Higher TREM2 levels and microglia activation associated with slower rates of amyloid PET increase in humans and a transgenic mouse model of beta‐amyloid

Abstract

AbstractBackgroundLoss‐of‐function mutations in the TREM2 gene, a key receptor molecule on microglia, are associated with a 2 – 3 fold increase in the risk of Alzheimer’s disease (AD). Biomarker‐levels of soluble TREM2 (sTREM2) are increased in AD and associated with slower cognitive decline, suggesting a protective role of sTREM2‐related microglia activity (Suarez Calvet et al. Science Trans Med, 2016; Ewers et al. Science Trans Med., 2019). However, whether microglia activity reduces the future accumulation of core AD‐pathology remains unclear. Here we 1) tested in elderly subjects whether higher cerebrospinal fluid (CSF) levels of sTREM2 are associated with slower longitudinal rates of global amyloid‐PET accumulation, and 2) in a transgenic mouse model of Ab, whether higher baseline microglia‐PET is associated with slower rates of amyloid‐PET accumulation.Method206 Ab‐positive participants (global 18F‐AV‐45‐PET SUVR > 0.79, Landau et al. 2015) comprising 55 cognitively normal, 136 amnestic mild cognitive impairment and 15 AD dementia participants, and in addition, 94 Ab‐negative CN were included from ADNI. CSF sTREM2 and 18F‐AV‐45 PET were measured at baseline, and 18F ‐AV‐45 PET was repeated during follow‐up (mean = 2 years, range = 1.71‐6.1 years). 15 APPNL‐G‐F transgenic mice and 43 age‐ and gender matched C57BL/6 control mice were assessed with 18F‐GE180 TSPO‐PET at age 5 months and 18F‐AV‐45 PET at ages 5 and 10 months.ResultIn linear mixed effects analysis across all participants, the rate of change in amyloid PET showed a quadratic curve as a function of baseline amyloid‐PET levels, peaking at SUVR = 0.95 (Fig. 1A). Baseline levels of CSF sTREM2 modulated the rate of change in amyloid‐PET, such that at higher CSF sTREM2, the rate of subsequent increase in amyloid‐PET was reduced, controlled for demographics, diagnosis, CSF p‐tau181, and ApoE e4 (Figure 1B). In the AppNL‐G‐F mice, higher microglia‐PET at baseline was associated with slower rate of increase in global amyloid‐PET increase, controlled for baseline amyloid‐PET (Figure 2).ConclusionAcross humans and mice, higher microglia activation as measured by CSF sTREM2 or microglia PET showed protective effects on subsequent amyloid accumulation, supporting the critical role of microglia activation in the development of AD.