title: Early onset familial Alzheimer's disease: Mutation frequency in 31 families.
abstract: BACKGROUND
  Three causative genes have been identified for autosomal dominant AD.
  
  
  OBJECTIVE
  To determine the proportion of patients with early onset AD with a positive family history accounted for by mutations in these genes.
  
  
  METHODS
  A mutational analysis of the amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) genes was performed in 31 probands with probable or definite AD from UK families with an age at onset (AAO) <61 years.
  
  
  RESULTS
  The mean AAO was 46.9 years (median 45 years; range 33 to 60 years). The majority of patients (23 of 31; 74%) fulfilled recognized criteria for autosomal dominant inheritance. In 17 (55%) probands the authors identified eight novel PSEN1 sequence variants and eight recognized pathogenic mutations. In 4 (13%) probands the authors identified one novel APP sequence variant (H677R) and two recognized mutations. Thus in this series 21 of 31 (68%) probands were associated with a sequence variant in APP or PSEN1. Nine of the 11 (82%) probands with neuropathologically confirmed AD who additionally fulfilled recognized criteria for autosomal dominant inheritance were associated with a sequence variant in APP or PSEN1. The 10 patients in whom the authors were unable to identify a mutation in APP, PSEN1, or PSEN2 were older than the probands with sequence variants (55.4 vs 44.7 years: p = 0.001).
  
  
  CONCLUSIONS
  Sequence variants in APP and PSEN1 accounted for the majority of neuropathologically confirmed autosomal dominant early onset AD; no mutations in PSEN2 were detected. There may be a further genetic factor involved in the etiology of autosomal dominant early onset AD.
authors.affiliation: Dementia Research Group, Department of Clinical Neurology, Institute of Neurology, The National Hospital for Neurology and Neurosurgery, London, UK.
authors.forename: J C
authors.initials: JC
authors.lastname: Janssen
authors.forename: J A
authors.initials: JA
authors.lastname: Beck
authors.forename: T A
authors.initials: TA
authors.lastname: Campbell
authors.forename: A
authors.initials: A
authors.lastname: Dickinson
authors.forename: N C
authors.initials: NC
authors.lastname: Fox
authors.forename: R J
authors.initials: RJ
authors.lastname: Harvey
authors.forename: H
authors.initials: H
authors.lastname: Houlden
authors.forename: M N
authors.initials: MN
authors.lastname: Rossor
authors.forename: J
authors.initials: J
authors.lastname: Collinge
mesh_terms: D000328:Adult; D017668:Age of Onset; D000544:Alzheimer Disease / Q000453:epidemiology / Q000235:genetics*; D019943:Amino Acid Substitution; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D053327:Apolipoprotein E4; D001057:Apolipoproteins E / Q000235:genetics; D004252:DNA Mutational Analysis; D005787:Gene Frequency; D005799:Genes, Dominant / Q000235:genetics; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D053764:Presenilin-1; D053766:Presenilin-2; D017384:Sequence Deletion; D006113:United Kingdom / Q000453:epidemiology
chemical_list: D016564:Amyloid beta-Protein Precursor; D053327:Apolipoprotein E4; D001057:Apolipoproteins E; D008565:Membrane Proteins; C508853:PSEN1 protein, human; C508861:PSEN2 protein, human; D053764:Presenilin-1; D053766:Presenilin-2