Mean age-of-onset of familial alzheimer disease caused by presenilin mutations correlates with both increased Abeta42 and decreased Abeta40

Hum Mutat. 2006 Jul;27(7):686-95. doi: 10.1002/humu.20336.


The varied ways in which mutations in presenilins (PSEN1 and PSEN2) affect amyloid b precursor protein (APP) processing in causing early-onset familial Alzheimer disease (FAD) are complex and not yet properly understood. Nonetheless, one useful diagnostic marker is an increased ratio of Ab42 to Ab40 (Ab42/Ab40) in patients' brain and biological fluids as well as in transgenic mice and cells. We studied Ab and APP processing for a set of nine clinical PSEN mutations on a novel and highly reproducible enzyme-linked immunosorbent assay (ELISA)-based in vitro method and also sought correlation with brain Ab analyzed by image densitometry and mass spectrometry. All mutations significantly increased Ab42/Ab40 in vitro by significantly decreasing Ab40 with accumulation of APP C-terminal fragments, a sign of decreased PSEN activity. A significant increase in absolute levels of Ab42 was observed for only half of the mutations tested. We also showed that age-of-onset of PSEN1-linked FAD correlated inversely with Ab42/Ab40 (r = -0.89; P = 0.001) and absolute levels of Ab42 (r = -0.83; P = 0.006), but directly with Ab40 levels (r = 0.69; P = 0.035). These changes also partly correlated with brain Ab42 and Ab40 levels. Together, our data suggested that Ab40 might be protective by perhaps sequestering the more toxic Ab42 and facilitating its clearance. Also, the in vitro method we describe here is a valid tool for assaying the pathogenic potential of clinical PSEN mutations in a molecular diagnostic setting.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Age of Onset
  • Alzheimer Disease / diagnosis*
  • Alzheimer Disease / epidemiology
  • Alzheimer Disease / genetics
  • Amyloid beta-Peptides / metabolism*
  • Biomarkers
  • Brain / metabolism
  • Cell Line
  • Densitometry
  • Enzyme-Linked Immunosorbent Assay
  • Humans
  • Membrane Proteins / chemistry
  • Membrane Proteins / genetics*
  • Middle Aged
  • Mutation*
  • Peptide Fragments / metabolism*
  • Presenilin-1
  • Presenilin-2
  • Protein Structure, Tertiary
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization


  • Amyloid beta-Peptides
  • Biomarkers
  • Membrane Proteins
  • PSEN1 protein, human
  • PSEN2 protein, human
  • Peptide Fragments
  • Presenilin-1
  • Presenilin-2
  • amyloid beta-protein (1-40)
  • amyloid beta-protein (1-42)