Alterations in the Brain Lipidome of Alzheimer’s Disease Donors with Rare TREM2 Risk Variants

Abstract TREM2 is a microglial receptor, sensitive to Phospholipids and Sphingomyelins, associated with neurodegeneration. Hypomorphic variants in the TREM2 gene significantly increase the risk of developing AD. The main aim of this study was to characterize networks of lipids in post-mortem brain from AD and control donors, and to identify key lipids that are associated with AD and impacted by dysfunctional TREM2. We studied human post-mortem brain tissue from the hippocampus and the BA9 pre-association cortex from a total of 102 post-mortem brains. Specifically, brain tissue from the BA9 pre-association cortex was available for n=55 donors and brain tissue from the hippocampus was available for n=47 brain donors from three groups: AD donors with a non-synonymous risk DNA variant in TREM2 (AD-TREM2 var ), AD donors with no TREM2 -associated variant (AD-TREM2 wt ), and control donors. Mass Spectrometry was performed to obtain lipidomic signatures spanning 99 lipid species that included the following lipid classes: Ceramides, Sphingomyelins, Phosphatidic acids, Phopshatidyl-cholines, Phosphatidyl-ethalonamines, Phosphatidyl-glycerols, Phosphatidyl-inositols, Phosphatidyl-serines and Triglycerides. Weighted gene co-expression network analysis (WGCNA) was used to identify highly correlated lipid modules and ‘hub’ lipids. Linear mixed models and linear regression analyses, adjusted for age, biological sex, number of APOEε4 alleles and post-mortem delay were used to assess the association of modules and individual hub lipids with AD and TREM2 status. Four lipid modules were found to be relatively well-preserved between the two brain regions, and three of these modules were altered in AD donors and/or in AD donors with TREM2 genetic variants. Levels of the BA9 “turquoise” module (“blue” hippocampus module), enriched in Sphingolipids and Phospholipids, were elevated in AD brain donors and in AD TREM2 carriers. The key lipid (hub) of the BA9 “turquoise”/ hippocampus “blue” module was a Phosphatidylserine (PS(32:1)), increased in both AD donors and TREM2 carriers (AD-TREM2 wt versus controls: beta=0.468, 95% CI 0.05 – 0.89, p= 3.02E-02; and AD-TREM2 var versus controls: beta=1.00, 95% CI 0.53 – 1.47, p= 5.57E-03), whereas the strongest association was observed with a Ceramide (Cer(d38:1)) (AD-TREM2 wt versus controls: beta=0.663, 95% CI 0.17 – 1.16, p= 8.9E-03; and AD-TREM2 var versus controls: beta=1.31, 95% CI 0.78 – 1.84, p= 4.35E-06). The consistent increase in TREM2 ligands such as Ceramides and Phosphatidyl-serines in the brains of AD donors, particularly in carriers of TREM2 risk variants, could reflect the presence of AD-associated damage signals in the form of stressed/apoptotic cells and damaged myelin.