We found that SMOC1 and SPON1—two proteins from the M42 matrisome AD brain coexpression module related to brain Aβ deposition—were elevated in AD CSF nearly 30 years before the onset of symptoms, and before a significant decrease in CSF Aβ42 levels or Aβ42/40 ratio, increase in PIB binding or increase in levels of different pTau species related to Aβ plaque formation. This evidence concerns the gene SPON1 and Alzheimer disease.