The associations between glial biomarkers and cognitive changes in individuals at risk of Alzheimer’s disease

Abstract

AbstractBackgroundIn preclinical Alzheimer’s disease (AD), previous evidence suggests that glial reactivity may affect cognitive performance. This study aimed to test whether glial markers cerebrospinal fluid (CSF) GFAP, YKL‐40, sTREM2, and plasma GFAP are associated with cognitive change in cognitively unimpaired individuals at risk of AD. We hypothesized that higher levels of glial markers may be associated with better cognitive outcomes.MethodWe included 353 individuals from the ALFA+ cohort with available baseline (BL) glial biomarkers and cognition at follow‐up (FU) 3 years later (Table 1). CSF Aβ42/40, pTau181, YKL‐40, GFAP, and sTREM2, were analyzed using the exploratory Roche NeuroToolKit, a panel of automated robust prototype immunoassays. Plasma GFAP was determined with the Simoa HD‐X (Quanterix) platform using the commercial Neurology 4‐Plex E assay (N4PE). Amyloid pathology was studied with Centiloids derived from [18F]flutemetamol PET. Rate of change ([FU‐BL]/time) in the Preclinical Alzheimer’s Cognitive Composite (PACC) and domain‐specific cognitive composites was used as the dependent variable, glial biomarkers at BL as predictors, and age, sex and education as covariates in linear models. Interaction terms between each glial biomarker and different AD pathology were also explored. Aβ+ was defined as CSF Aβ42/40 <0.071.ResultHigher baseline CSF sTREM2 was associated with a positive PACC rate of change (p = 0.002) (Table 2). These results remained significant after controlling for CSF Aβ42/40, pTau181 and Centiloid levels (all p < 0.01). Moreover, CSF sTREM2 at baseline was associated with a better memory outcome (p = 0.012), independently of amyloid and tau (all p < 0.02), and better executive functioning (p = 0.046), independently of tau pathology (p = 0.011). These positive associations remained in the Aβ‐ group regardless of AD pathology, but not in the Aβ+ group, in which some negative associations were observed when adjusting for Centiloids (YKL‐40, p = 0.024) (Figure 1).ConclusionHigher TREM2‐mediated microglial response in individuals at risk of AD is associated with better cognitive performance. These associations were driven by the Aβ‐ group. These results may have important implications for the design of clinical interventions targeting TREM2 in this early stage of AD.