Early onset familial Alzheimer's disease: Mutation frequency in 31 families

Neurology. 2003 Jan 28;60(2):235-9. doi: 10.1212/01.wnl.0000042088.22694.e3.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Age of Onset
  • Alzheimer Disease / epidemiology
  • Alzheimer Disease / genetics*
  • Amino Acid Substitution
  • Amyloid beta-Protein Precursor / genetics*
  • Apolipoprotein E4
  • Apolipoproteins E / genetics
  • DNA Mutational Analysis
  • Gene Frequency
  • Genes, Dominant / genetics
  • Heterozygote
  • Homozygote
  • Humans
  • Membrane Proteins / genetics*
  • Middle Aged
  • Mutation*
  • Presenilin-1
  • Presenilin-2
  • Sequence Deletion
  • United Kingdom / epidemiology

Substances

  • Amyloid beta-Protein Precursor
  • Apolipoprotein E4
  • Apolipoproteins E
  • Membrane Proteins
  • PSEN1 protein, human
  • PSEN2 protein, human
  • Presenilin-1
  • Presenilin-2