TREM2 (Triggering Receptor Expressed on Myeloid Cells 2) has emerged as one of the most promising therapeutic targets in Alzheimer disease and other neurodegenerative conditions. This page provides comprehensive information about TREM2 biology, therapeutic approaches, clinical development, and future directions.
TREM2 is a receptor expressed primarily on microglia in the central nervous system and has emerged as a critical therapeutic target for Alzheimer disease and other neurodegenerative conditions. TREM2 variants, particularly the R47H mutation, significantly increase Alzheimer disease risk, making it a high-priority target for drug development.
TREM2 plays a central role in microglial function, including phagocytosis of amyloid plaques, neuroinflammation modulation, and metabolic adaptation. Therapeutic approaches aim to either activate TREM2 signaling or increase TREM2 expression to enhance microglial protective functions.
¶ Structure and Expression
- Receptor type: Single-pass transmembrane receptor of the immunoglobulin superfamily
- Primary expression: Microglia in the CNS, peripheral myeloid cells
- Ligands: Lipids, amyloid-beta, apolipoprotein E (ApoE), TREM2 ligands
- Signaling: Associates with DAP12 (TYROBP) for intracellular signal transduction
Phagocytosis: TREM2 is essential for microglial phagocytosis of:
- Amyloid-beta plaques
- Apoptotic neurons
- Cellular debris
- Pathological protein aggregates
Metabolic Support: TREM2 supports microglial metabolic adaptation:
- Cholesterol metabolism
- Lipid handling
- Energy production for inflammatory responses
Inflammatory Regulation: TREM2 modulates neuroinflammation:
- Promotes anti-inflammatory (M2-like) microglial phenotype
- Suppresses excessive pro-inflammatory responses
- Maintains tissue homeostasis
The TREM2 R47H variant (rs75932628) increases AD risk approximately 3-fold, similar to APOE ε4. Other TREM2 variants associated with AD include:
Rare loss-of-function variants cause Nasu-Hakola disease (polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy - PLOSL).
TREM2 agonistic antibodies are designed to replicate the effect of natural TREM2 ligands and enhance microglial function. These antibodies bind to the extracellular domain of TREM2, triggering downstream signaling through DAP12.
AL002 (Alector/AbbVie)
- Humanized monoclonal antibody targeting TREM2
- Designed to activate TREM2 signaling and enhance microglial function
- Phase 2 clinical trials in early Alzheimer disease (INVOKE-2)
- Showed evidence of target engagement and reduced CSF sTREM2
- Phase 3 trials planned as of 2024
AL003 (Alector/AbbVie)
- Similar mechanism to AL002
- Different epitope binding properties
- Preclinical data showed enhanced plaque clearance
SHR-1707 (Hengrui)
- TREM2-targeting antibody from Hengrui Therapeutics
- Entered Phase 1/2 clinical trials in China
- First China-developed TREM2 antibody for AD
Mechanism of Action: TREM2 agonists work by:
- Binding to the extracellular domain of TREM2
- Inducing receptor clustering and dimerization
- Activating DAP12-mediated signaling cascades
- Enhancing microglial phagocytosis and metabolic function
- Promoting the transition to a disease-associated microglia (DAM) phenotype
These approaches aim to increase TREM2 protein levels in the brain through indirect mechanisms.
Anti-APOE Antibodies
- Reduce amyloid pathology and associated neuroinflammation
- May act partly through TREM2-dependent mechanisms
- Examples: simulengene body, celemab
NLRP3 Inhibitors
- Reduce neuroinflammation that impairs TREM2 function
- Protect microglial TREM2 expression
- Several candidates in preclinical development
- Currently in preclinical development
- Challenge: Achieving sufficient brain penetration
- Focus on allosteric modulators of TREM2 signaling
- AAV-mediated TREM2 delivery to microglia
- CRISPR-based TREM2 editing
- Still in early preclinical stages
An emerging approach involves engineering antibodies that target TREM2 while also engaging other therapeutic targets:
- TREM2 x amyloid bispecifics
- TREM2 x tau bispecifics
- TREM2 x APOE bispecifics
These are primarily in preclinical development.
