title: Alzheimer's disease due to an intronic presenilin-1 (PSEN1 intron 4) mutation: A clinicopathological study.
abstract: We describe 21 affected individuals from a kindred with early-onset autosomal dominant familial Alzheimer's disease caused by an intronic presenilin-1 mutation (in intron 4). Mean age at onset of symptoms was 37.4 years [95% confidence interval (CI): 36.6-38.2 years], mean age at death was 44.7 years (95% CI: 43.1-46.3 years) and mean duration of illness was 7.3 years (95% CI: 5.9-8.7 years). Myoclonus and seizures were prominent features of this pedigree. In the four cases for whom neuropsychometric data were available, verbal memory impairment preceded visual memory deficits; naming was relatively preserved until late in the disease. One of these four cases underwent serial volumetric MRI scans demonstrating in vivo brain tissue loss of 3.9% (38.9 ml, annualized rate of atrophy: 1. 7%) over 22 months of follow-up. The four individuals who had necropsies demonstrated the neuropathological hallmarks of Alzheimer's disease. Apolipoprotein E (APOE) status was assessed in five individuals: the case with the youngest age at onset at 33 years of age was found to be homozygous epsilon4/epsilon4, > 1 SD below the mean age of onset for those of known APOE genotype (36.4 +/- 2.3 years, mean +/- SD), and > 2 SDs below the mean age of onset for the pedigree as a whole (37.4 +/- 1.7 years, mean +/- SD). APOE genotype may therefore modulate age at onset in this pedigree.
authors.affiliation: Dementia Research Group, Institute of Neurology, London, UK.
authors.forename: J C
authors.initials: JC
authors.lastname: Janssen
authors.forename: M
authors.initials: M
authors.lastname: Hall
authors.forename: N C
authors.initials: NC
authors.lastname: Fox
authors.forename: R J
authors.initials: RJ
authors.lastname: Harvey
authors.forename: J
authors.initials: J
authors.lastname: Beck
authors.forename: A
authors.initials: A
authors.lastname: Dickinson
authors.forename: T
authors.initials: T
authors.lastname: Campbell
authors.forename: J
authors.initials: J
authors.lastname: Collinge
authors.forename: P L
authors.initials: PL
authors.lastname: Lantos
authors.forename: L
authors.initials: L
authors.lastname: Cipolotti
authors.forename: J M
authors.initials: JM
authors.lastname: Stevens
authors.forename: M N
authors.initials: MN
authors.lastname: Rossor
mesh_terms: D000328:Adult; D017668:Age of Onset; D000544:Alzheimer Disease / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D001057:Apolipoproteins E / Q000235:genetics; D001921:Brain / Q000473:pathology*; D016001:Confidence Intervals; D005260:Female; D006801:Humans; D007438:Introns; D008279:Magnetic Resonance Imaging; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D016874:Neurofibrillary Tangles / Q000473:pathology; D009483:Neuropsychological Tests; D010375:Pedigree; D058225:Plaque, Amyloid / Q000473:pathology; D053764:Presenilin-1
chemical_list: D001057:Apolipoproteins E; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1