Apolipoprotein E4 promotes the early deposition of Aβ42 and then Aβ40 in the elderly

The apolipoprotein Eɛ4 allele (ApoEɛ4) is associated with a selective increase in deposition of the 40-amino acid form of the β-amyloid peptide (Aβ40) in end-stage Alzheimer’s disease. To determine how apoE genotype affects the early events in β-amyloid pathogenesis, we analyzed the medial temporal lobes of 244 elderly persons who were not clinically demented using antibodies selective for the C termini of Aβ40 and Aβ42. We found that: (1) the number of both Aβ42- and Aβ40-positive senile plaques increase with age; (2) Aβ42 appears at younger ages, and in more amyloid deposits, than does Aβ40 in all ApoE groups; (3) when compared at similar ages, older persons with ApoEɛ4 are more likely to have Aβ42- and Aβ40-immunoreactive deposits than are persons without ApoEɛ4; (4) Aβ40-containing plaques arise at least a decade later than do Aβ42 plaques, and are seldom found in the medial temporal lobe of older persons lacking ApoEɛ4; and (5) in the absence of overt Alzheimer’s disease, cerebral amyloid angiopathy is rare in the elderly, but in our sample was significantly augmented in ApoEɛ4 homozygotes. We conclude that ApoEɛ4 hastens the onset of Aβ42 deposition in the senescent brain, which in turn fosters the earlier evolution of fibrillar, Aβ40-positive plaques, thereby increasing the risk of Alzheimer’s disease.