TREM2
TREM2 is one of the most important Alzheimer’s genes because it highlights the role of microglia and brain immunity in disease. Unlike APP or PSEN1, TREM2 usually acts as a risk gene rather than a deterministic cause of classic familial Alzheimer’s. Since its discovery, it has brought immune biology to the center of Alzheimer’s research.
Normal function
TREM2 encodes a receptor expressed mainly on microglia, the brain’s resident immune cells. It helps regulate how microglia sense damage, clear debris, and shift into activated states involved in phagocytosis (eating plaques damaged cells) and tissue response. In broad terms, TREM2 helps microglia respond appropriately to stress in the brain.
Mutation and effect
Risk-associated TREM2 variants can impair receptor function or alter signaling, weakening the ability of microglia to mount an effective response to accumulating debris and damage. Importantly for Alzheimer’s, this reduces the immune system’s ability to respond to amyloid beta accumulation.
Implications for treatment
TREM2-associated Alzheimer’s generally does not create a completely separate pathology from standard AD, but it may shift the disease toward a form with more prominent microglial dysfunction and impaired immune containment of pathology. In that sense, it changes the biological emphasis of the disease rather than altering disease course. TREM2 has become a major therapeutic target because it suggests that modulating microglial behavior could change disease course. This is conceptually different from simply lowering amyloid: it aims to improve the brain’s own response to pathology. TREM2-targeted therapies remain investigational, but Novartis has now entered a drug into phase II clinical trials that targets it.
Research focus
Research is focused on how TREM2 shapes disease-associated microglial states, how much activation is protective versus harmful, and whether TREM2-targeted therapy can improve amyloid clearance or reduce neurodegeneration. It is one of the best examples of how Alzheimer’s research has expanded beyond neurons alone.
Sources
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Ulrich, J. D., Ulland, T. K., Colonna, M., & Holtzman, D. M. (2017). Elucidating the Role of TREM2 in Alzheimer’s Disease.
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Deczkowska, A., Keren-Shaul, H., Weiner, A., et al. (2018). Disease-Associated Microglia: A Universal Immune Sensor of Neurodegeneration.
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Guerreiro, R., Wojtas, A., Bras, J., et al. (2013). TREM2 Variants in Alzheimer’s Disease.
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Shi, Q., Chowdhury, S., & Colonna, M. (2025). Microglia, Trem2, and Neurodegeneration.