title: Variant Alzheimer's disease with spastic paraparesis and cotton wool plaques is caused by PS-1 mutations that lead to exceptionally high amyloid-beta concentrations.
abstract: We describe 3 new families affected by Alzheimer's disease with spastic paraparesis. In affected individuals, including the earliest known patient with this clinical syndrome, neuropathological examination revealed large "cotton wool" plaques similar to those we have previously described in a Finnish family. In the families in which DNA was available, presenilin-1 mutations were observed. Transfection of cells with these mutant genes caused exceptionally large increases in secreted Abeta42 levels. Furthermore, brain tissue from individuals with this syndrome had very high amyloid-beta concentrations. 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.
authors.affiliation: Department of Clinical Neurology and Neuropathology, Institute of Neurology, London, UK.
authors.forename: H
authors.initials: H
authors.lastname: Houlden
authors.forename: M
authors.initials: M
authors.lastname: Baker
authors.forename: E
authors.initials: E
authors.lastname: McGowan
authors.forename: P
authors.initials: P
authors.lastname: Lewis
authors.forename: M
authors.initials: M
authors.lastname: Hutton
authors.forename: R
authors.initials: R
authors.lastname: Crook
authors.forename: N W
authors.initials: NW
authors.lastname: Wood
authors.forename: S
authors.initials: S
authors.lastname: Kumar-Singh
authors.forename: J
authors.initials: J
authors.lastname: Geddes
authors.forename: M
authors.initials: M
authors.lastname: Swash
authors.forename: F
authors.initials: F
authors.lastname: Scaravilli
authors.forename: J L
authors.initials: JL
authors.lastname: Holton
authors.forename: T
authors.initials: T
authors.lastname: Lashley
authors.forename: T
authors.initials: T
authors.lastname: Tomita
authors.forename: T
authors.initials: T
authors.lastname: Hashimoto
authors.forename: A
authors.initials: A
authors.lastname: Verkkoniemi
authors.forename: H
authors.initials: H
authors.lastname: Kalimo
authors.forename: M
authors.initials: M
authors.lastname: Somer
authors.forename: A
authors.initials: A
authors.lastname: Paetau
authors.forename: J J
authors.initials: JJ
authors.lastname: Martin
authors.forename: C
authors.initials: C
authors.lastname: Van Broeckhoven
authors.forename: T
authors.initials: T
authors.lastname: Golde
authors.forename: J
authors.initials: J
authors.lastname: Hardy
authors.forename: M
authors.initials: M
authors.lastname: Haltia
authors.forename: T
authors.initials: T
authors.lastname: Revesz
mesh_terms: D000544:Alzheimer Disease / Q000150:complications / Q000235:genetics* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000032:analysis*; D005387:Finland; D006801:Humans; D009154:Mutation / Q000235:genetics; D020336:Paraparesis, Spastic / Q000150:complications / Q000235:genetics* / Q000473:pathology*
chemical_list: D016229:Amyloid beta-Peptides