¶ Clinical Trial Landscape
| Drug |
Company |
Phase |
Mechanism |
Status |
| AL002 |
Alector/AbbVie |
Phase 2/3 |
TREM2 agonist |
Recruiting |
| AL003 |
Alector/AbbVie |
Phase 1 |
TREM2 agonist |
Completed |
| SHR-1707 |
Hengrui |
Phase 1/2 |
TREM2 agonist |
Recruiting |
| JBH-436 |
Janssen |
Preclinical |
TREM2 agonist |
IND-enabling |
Key endpoints in TREM2-targeted trials include:
- Cognitive measures: ADAS-Cog13, CDR-SB, MMSE
- Biomarkers: CSF sTREM2, Aβ PET, tau PET
- Imaging: MRI brain volume, microglial activation (TSPO PET)
- Safety: Adverse event monitoring
- sTREM2: Soluble TREM2 fragment in CSF, reflects microglial activation. Changes in sTREM2 can indicate target engagement.
- YKL-40: Chitinase-3-like protein, microglial activation marker
- Neurofilament light chain (NfL): Axonal injury marker
- Aβ42/40 ratio: Amyloid status
- Total tau and p-tau: Neurodegeneration markers
- Plasma sTREM2: Emerging as a peripheral marker of microglial activation
- Plasma NfL: Neurodegeneration marker
- Aβ and tau in plasma: Increasingly used for patient selection
- PET imaging: Amyloid and tau PET for treatment response
- Microglial PET: TSPO PET to assess microglial activation
- Structural MRI: Brain volume changes
¶ Patient Selection and Stratification
- TREM2 genotype: Patients with TREM2 risk variants may respond differently
- APOE status: APOE ε4 carriers may have altered TREM2 function
- Risk variant carriers: R47H, R62H carriers may benefit from agonistic approaches
- Preclinical/Prodromal AD: Likely optimal for TREM2 therapies
- Mild Cognitive Impairment (MCI): Active enrollment in trials
- Mild to Moderate AD: Being studied, may have reduced benefit
- Amyloid-positive by PET or CSF
- Tau burden assessment
- Microglial activation status
¶ Challenges and Considerations
- TREM2 function varies with disease stage
- Need to understand TREM2 role in different microglial states
- Potential for different effects in early vs. late disease
- DAM (Disease-Associated Microglia) phenotype complex
- Immune-related adverse effects
- Potential for excessive immune activation
- Long-term effects on microglial function unknown
- Risk of cytokine release
TREM2 therapies being explored with:
- Anti-amyloid antibodies (lecanemab, donanemab)
- Anti-tau therapies
- Other immunomodulatory approaches
- Potential synergies with BACE inhibitors (caution due to toxicity)
- Antibody brain penetration is limited
- Need for engineered antibodies with enhanced brain delivery
- Dose optimization challenging
- Bispecific antibodies targeting TREM2 and other pathways
- Small molecules with improved brain penetration
- Cell-type specific delivery systems
- Engineered TREM2 variants
- TREM2 genotype-based patient stratification
- Biomarker-driven patient selection
- APOE status consideration
- Microglial activation status assessment
- Early intervention likely most effective
- Potential for prevention trials in at-risk individuals
- Long-term treatment effects under investigation
- TREM2 in Parkinson disease
- TREM2 in ALS
- TREM2 in multiple sclerosis
- TREM2 in frontotemporal dementia
¶ TREM2 and Other Neurodegenerative Diseases
TREM2 variants have been associated with increased PD risk in some studies. Microglial activation is a hallmark of PD, and TREM2-mediated phagocytosis may be relevant to alpha-synuclein clearance.
TREM2 expression is elevated in ALS, and genetic variants may modify disease progression. Clinical trials in ALS are being considered.
TREM2 plays a role in microglial responses in demyelinating diseases. TREM2 may be protective in MS models.
The study of Trem2 Targeting Therapies has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.