title: The impact of different presenilin 1 andpresenilin 2 mutations on amyloid deposition, neurofibrillary changes and neuronal loss in the familial Alzheimer's disease brain: evidence for other phenotype-modifying factors.
abstract: To assess the influence of the presenilin 1 (PS1) and 2 (PS2) mutations on amyloid deposition, neurofibrillary tangle (NFT) formation and neuronal loss, we performed stereologically based counts in a high-order association cortex, the superior temporal sulcus, of 30 familial Alzheimer's disease cases carrying 10 different PS1 and PS2 mutations, 51 sporadic Alzheimer's disease cases and 33 non-demented control subjects. All the PS1 and PS2 mutations assessed in this series led to enhanced deposition of total Abeta and Abeta(x-42/43) but not Abeta(x-40) senile plaques in the superior temporal sulcus when compared with brains from sporadic Alzheimer's disease patients. Some of the PS1 mutations studied (M139V, I143F, G209V, R269H, E280A), but not others, were also associated with faster rates of NFT formation and accelerated neuronal loss in the majority of the patients who harboured them when compared with sporadic Alzheimer's disease patients. In addition, our analysis showed that dramatic quantitative differences in clinical and neuropathological features can exist even among family members with the identical PS mutation. This suggests that further individual or pedigree genetic or epigenetic factors are likely to modulate PS phenotypes strongly.
authors.affiliation: Neurology Service, Massachusetts General Hospital, Neurology Service, Brigham and Women's Hospital, Boston, USA. gomez010@tc.umn.edu
authors.forename: T
authors.initials: T
authors.lastname: Gómez-Isla
authors.forename: W B
authors.initials: WB
authors.lastname: Growdon
authors.forename: M J
authors.initials: MJ
authors.lastname: McNamara
authors.forename: D
authors.initials: D
authors.lastname: Nochlin
authors.forename: T D
authors.initials: TD
authors.lastname: Bird
authors.forename: J C
authors.initials: JC
authors.lastname: Arango
authors.forename: F
authors.initials: F
authors.lastname: Lopera
authors.forename: K S
authors.initials: KS
authors.lastname: Kosik
authors.forename: P L
authors.initials: PL
authors.lastname: Lantos
authors.forename: N J
authors.initials: NJ
authors.lastname: Cairns
authors.forename: B T
authors.initials: BT
authors.lastname: Hyman
mesh_terms: D017668:Age of Onset; D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D019943:Amino Acid Substitution; D000682:Amyloid / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000032:analysis / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D016874:Neurofibrillary Tangles / Q000473:pathology*; D009474:Neurons / Q000473:pathology*; D010641:Phenotype; D058225:Plaque, Amyloid / Q000473:pathology; D017354:Point Mutation; D053764:Presenilin-1; D053766:Presenilin-2; D012044:Regression Analysis; D013702:Temporal Lobe / Q000378:metabolism* / Q000473:pathology*
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D008565:Membrane Proteins; C508853:PSEN1 protein, human; C508861:PSEN2 protein, human; D053764:Presenilin-1; D053766:Presenilin-2