Alzheimer's disease cerebrospinal fluid biomarker in cognitively normal subjects.

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In a large multicentre sample of cognitively normal subjects, as a function of age, gender and APOE genotype, we studied the frequency of abnormal cerebrospinal fluid levels of Alzheimer's disease biomarkers including: total tau, phosphorylated tau and amyloid-β1-42. Fifteen cohorts from 12 different centres with either enzyme-linked immunosorbent assays or Luminex® measurements were selected for this study. Each centre sent nine new cerebrospinal fluid aliquots that were used to measure total tau, phosphorylated tau and amyloid-β1-42 in the Gothenburg laboratory. Seven centres showed a high correlation with the new Gothenburg measurements; therefore, 10 cohorts from these centres are included in the analyses here (1233 healthy control subjects, 40-84 years old). Amyloid-β amyloid status (negative or positive) and neurodegeneration status (negative or positive) was established based on the pathological cerebrospinal fluid Alzheimer's disease cut-off values for cerebrospinal fluid amyloid-β1-42 and total tau, respectively. While gender did not affect these biomarker values, APOE genotype modified the age-associated changes in cerebrospinal fluid biomarkers such that APOE ε4 carriers showed stronger age-related changes in cerebrospinal fluid phosphorylated tau, total tau and amyloid-β1-42 values and APOE ε2 carriers showed the opposite effect. At 40 years of age, 76% of the subjects were classified as amyloid negative, neurodegeneration negative and their frequency decreased to 32% at 85 years. The amyloid-positive neurodegeneration-negative group remained stable. The amyloid-negative neurodegeneration-positive group frequency increased slowly from 1% at 44 years to 16% at 85 years, but its frequency was not affected by APOE genotype. The amyloid-positive neurodegeneration-positive frequency increased from 1% at 53 years to 28% at 85 years. Abnormally low cerebrospinal fluid amyloid-β1-42 levels were already frequent in midlife and APOE genotype strongly affects the levels of cerebrospinal fluid amyloid-β1-42, phosphorylated tau and total tau across the lifespan without influencing the frequency of subjects with suspected non-amyloid pathology.


  • Jon B Toledo
  • Henrik Zetterberg
  • Argonde C van Harten
  • Lidia Glodzik
  • Pablo Martinez-Lage
  • Luisella Bocchio-Chiavetto
  • Lorena Rami
  • Reisa Sperling
  • Sebastiaan Engelborghs
  • Ricardo S Osorio
  • Hugo Vanderstichele
  • Manu Vandijck
  • Harald Hampel
  • Stefan Teipl
  • Abhay Moghekar
  • Marilyn Albert
  • William T Hu
  • Jose A Monge Argilés
  • Ana Gorostidi
  • Charlotte E Teunissen
  • Peter P De Deyn
  • Bradley T Hyman
  • Jose L Molinuevo
  • Giovanni B Frisoni
  • Gurutz Linazasoro
  • Mony J de Leon
  • Wiesje M van der Flier
  • Philip Scheltens
  • Kaj Blennow
  • Leslie M Shaw
  • John Q Trojanowski
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Neurology
Original languageEnglish
Pages (from-to)2701-2715
Issue numberJul 27
Publication statusPublished - 2015
Publication categoryResearch