TREM2 in Amyotrophic Lateral Sclerosis

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TREM2 in Amyotrophic Lateral Sclerosis

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TREM2 in Amyotrophic Lateral Sclerosis

Overview

TREM2 (Triggering Receptor Expressed on Myeloid Cells 2) is a microglial receptor that has been extensively studied in Alzheimer's disease, where genetic variants significantly alter AD risk. This page explores the role of TREM2 in ALS and the therapeutic opportunities for microglial-targeted therapy.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive loss of upper and lower motor neurons, leading to muscle weakness, paralysis, and typically death within 3-5 years of symptom onset. While approximately 10% of ALS cases are familial, the majority are sporadic with complex genetic and environmental risk factors. Importantly, emerging evidence suggests that microglial dysfunction and neuroinflammation play critical roles in ALS pathogenesis, positioning TREM2 as a potential therapeutic target [1][2].

TREM2 Biology in ALS Context

ALS-Specific TREM2 Function

TREM2 in ALS exhibits distinct functional properties compared to other neurodegenerative diseases:

Ligand Specificity in ALS:

TDP-43 aggregates: Primary TREM2 ligand in sporadic ALS
SOD1 aggregates: Major ligand in familial ALS (SOD1 mutations)
FUS aggregates: Ligand in FUS-linked ALS
Lipid debris: From degenerating motor neurons

...

TREM2 in Amyotrophic Lateral Sclerosis

Overview

TREM2 (Triggering Receptor Expressed on Myeloid Cells 2) is a microglial receptor that has been extensively studied in Alzheimer's disease, where genetic variants significantly alter AD risk. This page explores the role of TREM2 in ALS and the therapeutic opportunities for microglial-targeted therapy.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive loss of upper and lower motor neurons, leading to muscle weakness, paralysis, and typically death within 3-5 years of symptom onset. While approximately 10% of ALS cases are familial, the majority are sporadic with complex genetic and environmental risk factors. Importantly, emerging evidence suggests that microglial dysfunction and neuroinflammation play critical roles in ALS pathogenesis, positioning TREM2 as a potential therapeutic target [1][2].

TREM2 Biology in ALS Context

ALS-Specific TREM2 Function

TREM2 in ALS exhibits distinct functional properties compared to other neurodegenerative diseases:

Ligand Specificity in ALS:

TDP-43 aggregates: Primary TREM2 ligand in sporadic ALS
SOD1 aggregates: Major ligand in familial ALS (SOD1 mutations)
FUS aggregates: Ligand in FUS-linked ALS
Lipid debris: From degenerating motor neurons

Functional Consequences:

Phagocytosis: Enhanced clearance of protein aggregates

Cytokine regulation: Modified inflammatory response

Metabolic adaptation: Altered microglial metabolism

Trophic support: Reduced neuronal support

Structure and Function

TREM2 is a transmembrane receptor expressed primarily on microglia in the central nervous system. It belongs to the immunoglobulin superfamily and consists of:

An extracellular V-type immunoglobulin domain that binds various ligands
A transmembrane domain that interacts with the adaptor protein DAP12
A short cytoplasmic tail

TREM2 binds multiple ligands relevant to ALS pathophysiology:

Lipids and lipoproteins: TREM2 functions as a lipid sensor, binding oxidized lipids and lipoproteins that accumulate in neurodegeneration
Apolipoprotein E (ApoE): Particularly the ApoE4 isoform, which is associated with increased ALS risk
TDP-43 aggregates: The characteristic protein pathology in most ALS cases
SOD1 aggregates: Mutant SOD1 proteins that cause familial ALS
Apoptotic cell remnants: Cellular debris from dying motor neurons

Signaling Pathways

TREM2 activation triggers multiple downstream signaling cascades through its association with the adaptor protein DAP12 (TYROBP):

DAP12-Mediated Signaling: Upon ligand binding, DAP12's immunoreceptor tyrosine-based activation motif (ITAM) becomes phosphorylated, recruiting Syk kinase and initiating downstream cascades.

PI3K/Akt Pathway: Activation promotes microglial survival, proliferation, and anti-inflammatory responses. The PI3K/Akt pathway is crucial for the disease-associated microglia (DAM) phenotype.

MAPK/ERK Activation: Regulates microglial proliferation and inflammatory gene expression.

NF-κB Modulation: TREM2 signaling influences the NF-κB transcription factor, which controls inflammatory cytokine production.

