from a small number of founder couples, large family size, extensive genealogical records, few marriages outside the Amish communities, and stable social and environmental influences. Over the past six years, we have successfully approached and studied several Amish families with DAT in Indiana/Michigan and Ohio. Our initial studies of the Indiana/Michigan Amish have shown a lower frequency of the APOE-4 allele yet strong clustering of DAT cases in families, suggesting that genetic factors other than APOE are at work. At the same time, progress in completing the human genome sequence and in developing molecular and statistical tools has opened many new avenues for gene identification. We wish to avail ourselves of these strengths to map the DAT genes in the Amish families.
Our specific aims are to: 1). Ascertain every Amish DAT family in Adams and surrounding counties of Indiana/Michigan and Holmes and surrounding counties of Ohio with the goal of identifying all DAT cases; 2). Screen the Amish pedigrees for genetic linkage to known loci and perform a genomic screen; 3). Perform fine mapping to identify the minimal candidate region and use SNPs to identify the underlying genes; and 4). Develop new methods to examine gene-gene interactions in large and complex pedigrees such as those found in the Amish.
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