Alterations in the brain lipidome of Alzheimer's disease donors with rare TREM2 risk variants

Abstract Triggering Receptor Expressed on Myeloid Cells 2 (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 Alzheimer’s disease (AD). The aim of this study was to characterize networks of lipids in post-mortem brain tissue from AD and Control donors, and to identify lipids associated with AD and impacted by dysfunctional TREM2. We studied human post-mortem brain tissue from the hippocampus and Brodmann area 9 (BA9) from 102 brains. Brain tissue from BA9 was available from n = 55 donors (14 Ad donors with a non-synonymous TREM2 risk variant AD(TREM2+), 20 Ad donors with no TREM2 risk variants Ad(TREM2−) and 21 Control donors), and brain tissue from the Hippocampus was available for n = 47 brain donors (7 AdTREM2+, 20 AdTREM2− and 20 Control donors). Mass Spectrometry was performed to obtain lipidomic signatures spanning 99 lipid species that included the following lipid classes: Ceramides, Sphingomyelins, Phosphatidic acids, Phosphatidyl-cholines, Phosphatidyl-ethanolamines, Phosphatidyl-glycerols, Phosphatidyl-inositols, Phosphatidyl-serines and Triglycerides. Weighted gene co-expression network analysis (WGCNA) was used to identify highly correlated lipid modules and hubs in each brain region. Generalized least squares and linear regression analyses, adjusted for age at death, biological sex, number of Apolipoprotein E (APOE) ε4 alleles, and post-mortem delay, were used to assess the associations of lipid modules and hubs with AD and TREM2, in combined analyses across regions and in each region separately. Four lipid modules were relatively well-preserved between the two brain regions, and three of these modules were altered in AD donors and/or in AD TREM2 carriers. Levels of the BA9 ‘turquoise’ module (‘blue’ hippocampus module), enriched in Sphingolipids and Phospholipids, were elevated in AD donors and particularly in AD TREM2 carriers AD(TREM2+). The hub lipid of the BA9 ‘turquoise’/hippocampus ‘blue’ module, Phosphatidyl-serine PS(32:1), was increased in AD versus Control donors (beta = 0.677, 95% CI 0.28–1.08, P = 1.14E−03), and in AD(TREM2+) versus Control donors (beta = 1.00, 95% CI 0.53–1.48, P = 5.57E−03), whereas the strongest association was observed with Ceramide Cer(d38:1) increased in AD versus Control donors (beta = 0.929, 95% CI 0.46–1.40, P = 1.67E−04) and in AD(TREM2+) versus Controls donors (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 TREM2 risk variants carriers, could reflect the presence of AD-associated damage signals in the form of stressed or apoptotic cells and damaged myelin.