The presenilins (PSs) are components of large molecular complexes that contain beta-catenin and function as gamma-secretase. We report here a striking correlation between amyloid angiopathy and the location of mutation in PS-1 linked Alzheimer's disease. The amount of amyloid beta protein, Abeta(42(43)), but not Abeta(40,) deposited in the frontal cortex of the brain is increased in 54 cases of early-onset familial Alzheimer's disease, encompassing 25 mutations in the presenilin-1 (PS-1) gene, compared to sporadic Alzheimer's disease. The amount of Abeta(40) in PS-1 Alzheimer's disease varied according to the copy number of epsilon4 alleles of the Apolipoprotein E gene. Although the amounts of Abeta(40) and Abeta(42(43)) deposited did not correlate with the genetic location of the mutation in a strict linear sense, the histological profile did so vary. Cases with mutations between codon 1 and 200 showed, in frontal cortex, many diffuse plaques, few cored plaques, and mild or moderate amyloid angiopathy. Cases with mutations occurring after codon 200 also showed many diffuse plaques, but the number and size of cored plaques were increased (even when epsilon4 allele was not present) and these were often clustered around blood vessels severely affected by amyloid angiopathy. Similarly, diverging histological profiles, mainly according to the degree of amyloid angiopathy, were seen in the cerebellum. Mutations in the PS-1 gene may therefore alter the topology of the PS-1 protein so as to favor Abeta formation and deposition, generally, but also to facilitate amyloid angiopathy particularly in cases in which the mutation lies beyond codon 200. Finally we report that the amount of Abeta(42(43)) deposited in the brain correlated with the amount of this produced in culture by cells bearing the equivalent mutations.