Mechanisms of increased Alzheimer’s Disease pathology with R47H and R62H TREM2 variants

ABSTRACT: TREM2 plays multiple functional roles in microglia and variants are associated with increased risks of Alzheimer’s disease (AD). CD33 polymorphisms are protective. Here we have contrasted cellular pathology in human post mortem brain with and without AD to test mechanisms associated with the differential genetic risks conferred by R47H and R62H TREM2 variants (TREM2var) with and without heterozygosity for the protective rs3865344 CD33 polymorphism. Epistasis between CD33 and TREM2 was demonstrated by both relative normalisation of differences in β-amyloid load and microglial transcriptomic responses to β-amyloid with the TREM2var. Controlling for CD33 genotype, microglial transcriptional responses to increasing β-amyloid were lower for TREM2var, particularly for R47H. R62H microglial signatures were distinguished from those of R47H by upregulation of genes associated with the MHC Class Ib response and phagocytosis. By contrast, TREM2var astrocytes differentially expressed greater numbers of genes than for the common allele (CV), including those involved in β-amyloid clearance pathways. Differential gene expression with increasing β-amyloid suggested upregulation of the β-amyloid production pathway in R62H excitatory neurons and lower enrichment for pathways positively adaptive to pathology in CV inhibitory neurons for both TREM2var. Exploratory bulk tissue proteomics support these observations with evidence for adaptive plasticity in response to β-amyloid pathology in CV tissue not found for the TREM2var which showed evidence for integrated stress responses and increased β-amyloid synthesis. Together, these results highlight differences in molecular pathology between the TREM2var risk variants. They describe impacts on mechanisms of AD risk mediated by secondary effects on astroglial and neuronal function, as well as the primary microglial functional pathology. Demonstration of strong epistasis between TREM2 and CD33 with AD supports the therapeutic potential of modulators of CD33 expression or its inhibition.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Brain

DISEASE(S): Alzheimer's Disease

SUBMITTER: Harry Whitwell  

LAB HEAD: Harry J Whitwell

PROVIDER: PXD074536 | Pride | 2026-06-29

REPOSITORIES: Pride