Effect of Apolipoprotein E Allele ε4 on the Initial Phase of Amyloid β-Protein Accumulation in the Human Brain

Deposition of amyloid β-protein (Aβ), a hallmark of Alzheimer's disease, occurs to some extent in the brains of most elderly individuals. We sought to learn when Aβ deposition begins and how deposition is affected by apolipoprotein E allele e4, a strong risk factor for late-onset Alzheimer's disease. Using an improved extraction protocol and specific enzyme-linked immunosorbent assay, we quantified the levels of Aβ40 and Aβ42 in the insoluble fractions of brains from 105 autopsy cases, aged 22 to 81 years at death, who showed no signs of dementia. Aβ40 and Aβ42 were detected in the insoluble fractions from all of the brains examined; low levels were even found in the brains of patients as young as 20 to 30 years of age. The incidence of significant Aβ accumulation increased age-dependently, with Aβ42 levels beginning to rise steeply in some patients in their late 40's, accompanied by much smaller increases in Aβ40 levels. The presence of the apolipoprotein E e4 allele was found to significantly enhance the accumulation of Aβ42 and, to a lesser extent, that of Aβ40. These findings strongly suggest that the presence of e4 allele results in an earlier onset of Aβ42 accumulation in the brain.