Interplay of TREM2 and APOE in Alzheimer’s disease: mechanisms, imaging biomarkers, and therapeutic opportunities

Alzheimer’s disease (AD) is the most common neurodegenerative disorder. AD features dysregulated innate immune elements and lipid metabolism which could contribute to its neuropathology. In this line, microglial triggering receptor expressed on myeloid cells 2 (TREM2) and the different isoforms of apolipoprotein E (APOE) have been recently studied as potential interacting modulators of the cellular phenotype of microglia as well as processing of amyloid-β (Aβ), tauopathy and neuroinflammation. Recent investigations have indicated how TREM2 and APOE react at a molecular level as well as how various APOE isoforms influence TREM2-dependent microglia state along with lipid metabolism; CSF sTREM2 has emerged as an investigational marker whose associations vary by stage, assay and cohort. Amyloid and tau PET and structural MRI characterise established AD pathology and neurodegeneration, and TSPO PET provides an indirect, non-specific neuroinflammatory signal, whereas TREM2-targeted PET remains preclinical. Additionally, functional data derived from both pre-clinical and clinical research, iPSC-derived human microglia along with cell studies, that could reveal a double-edged context-dependent aspect of TREM2 with respect to the APOE isoform, sex, or disease stage. In this article, we review the translational strategies against AD, targeting TREM2 with agonists, role of APOE, as well as discuss approaches for restoration of microglial lipid homeostasis and preclinical TREM2-targeted tracer development. Furthermore, the challenge of context-dependency based on disease stage and ligands is evaluated. In the future, a mechanistic framework of the TREM2-APOE axis, together with longitudinal biomarker and imaging studies, may help to achieve patient stratification and immunomodulatory treatments in AD.