Effect of apolipoprotein E allele ε4 on the initial phase of amyloid β-protein accumulation in the human brain

Deposition of amyloid. beta -protein (A beta), a hallmark of Alzheimer's disease, occurs to some extent in the brains of most elderly individuals. We sought to learn when A beta deposition begins and how deposition is affected by apolipoprotein E allele epsilon4, 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 A beta 40 and A beta 42 in the insoluble fractions of brains from 105 autopsy cases, aged 22 to 81 years at death, who showed no signs of dementia. A beta 40 and A beta 42 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 A beta accumulation increased age-dependently, with A beta 42 levels beginning to rise steeply in some patients in their late 40's, accompanied by much smaller increases in A beta 40 levels. The presence of the apolipoprotein E epsilon4 allele was found to significantly enhance the accumulation of A beta 42 and, to a lesser extent, that of A beta 40. These findings strongly suggest that the presence of epsilon4 allele results in an earlier onset of A beta 42 accumulation in the brain.