Association of TREM2 variants and sphingolipid levels with AD in blood and brain

Abstract

AbstractBackgroundThe TREM2 gene has an effect on AD risk similar to that of ApoE ε4. TREM2 is a microglial receptor, sensitive to lipids associated with neurodegeneration, such as glycerophospholipids and sphingomyelins (SM). Reduced levels of S1P in AD brain and elevated ceramides (CER), likely contribute to disease pathogenesis. The ability to respond to this signal may have important implications for AD. However, the extent to which TREM2 genetic variants affect the relationship between lipid levels and AD has not been examined. Here we investigated the association of lipid levels with AD in post‐mortem brain samples and blood and we interrogated how TREM2 genetic variants modify these associations.MethodBrain tissue from the hippocampus and BA9 was collected from 48 AD patients and 24 controls, and blood was collected from 58 AD patients, 21 controls and 16 participants with Mild Cognitive Impairment (non‐overlapping). All participants were genotyped for TREM2 AD‐related variants. LCMS analyses were performed on both brain and blood and >250 lipid species were annotated. Linear and mixed effects regression models adjusted for age, sex, APOE ε4 allele, and post‐mortem delay (in brain samples), were used to investigate the association of lipids with AD and to examine whether TREM2 variants modified these associations.ResultOverall CER and SM levels, especially those of shorter chain lengths, were increased in AD in both hippocampus and BA9 (e.g. AD patients had 1.02 SD higher Cer.d36.1 levels compared to controls (P‐value<1x10‐4 ; pooled estimate across the two brain regions ). TREM2 seemed to modify the associations of specific CER and SM with AD, with lipid levels of AD TREM2 carriers resembling those of controls. Although the associations of lipids with AD in blood were not as strong (with some in opposite direction) the way TREM2 affected association of some lipids with AD was analogous to that in brain.ConclusionThis is the first study to investigate how TREM2 variants contribute to disease vulnerability through changes in lipid levels in post‐mortem brain tissue and blood. These results could hold special value in AD as they suggest vulnerable processes that could be targeted for therapeutic development.