Frequency of mutations in the presenilin and amyloid precursor protein genes in early-onset Alzheimer disease in Spain

Arch Neurol. 2002 Nov;59(11):1759-63. doi: 10.1001/archneur.59.11.1759.


Background: The relative contribution of mutations in the presenilin (PSEN) and amyloid precursor protein genes to autosomal dominant and other early-onset Alzheimer disease (AD) cases is not well established.

Objectives: To clarify the respective contribution of the amyloid precursor protein and PSEN mutations to autosomal dominant AD and to determine its contribution to sporadic and familial nonautosomal dominant early-onset AD and familial late-onset AD in a referral-based Spanish population.

Subjects and methods: Ninety-four patients with AD (60 with early-onset AD and 34 with late-onset AD) from 82 independent families were studied. According to the family history, patients were classified into the following groups: autosomal dominant, familial nonautosomal dominant, and sporadic. Mutational analysis of the coding regions of the amyloid precursor protein, presenilin 1, and presenilin 2 was performed in all patients. Apolipoprotein E was also genotyped.

Results: Of the 60 early-onset cases, 44 from 36 families had a positive family history (11 with autosomal dominant AD and 25 with familial nonautosomal dominant AD) and 16 were sporadic. The frequency of mutations was 54.6% (6/11) among the autosomal dominant group, 6.2% (1/16) among the sporadic group, and 4% (1/25) among the familial nonautosomal dominant AD group. Most PSEN mutations (92%) would have been detected using a cutoff age of 58 years. The apolipoprotein E epsilon4 allele frequency was increased among early-onset AD without PSEN mutations.

Conclusions: More than half of the families with autosomal dominant early-onset AD can be explained by coding mutations in the PSEN genes. In the familial and sporadic early-onset groups mutations are rare. When family history is unavailable, an age of 58 years may be used as a cutoff point for genetic analysis. The increased apolipoprotein E epsilon4 allele in patients without PSEN mutations confirms that it is an important risk factor in the cause of non-PSEN early-onset AD.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Alzheimer Disease / genetics*
  • Amyloid beta-Protein Precursor / genetics*
  • Apolipoprotein E4
  • Apolipoproteins E / genetics
  • Female
  • Gene Frequency / genetics*
  • Humans
  • Male
  • Membrane Proteins / genetics*
  • Middle Aged
  • Mutation / genetics*
  • Presenilin-1
  • Presenilin-2
  • Spain


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