TREM2 R47H and R62H variants increase Alzheimer's pathology by altering microglial and neuronal responses

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) plaques and tau tangles, leading to cognitive decline. Microglia, the brain's resident immune cells, play a critical role in AD pathogenesis, influencing Aβ clearance and neuroinflammation. Genetic variants in TREM2 (Triggering Receptor Expressed on Myeloid cells 2) and CD33 are strongly associated with AD risk, with TREM2 variants like R47H and R62H increasing risk, while reduced CD33 expression is protective. Understanding the precise molecular mechanisms by which these genetic factors modulate microglial function and AD pathology is crucial for developing targeted therapies.

Researchers investigated the cellular pathology in human post-mortem brain tissue from individuals with and without AD, focusing on the impact of TREM2 R47H and R62H variants (TREM2var) and heterozygosity for the protective CD33 rs3865444 polymorphism. The study contrasted these genetic profiles to elucidate mechanisms associated with differential AD risks. They employed microglial transcriptomics to analyze gene expression responses to increasing β-amyloid, neuronal transcriptomics to assess cell-specific changes, and bulk tissue proteomics to support observations of adaptive plasticity.

Epistasis between CD33 and TREM2 was evident, as the protective CD33 allele relatively normalized differences in β-amyloid load in TREM2var carriers. Microglial transcriptional responses to increasing β-amyloid were significantly lower for TREM2var compared to common variant (CV) individuals, particularly for R47H. This included a reduction in expression of neuroplasticity pathways in TREM2var.

R62H microglial signatures were distinguished from R47H by upregulation of genes associated with phagocytosis, and from CV by differences in inflammatory gene expression, including those involved in NF-κB signaling. Differential gene expression with increasing β-amyloid also suggested upregulation of β-amyloid production and binding pathways in excitatory neurons in TREM2var heterozygotes. Furthermore, there was lower enrichment for pathways positively adaptive to pathology and expressed in inhibitory neurons from CV samples for both TREM2var. Exploratory bulk tissue proteomics corroborated these findings, showing evidence for adaptive plasticity in response to β-amyloid pathology in CV tissue that was absent in TREM2var, which instead showed increased β-amyloid formation and neuroplasticity changes.