Longitudinal increase of sTREM2 in CSF and its relationship with other biomarkers and cognition along the evolution of autosomal dominant Alzheimer’s disease

Abstract

AbstractBackgroundTherapeutic modulation of TREM2‐dependent microglial function provides an additional strategy to slow progression of Alzheimer’s disease (AD). Although studies on animal models suggest that TREM2 is protective, clinical biomarker studies reach different conclusions regarding TREM2 effect on tau pathology and its potential beneficial role in human AD. The longitudinal study of cerebrospinal fluid (CSF) soluble TREM2 (sTREM2) as a biomarker of TREM2 signalling during the evolution of autosomal dominant AD and its relationship with different biomarkers shed additional light on these controversies.MethodWe measured sTREM2 by a novel MSD‐immunoassay selectively detecting ADAM10/17 generated sTREM2 in longitudinal CSF samples from 93 non‐carriers (NC) and 155 mutation carriers (MC) ‐presenilin 1, presenilin 2 and amyloid precursor protein genes‐, participating in the Dominantly Inherited Alzheimer Network (DIAN) observational study, and with available longitudinal data on amyloid‐β (Aβ) and tau‐related CSF biomarkers, structural MRI, Pittsburgh compound B PET (PIB‐PET) and cognition. We based our statistical analysis on univariate and bivariate linear mixed effects models.ResultOur recent results showed that longitudinal sTREM2 increase was predicted by the earliest Aβ‐aggregation captured by lower CSF‐Aβ42, but not yet by a higher cortical uptake in PiB‐PET. In line with previous cross‐sectional studies, higher sTREM2 increase rate was associated with slower Aβ‐deposition, as measured by CSF Aβ42 in presymptomatic MC, and by PIB‐PET in symptomatic MC. Furthermore, MC with high or low sTREM2 increase rates had opposite associations between CSF Aβ42 and PiB‐PET longitudinal changes, further suggesting that TREM2 modifies Aβ‐plaque deposition and compaction. Regarding tau‐related pathology, we found that lower sTREM2 increase rate enhanced the increase of CSF p‐tau associated with PiB‐PET signal increase. Finally, higher sTREM2 increase rate in presymptomatic MC was associated with slower cortical shrinkage in the precuneus and slower cognitive decline.ConclusionThe most novel results on longitudinal sTREM2 in CSF position the TREM2 response right after the first pathological changes in Aβ‐aggregation and support its beneficial effect on Aβ‐deposition, Aβ‐dependent tau pathology, cortical shrinkage, and cognitive decline. These findings strongly support ongoing efforts to develop TREM2‐boosting therapies and suggest sTREM2 as a key marker for clinical trial design and interpretation.