In the present study, we used CSF soluble TREM2 (sTREM2) as an in vivo marker of TREM2‐related microglial responses in a well‐characterized sample of AD patients and controls to investigate drivers of microglial activation across early versus late‐stage Aβ accumulation in AD and its effects on the development of downstream p‐tau and metabolic brain changes. Here, MAPT is linked to Alzheimer disease.