Longitudinal increase of CSF soluble TREM2 is driven by early aggregation of Aβ42 and associates with slower amyloid deposition and clinical decline in autosomal-dominant Alzheimer’s disease
Abstract Therapeutic modulation of TREM2-dependent microglial function provides an additional strategy to slow progression of Alzheimer disease (AD). Although studies on animal models suggest that TREM2 is protective, the trigger of increased TREM2 expression during disease progression and its clinical and pathological consequences in AD remain unclear. We measured longitudinally soluble TREM2 (sTREM2) as a surrogate marker for protective TREM2-signalling in cerebrospinal fluid (CSF) from participants in the Dominantly Inherited Alzheimer Network (DIAN) observational study. In mutation carriers (MC), the longitudinal sTREM2 increase followed the earliest aggregation of Aβ42 captured by CSF-Aβ42 decrease, but not yet by Pittsburg compound-B Positron Emission Tomography (PiB-PET). Higher sTREM2 increase rates provided protection from Aβ-deposition, whereas lower rates enhanced p-tau increase associated with PiB-PET increase. Moreover, presymptomatic MC with high or low sTREM2 increase rates have opposite associations between CSF Aβ42 and PiB-PET longitudinal changes, suggesting that TREM2 modifies Aβ plaque deposition and compaction. Finally, higher sTREM2 increase rates protected from cortical shrinkage and cognitive decline. Our findings position the TREM2 response within the amyloid cascade right after the first pathological changes in Aβ42 aggregation, support ongoing efforts to develop TREM2 modulating therapies, and predict a very early window for therapeutic intervention.
