Apolipoprotein E4 promotes the early deposition of A beta 42 and then A beta 40 in the elderly

The apolipoprotein E epsilon 4 allele (ApoE epsilon 4) is associated with a selective increase in deposition of the 40-amino acid form of the beta-amy loid peptide (A beta 40) in endstage Alzheimer's disease. To determine how apoE genotype affects the early events in beta-amyloid pathogenesis, we ana lyzed the medial temporal lobes of 244 elderly persons who were not clinica lly demented using antibodies selective for the C termini of A beta 40 and A beta 42. We found that: (I) the number of both A beta 42- and A beta 40-p ositive senile plaques increase with age; (2) A beta 42 appears at younger ages, and in more amyloid deposits, than does A beta 40 in all ApoE groups; (3) when compared at similar ages, older persons with ApoE epsilon 4 are m ore likely to have A beta 42- and A beta 40-immunoreactive deposits than ar e persons without ApoE epsilon 4; (4) A beta 40-containing plaques arise at least a decade later than do A beta 42 plaques, and are seldom found in th e medial temporal lobe of older persons lacking ApoE epsilon 4; and (5) in the absence of overt Alzheimer's disease, cerebral amyloid angiopathy is ra re in the elderly, but in our sample was significantly augmented in ApoE ep silon 4 homozygotes. We conclude that ApoE epsilon 4 hastens the onset of A beta 42 deposition in the senescent brain, which in turn fosters the earli er evolution of fibrillar, A beta 40-positive plaques, thereby increasing t he risk of Alzheimer's disease.