TREM2‐related Polygenic Risk Score predicts defect Innate Immune Activation in Alzheimer’s Disease

Abstract

AbstractBackgroundTREM2 plays a central role in immune response which, in turn, is strongly related to Alzheimer’s disease (AD) pathology. We previously found an AD‐subtype with and without innate immune activation based on CSF proteomics. Possibly, genes associated with TREM2 pathways could explain differences between these two subtypes since R47H and R62H mutations are associated with decreased microglial activation. We tested this hypothesis in a large single site cohort, and compared them on PRS including previously reported GWAS genes associated with TREM2 pathways.MethodWe included participants from the Amsterdam Dementia Cohort who had AD subtyping based on CSF proteomics available (n = 466). Based on literature, we labelled 19 of 83 known AD risk genes as belonging to TREM2 pathways and used these to construct a TREM2‐PRS. We studied associations between a standard AD‐PRS with 83 SNPs, TREM2‐PRS with 19 SNPs and non‐TREM2‐PRS with 64 SNPs between two AD‐subtypes being (1) without innate immune activation and (2) with innate immune activation, using logistic regression models (correcting for sex, age and 5 principal components).ResultThe cohort involved 146 controls (mean age 61 years, 34% female) and 195 AD cases: 97 without immune activation subtype (mean age 64 years, 52% female) and 98 with immune activation subtype (mean age 68 years, 54% female). Both subtypes showed comparable increased risk on the standard AD‐PRS compared to controls (OR 1.65, 95%CI 1.2‐2.3, p = 0.002 and OR 1.7, 95%CI 1.1‐2.5, p = 0.006) (Table 1). A higher TREM2‐PRS was associated with no immune activation subtype (OR 1.5, 95%CI 1.1‐2.1, p = 0.008). The PRS of the other 64 risk variants, which were not labelled as belonging to TREM2 pathways, was associated with immune activation subtype (OR 1.5, 95%CI 1.1‐2.1, p = 0.02).ConclusionAD individuals with a CSF proteomic‐based subtype without immune activation show more genetic variants in TREM2 pathways, whereas these SNPs are not related to the subtype with innate immune activation. These findings provide evidence for genetic differences underlying AD‐subtypes, and suggest that therapies targeting immune functioning may need to tailor therapies to AD‐subtype (i.e., additional activation vs. decreasing activation).