CSF glial biomarkers are associated with cognition in individuals at risk of Alzheimer's disease

INTRODUCTION We examined whether baseline glial markers soluble triggering receptor expressed on myeloid cell 2 (sTREM2), chitinase 3‐like protein 1 (YKL‐40), and glial fibrillary acidic protein (GFAP) in cerebrospinal fluid (CSF), and plasma GFAP are associated with cognitive change in cognitively unimpaired (CU) individuals at risk of Alzheimer's disease (AD). METHODS A total of 353 CU (mean age 60.9 years) participants were included (mean follow‐up time 3.28 years). Linear regression models with cognition as outcome were used. We also tested whether amyloid beta (Aβ) status modified these associations. RESULTS Higher baseline CSF sTREM2 was associated with a positive global cognition (Preclinical Alzheimer's Cognitive Composite) rate of change, and better memory and executive outcomes, independently of AD pathology. Higher baseline plasma GFAP was associated with a decline on attention rate of change. Stratified analyses by Aβ status showed that CSF sTREM2 and YKL‐40 were positively associated with executive functioning in amyloid negative (Aβ−) individuals. DISCUSSION Our results suggest that a TREM2‐mediated microglial response may be associated with better longitudinal cognitive performance. Highlights Higher cerebrospinal fluid (CSF) soluble triggering receptor expressed on myeloid cell 2 (sTREM2) relates to better longitudinal cognitive performance. The association between CSF sTREM2 and cognition is independent of Alzheimer's disease (AD) pathology. Targeting microglial reactivity may be a therapeutic strategy for AD prevention.