Molecular genetics of Alzheimer's disease and the amyloid beta peptide precursor gene.

Alzheimer's disease is a neurodegenerative disorder characterized by global cognitive decline. An autopsy of the Alzheimer patient's brain reveals two major neuropathological lesions: neurofibrillary tangles, and amyloid deposits in the form of senile plaques and cerebrovascular accumulations. While tangles appear to be a universal hallmark of dying neurons in several neurodegenerative diseases, amyloid plaques occur in only three conditions including Alzheimer's disease, Down syndrome, and to a limited extent, normal aging. The frequency of senile plaques appears to correlate well with the degree of dementia in the Alzheimer's patient. It remains unclear, however, whether amyloid formation represents one of the final stages of a long neuropathological process in the brain, or initially participates in promoting neuronal dysfunction. To address this question, we have isolated the gene encoding the precursor of the principle component of the plaque, the amyloid beta peptide. We have mapped this gene to chromosome 21, the same chromosome in which we have detected linkage between anonymous DNA markers and the familial form of Alzheimer's disease. Employing direct genetic linkage analysis, we have shown that the amyloid gene and the familial Alzheimer's disease gene represent two separate and distinct genetic loci. Here we present further information on the location of the familial Alzheimer's disease gene on chromosome 21. We also discuss the recent discovery of an alternate form of the amyloid beta peptide precursor gene which encodes a serine protease inhibitor in the Kunitz family. The presence of a protease inhibitor domain within the amyloid beta peptide precursor, itself, has profound implications for its possible role in the process of amyloid formation.(ABSTRACT TRUNCATED AT 250 WORDS)