Amyloid-β peptide (Aβ), the cerebral accumulation of which is thought to cause Alzheimer's disease (AD), is produced throughout life. The level of insoluble Aβ rises with age and is further increased in AD. In contrast, we showed previously that in mid-frontal cortex in a cohort without neurological disease, soluble Aβ declined progressively between 16 and 95 y. We speculated that the divergent changes in the levels of soluble and insoluble Aβ with age might reflect an increasing tendency to favor the production or retention within the brain of Aβ42 over Aβ40, leading to elevation of Aβ42 : 40 even as total soluble Aβ decreased. We have now measured Aβ40 and Aβ42 in soluble and insoluble (guanidine-extractable) fractions of human postmortem brain tissue from the same cohort studied previously. Although in normal brains the absolute level of Aβ40 in both soluble and insoluble fractions and that of Aβ42 in the soluble fraction declined with age, those declines were predominantly before about 50 y, after which Aβ42 : 40 tended to increase in both the soluble and insoluble fractions. Insoluble Aβ42 increased progressively with age. Differential production or retention of Aβ40 and Aβ42 in the over-50 s is likely to contribute to the influence of age on the risk of sporadic AD.