This approach indicated that the earliest AD biomarker change was a gradual decline of free Aβ42 monomers in CSF due to their aggregation into oligomers and plaques in the brain, followed by an increase of microglial-produced soluble TREM2 [54], the detection by PET of fibrous amyloid plaques, and somewhat later, decreased cerebral metabolism (visible using fluorodeoxyglucose-PET scans) and progressive cerebral atrophy (as seen on MRI scans). Here, TREM2 is linked to Alzheimer disease.