How and when does amyloid beta-protein accumulate in the brain? We sought to learn about when and how amyloid beta-protein (A beta) accumulates in the cortex of normal individuals and about the difference in the A beta accumulation between normal aged and Alzheimer's disease brains. From consecutive autopsy cases (n = 76; age range: 24-92 years) and confirmed Alzheimer's disease cases (n = 7; age range: 60-79 years), hippocampus CA1 and occipitotemporal cortex T4 were sampled for A beta quantitation. The A beta 42 level increased steeply from age 50 to age 70 years in T4 and a little later in CA1. It was consistently higher in T4 than those in CA1 in a given case. There was a critical level of A beta 42 below which no senile plaques were detected. In the Alzheimer's disease brains the A beta 42 levels were significantly higher, and the extents of A beta 42 amino-terminal modifications were also much greater, than those in the control brains. In contrast to A beta 42, A beta 40 showed no age-dependent accumulation and its level was increased in most of the Alzheimer's disease brains. A beta 40 appears to invariably accumulate in the cortex during aging, and to a greater extent in Alzheimer's disease. Increased A beta 40 levels are associated with most Alzheimer's disease cases. An early onset of A beta 42 accumulation may lead to development of Alzheimer's disease late in life and increased levels of A beta 40 may be involved in acceleration of development of the disease.