Unraveling TREM2’s Role in Cognitive Decline and Neuroinflammation in Parkinson’s Disease

A growing body of research is zeroing in on a key molecular player in Parkinson’s disease—TREM2, or Triggering Receptor Expressed on Myeloid cells 2—as a critical modulator of neuroinflammation and cognitive deterioration. Once primarily associated with Alzheimer’s disease, TREM2 is now emerging as a central figure in the pathology of Parkinson’s, particularly in how the brain’s immune cells respond to accumulating α-synuclein.

Recent investigations reveal that loss-of-function mutations and other genetic variations in TREM2 disrupt its regulatory role in microglial activity. Microglia, the brain’s resident immune cells, normally maintain a balance between clearing toxic proteins and preserving neural tissue. But when TREM2 function is compromised, this balance skews—microglia become hyperactivated and tilt toward a proinflammatory phenotype, especially in the presence of aggregated α-synuclein. This shift doesn’t just inflame brain tissue; it appears to accelerate cognitive decline in patients already grappling with Parkinson’s motor symptoms.

One compelling marker of this dysfunction is soluble TREM2 (sTREM2), which is cleaved from the membrane-bound receptor and detectable in cerebrospinal fluid (CSF). Elevated levels of sTREM2 in CSF have now been correlated with more rapid cognitive decline, according to recent findings published in Aging Neuroscience (2022). In clinical cohorts, patients with higher sTREM2 concentrations showed steeper declines in executive function and memory, suggesting that sTREM2 may serve not only as a marker of ongoing neuroinflammation but also as a harbinger of cognitive trajectory.

This builds on foundational preclinical work, including a pivotal study from Embopress (2021), which demonstrated that TREM2 deficiency in murine models led to an exaggerated inflammatory response when exposed to α-synuclein. In these models, microglia failed to transition from an activated to a resolving state, resulting in sustained neural damage. The implication is that TREM2 isn’t merely a bystander in neurodegenerative disease—it’s a gatekeeper for immune homeostasis in the central nervous system.

Still, the landscape isn’t without complexity. Some preclinical studies have reported divergent outcomes depending on disease stage, experimental design, and genetic background. In some cases, TREM2 deletion paradoxically reduced inflammation, underscoring the receptor’s context-dependent effects. But the broader consensus across animal models and human data points to a net detrimental impact when TREM2 signaling is impaired.

What makes these findings particularly urgent is their translational potential. As neurology and geriatrics move toward more personalized approaches, biomarkers like sTREM2 could help identify patients at highest risk for cognitive decline and guide early interventions—especially in those with known genetic risk factors affecting TREM2 function. Furthermore, modulating TREM2 activity pharmacologically may open the door to targeted therapies aimed at recalibrating the brain’s immune response before irreversible damage occurs.

The road ahead involves careful parsing of TREM2’s role across neurodegenerative disorders. Is its dysfunction a shared node linking Alzheimer’s, Parkinson’s, and other tauopathies? Could restoring TREM2 function attenuate both inflammation and protein aggregation? And critically, at what point in the disease course would intervention yield the greatest cognitive benefit?

While those questions remain active areas of investigation, one thing is increasingly clear: TREM2 is no longer on the periphery of Parkinson’s disease research. It stands at a crossroads of genetics, immunology, and neurodegeneration—offering both a window into disease mechanisms and a potential lever for clinical action. For healthcare professionals navigating the complexities of Parkinson’s, these insights invite a reexamination of how we define and treat cognitive decline in the context of a disease long thought to be primarily motor.