A novel presenilin-1 mutation: increased beta-amyloid and neurofibrillary changes

Ann Neurol. 1997 Jun;41(6):809-13. doi: 10.1002/ana.410410618.


The prevalence of known mutations in presenilin genes (PS1 and PS2) causing early-onset familial Alzheimer's disease (FAD) was assessed in a population of 98 singleton early-onset AD cases, 29 early-onset FAD cases, and 15 late-onset FAD cases. None of the cases tested positive for the eight mutations initially reported, and none of these mutations were observed in 60 age-matched controls. A novel mutation (R269H) in PS1 was found in a single case of early-onset AD but not in any other AD or control case. Thus, the PS mutations tested are quite rare in early-onset AD. Amyloid beta protein (A beta) deposition was investigated in the temporal cortex of the R269H mutation case using end-specific monoclonal antibodies to detect the presence of A beta x-40 and A beta x-42 subspecies. Stereologically unbiased tangle and neuropil thread counts were obtained from the same region. R269H PS1 mutation was associated with early age of dementia onset, higher amounts of total A beta and A beta x-42, and increased neuronal cytoskeletal changes. Thus, if the changes observed on this case prove to be typical of PS1 mutations, PS1 mutations may impact both amyloid deposition and neurofibrillary pathology.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Age of Onset
  • Aged
  • Alzheimer Disease / genetics*
  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology
  • Amyloid beta-Peptides / metabolism*
  • Brain / metabolism
  • Brain / pathology
  • Female
  • Humans
  • Male
  • Membrane Proteins / genetics*
  • Middle Aged
  • Mutation*
  • Neurofibrils / pathology*
  • Presenilin-1


  • Amyloid beta-Peptides
  • Membrane Proteins
  • PSEN1 protein, human
  • Presenilin-1