NOVEL AMYLOID PRECURSOR PROTEIN GENE MUTATION (CODON 665(ASP)) A PATIENT WITH LATE-ONSET ALZHEIMERS-DISEASE

Amyloid plaques in Alzheimer's disease contain beta-amyloid, encoded b y portions of exons 16 and 17 of the amyloid precursor protein. The sp ecific association of rare amyloid precursor protein mutations with so me kindreds with early-onset familial Alzheimer's disease suggests tha t specific abnormalities in amyloid precursor protein may contribute t o the pathogenesis of Alzheimer's disease. Until now, there has been n o evidence suggesting that amyloid precursor protein mutations could b e involved in late-onset or sporadic Alzheimer's disease. We used reve rse transcription-polymerase chain reaction, denaturing gradient gel e lectrophoresis, and direct DNA sequencing to analyze amyloid precursor protein exons 16 and 17 from postmortem cerebellar samples from patie nts with histologically confirmed Alzheimer's disease and control subj ects. We found a novel point mutation, substitution of cytosine for gu anine, at nucleotide 2119 (amyloid precursor protein 770 messenger RNA transcript) in a patient with late-onset Alzheimer's disease. This su bstitution deletes a BglII site and substitutes aspartate for glutamin e at codon 665. Denaturing gradient gel electrophoresis analysis showe d that this mutation was absent in 40 control subjects and 127 dementi a patients. Whether this mutation is a rare but normal variant or cont ributes to the development of Alzheimer's disease is not known. The Bg lII restriction fragment length polymorphism enables investigators to determine the frequency of this polymorphism in normal subjects and Al zheimer's disease patients.