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 (Aß) 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 Aß status showed that CSF sTREM2 and YKL-40 were positively associated with executive functioning in amyloid negative (Aß-) 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.

The APOE ε4 genotype modulates CSF YKL-40 levels and their structural brain correlates in the continuum of Alzheimer's disease but not those of sTREM2.

INTRODUCTION: Among other metabolic functions, the apolipoprotein E (APOE) plays a crucial role in neuroinflammation. We aimed at assessing whether APOE ε4 modulates levels of glial cerebrospinal fluid (CSF) biomarkers and their structural cerebral correlates along the continuum of Alzheimer's disease (AD). METHODS: Brain magnetic resonance imaging (MRI) scans were acquired in 110 participants (49 control; 19 preclinical; 27 mild cognitive impairment [MCI] due to AD; 15 mild AD dementia) and CSF concentrations of YKL-40 and sTREM2 were determined. Differences in CSF biomarker concentrations and interactions in their association with gray-matter volume according to APOE ε4 status were sought after. RESULTS: Preclinical and MCI carriers showed higher YKL-40 levels. There was a significant interaction in the association between YKL-40 levels and gray-matter volume according to ε4 status. No similar effects could be detected for sTREM2 levels. DISCUSSION: Our findings are indicative of an increased astroglial activation in APOE ε4 carriers while both groups displayed similar levels of CSF AD core biomarkers.