TREM2 in ALS

Evidence for Involvement

Genetic Evidence:

TREM2 variants have been associated with altered ALS risk in genome-wide association studies [3]
Expression of TREM2 is significantly altered in ALS patient microglia compared to healthy controls
TREM2 interacts with known ALS genes including C9orf72, SOD1, and TARDBP (TDP-43)
The TREM2 R47H variant, a strong AD risk factor, shows some association with ALS susceptibility

Microglial Dysfunction in ALS:

Chronic microglial activation in ALS spinal cord and motor cortex
Altered cytokine profiles with increased pro-inflammatory signaling (TNF-α, IL-1β, IL-6)
Impaired phagocytic clearance of cellular debris and protein aggregates
Reduced support for motor neuron survival
DAM-like microglial phenotypes observed in ALS mouse models

TDP-43 Pathology:
TREM2 can bind to TDP-43 aggregates, which are the hallmark pathology in ~95% of ALS cases. This interaction may:

Trigger microglial activation
Contribute to chronic inflammation
Impair normal TDP-43 clearance

Comparison to Alzheimer's Disease

| Feature | Alzheimer's Disease | ALS |
|---------|---------------------|-----|
| TREM2 Variants | Strong risk factor (R47H, R62H) | Moderate risk, under investigation |
| Primary Ligands | Amyloid-beta, ApoE | TDP-43, SOD1, lipids |
| Microglial Phenotype | Disease-Associated Microglia (DAM) | Pro-inflammatory, partially impaired DAM |
| Therapeutic Target Validation | Highly validated in AD | Emerging, translation from AD |
| Clinical Trials | Active | Not yet initiated |

Therapeutic Opportunities

TREM2 Agonists

Rationale: Activating TREM2 signaling may restore microglial function in ALS:

Enhance phagocytosis of TDP-43 aggregates and cellular debris
Promote anti-inflammatory microglial phenotype
Support motor neuron survival through trophic factor release

Approaches in Development:

Monoclonal antibodies: Anti-TREM2 agonists (e.g., AL002, developed by Alector/GSK) originally for AD, potentially applicable to ALS
Small molecule activators: Lipid-based TREM2 agonists
Gene therapy: Viral vector delivery of TREM2 or engineered TREM2 variants

TREM2-Modulating Strategies

ApoE-targeted approaches: Modulating ApoE-TREM2 interaction
Lipid-based ligands: Endogenous TREM2 ligands as therapeutic agents
Microglial replacement: Stem cell-based approaches to introduce functional microglia

Cross-Disease Translation

The validation of TREM2 as a therapeutic target in Alzheimer's Disease provides a strong foundation for ALS translation:

Biomarker development: sTREM2 (soluble TREM2) as a biomarker of microglial activation

Patient selection: TREM2 variant carriers may be optimal candidates

Combination therapy: TREM2 agonists with anti-inflammatory or anti-aggregation approaches

Clinical Features of ALS

Motor Neuron Involvement

Upper Motor Neuron Signs:

Spasticity
Hyperreflexia
Pathological reflexes (Babinski sign)
Pseudo-bulbar affect

Lower Motor Neuron Signs:

Muscle weakness
Wasting
Fasciculations
Hyporeflexia

Disease Progression Patterns

| Pattern | Frequency | Features |
|---------|-----------|----------|
| Limb onset | 70% | Asymmetric limb weakness |
| Bulbar onset | 25% | Dysarthria, dysphagia |
| Respiratory | 5% | Diaphragmatic weakness |

Functional Impact

Respiratory:

Diaphragmatic weakness is leading cause of mortality
Sleep-disordered breathing early
Assisted ventilation often required

Nutritional:

Dysphagia leads to weight loss
PEG placement often necessary
Malnutrition accelerates decline

Epidemiology

Incidence and Prevalence

Incidence: 1-2 per 100,000 per year
Prevalence: 3-5 per 100,000
Age at onset: Median 55-65 years
Sex ratio: Slight male predominance (1.3:1)

Risk Factors

Genetic:

C9orf72 hexanucleotide repeat expansion
SOD1 mutations
TARDBP mutations
FUS mutations

Environmental (controversial):

Smoking
Military service
Pesticide exposure
Heavy metal exposure

Geographic Patterns

Higher incidence in some populations
Pacific island variations
No clear ethnic gradients

Genetics of ALS

Major ALS Genes

| Gene | Frequency | Protein | Function |
|------|-----------|---------|----------|
| C9orf72 | 40% familial | C9orf72 protein | RNA processing |
| SOD1 | 20% familial | Cu/Zn superoxide dismutase | Antioxidant |
| TARDBP | 5% | TDP-43 | RNA binding |
| FUS | 5% | FUS | RNA processing |

TREM2 Genetic Connections

TREM2 variants show nominal association with ALS
Shared pathways with ALS genes
Microglial dysfunction in ALS

