Jon B. Toledo, Henrik Zetterberg, Argonde C. van Harten, Lidia Glodzik, Pablo Martinez-Lage, Luisella Bocchio-Chiavetto, Lorena Rami, Oskar Hansson, 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

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.