Amyloid angiopathy and variability in amyloid β deposition is determined by mutation position in presenilin-1-linked Alzheimer's disease

The presenilins (PSs) are components of large molecular complexes that contain β-catenin and function as γ-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 β protein, Aβ₄₂₍₄₃₎, but not Aβ₄₀ 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 Aβ₄₀ in PS-1 Alzheimer's disease varied according to the copy number of ε4 alleles of the Apolipoprotein E gene. Although the amounts of Aβ₄₀ and Aβ₄₂₍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 ε4 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 Aβ 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 Aβ₄₂₍₄₃₎ deposited in the brain correlated with the amount of this produced in culture by cells bearing the equivalent mutations.