Higher levels of the astrocytic marker CSF YKL40 are associated with better memory performance only in amyloid‐positive individuals with subjective cognitive decline

Abstract

AbstractBackgroundIt is not clear whether neuroinflammation is a detrimental or a compensatory mechanism in Alzheimer’s disease (AD). Recent evidence suggests that increased levels of YKL40 are related to better memory performance in cognitively unimpaired older individuals with memory complaints. In this study, we aimed i) at replicating these previous findings and ii) extending to other markers by exploring the relationship between cognitive performance and cerebrospinal fluid (CSF) biomarkers of astrocytic (YKL40, GFAP and S100) and microglial (sTREM2) neuroinflammation‐related activation, and to explore whether this association is further modulated by amyloid status and presence of subjective cognitive decline (SCD) in a middle‐aged cohort of cognitively unimpaired individuals.MethodWe included data from 392 individuals from the ALFA+ cohort (mean age 61 years). CSF measures of amyloid pathology (Aβ42/40) pathology and YKL‐40, GFAP, S100 and sTREM2, were analyzed with the exploratory Roche NeuroToolKit assays, a panel of automated robust prototype immunoassays. Individuals were classified as amyloid positive (A+) or negative (A‐) using the Aβ42/40=0.071 cut‐off and as SCD or non‐SCD using the SCD‐Questionnaire. Memory and Executive cognitive composites were used as dependent variables in linear models using CSF biomarkers with covariates (age, sex, education) as predictors. Interaction terms with biomarker*Amyloid status*SCD status were also modeled.ResultOne hundred and thirty‐five individuals (34.4%) were A+ and 107 (27.3%) displayed SCD (Table 1). For Memory composite we found significant interactions for YKL40*Amyloid*SCD (p=0.04) and sTREM2* Amyloid *SCD (p=0.03). In stratified analyses by Aβ and SCD we observed that Memory performance was positively associated with YKL40 in Aβ+ that also display SCD (n=39, p=0.019, Figure 1). No significant associations were found in stratified analysis with sTREM2 (neither by Amyloid nor by SCD status). For GFAP and S100, no associations were observed nor for any analysis with the Executive composite.ConclusionAstrocytic (YKL40), but not microglial (sTREM2), activation was associated with better memory performance in those cognitively unimpaired individuals with evidence of Alzheimer’s pathophysiological changes and subjective cognitive decline. Thus, some specific neuroinflammation may be beneficial at the end of the AD preclinical stage, in which subjective SCD arise.