The long term goal of our investigations is to isolate the defective gene responsible for the autosomal dominantly inherited for of Alzheimer disease based on its chromosomal localization. The specific funding requested here will potentially expedite this goal by directly identifying and characterizing alterations in the level of expression of specific chromosome 21 genes in Alzheimer brain tissue. Familial Alzheimer's Disease (FAD) represents a subtype of Alzheimer's Disease (AD), in which the underlying cause is known to be a defect in an autosomal gene. The successful isolation and characterization of the FAD mutant gene and its normal homologue, could lead to a better understanding of the biochemical basis FAD. Recent epidemiological surveys have revealed that """"""""sporadic"""""""" cases of AD may also have a similar, but incompletely penetrant gene defect, suggesting that the discovery of the FAD gene might also provide insight into the pathogenesis of the more common form of AD. We have recently shown that at least one type of FAD is caused by a mutant gene in the proximal region of the chromosome 21 long arm. The nature of the genetic defect remains unknown, but does not involve a mutation in the gene encoding beta amyloid, which is also on chromosome 21. The similarity in neuropathology between elderly patients with trisomy 21 and patients with either type of AD suggests that AD could result from overexpression of a gene on chromosome 21. Consequently, we propose to search cDNA libraries from both sporadic and FAD brains for genes encoded on chromosome 21 which show abnormal levels of expression in AD brain. cDNA clones which are encoded on chromosome 21, and which exhibit evidence of differential expression on direct colony screening will be further examined to determine true differences in MRNA quantity or size on Northern blots, and will be assessed for genetic linkage to FAD in currently available large FAD pedigrees. This proposal, when combined with on-going linkage and genomic cloning strategies, may provide a potential short cut to the discovery of the actual FAD gene.

National Institute of Health (NIH)
National Institute on Aging (NIA)
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Mc Lean Hospital (Belmont, MA)
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