Variant Alzheimer's disease with spastic paraparesis and cotton wool plaques is caused by PS-1 mutations that lead to exceptionally high amyloid-betaconcentrations

We describe 3 new families affected by Alzheimer's disease with spastic par aparesis. In affected individuals, including the earliest known patient wit h this clinical syndrome, neuropathological examination revealed large "cot ton wool" plaques similar to those we have previously described in a Finnis h family. In the families in which DNA was available, presenilin-1 mutation s were observed. Transfection of cells with these mutant genes caused excep tionally large increases in secreted A beta 42 levels. Furthermore, brain t issue from individuals with this syndrome had very high amyloid-beta concen trations. These findings define the molecular pathogenesis of an important subgroup of Alzheimer's disease and have implications for the pathogenesis of the disease in general.