APOLIPOPROTEIN-E - HIGH-AVIDITY BINDING TO BETA-AMYLOID AND INCREASED FREQUENCY OF TYPE-4 ALLELE IN LATE-ONSET FAMILIAL ALZHEIMER-DISEASE

Apolipoprotein E is immunochemically localized to the senile plaques, vascular amyloid, and neurofibrillary tangles of Alzheimer disease. In vitro, apolipoprotein E in cerebrospinal fluid binds to synthetic betaA4 peptide (the primary constituent of the senile plaque) with high avidity. Amino acids 12-28 of the betaA4 peptide are required. The gene for apolipoprotein E is located on chromosome 19q13.2, within the region previously associated with linkage of late-onset familial Alzheimer disease. Analysis of apolipoprotein E alleles in Alzheimer disease and controls demonstrated that there was a highly significant association of apolipoprotein E type 4 allele (APOE-epsilon4) and late-onset familial Alzheimer disease. The allele frequency of the APOE-epsilon4 in 30 random affected patients, each from a different Alzheimer disease family, was 0.50 +/- 0.06; the allele frequency of APOE-epsilon4 in 91 age-matched unrelated controls was 0.16 +/- 0.03 (Z = 2.44, P = 0.014). A functional role of the apolipoprotein E-E4 isoform in the pathogenesis of late-onset familial Alzheimer disease is suggested.