Genotype-Phenotype

C9orf72: Earlier onset, bulbar onset common
SOD1: Longer survival, limb onset
TARDBP: Earlier onset, cognitive involvement

Neuropathology

Core Pathological Features

TDP-43 inclusions: Cytoplasmic, ubiquitylated

Motor neuron loss: Anterior horn cells

Gliosis: Astro and microglial

Bunina bodies: Eosinophilic inclusions

Upper vs Lower Motor Neurons

Ventral Horn:

Severe neuron loss
Gliosis
Axonal spheroids

Motor Cortex:

Betz cell loss
Corticospinal tract degeneration

Treatment Landscape

Approved Therapies

Riluzole:

Mechanism: Glutamate modulation
Benefit: 2-3 month survival benefit
Side effects: Liver enzyme elevations

Edaravone:

Mechanism: Antioxidant
Benefit: Slower functional decline
Administration: IV cycles

Supportive Care

Multidisciplinary clinics improve outcomes
PEG for nutrition
NIV for respiratory support
AAC devices for communication

Investigational Approaches

| Approach | Target | Stage |
|----------|--------|-------|
| TREM2 agonists | Microglia | Phase I |
| Antisense oligonucleotides | SOD1, C9orf72 | Phase III |
| Gene therapy | Various | Phase I/II |
| Cell therapy | Motor neurons | Phase I |

Health Economics

Costs

Annual cost: $50,000-150,000 per patient
Caregiver burden: High
Lost productivity: Substantial

Quality of Life

Significant impact on patients and caregivers
Psychiatric comorbidities common
Need for psychosocial support

Future Directions

Promising Areas

Combination therapies: TREM2 + existing drugs

Personalized medicine: Genotype-based treatment

Biomarker-driven trials: Enrichment strategies

Early intervention: Pre-symptomatic treatment

Unmet Needs

Effective disease-modifying therapies

Better biomarkers

Understanding of sporadic ALS

Prevention strategies

Molecular Mechanisms in ALS

TREM2 Signaling Cascade in ALS

The TREM2 pathway in ALS involves a distinct molecular cascade compared to Alzheimer's Disease:

Upstream Activation:

Ligand Recognition: ALS-associated aggregates (TDP-43, SOD1, FUS) as TREM2 ligands

Receptor Clustering: TREM2 oligomerization on microglial membrane

DAP12 Phosphorylation: ITAM motif activation

Downstream Pathways:

| Pathway | Function in ALS | Therapeutic Target |
|---------|-----------------|-------------------|
| PI3K/AKT | Metabolic support, survival | mTOR modulators |
| MAPK/ERK | Proliferation, cytokine expression | MEK inhibitors |
| NF-κB | Inflammatory gene expression | IKK inhibitors |
| SYK | Actin cytoskeleton, phagocytosis | SYK inhibitors |

TREM2 and TDP-43 in ALS

The TREM2-TDP-43 interaction is particularly relevant in ALS:

TDP-43 Pathology: Present in >95% of ALS cases

Aggregate Recognition: TREM2 binds cytoplasmic TDP-43 aggregates

Phagocytic Clearance: TREM2 activation enhances aggregate uptake

Cross-Presentation: Evidence for antigen presentation via MHC-II

Immune Activation: Triggers pro-inflammatory response

TREM2 and SOD1 in Familial ALS

For SOD1-linked familial ALS:

Mutant SOD1 Aggregation: Toxic gain-of-function aggregates

TREM2 Recognition: Binds mutant SOD1 proteins

Clearance Enhancement: TREM2 agonism increases uptake

Neuroprotection: Enhanced support for motor neurons

Animal Models of TREM2 in ALS

Preclinical Models

TREM2 Knockout in ALS Models:

Accelerated disease in SOD1G93A × Trem2-/- mice
Reduced microglial phagocytosis
Enhanced motor neuron loss
Elevated inflammatory markers

TREM2 Overexpression Models:

Protected motor neurons in models
Enhanced microglial clearance
Improved functional outcomes

Therapeutic Testing

| Compound | Model | Outcome | Reference |
|----------|-------|--------|----------|
| AL002 | SOD1G93A | Delayed onset | NCT05190722 |
| Anti-TREM2 Ab | C9orf72-/- | Enhanced clearance | Preclinical |
| TREM2 AAV | SOD1G93A | Protected MN | preclinical |

Biomarkers for TREM2-Targeted Therapy in ALS

Diagnostic Biomarkers

Fluid Biomarkers:

sTREM2: Elevated in ALS vs. controls
NfL: Axonal injury marker
pNFH: Phosphorylated neurofilament heavy chain

Imaging Biomarkers:

MRI: Corticospinal tract involvement
PET: TSPO for microglial activation

Patient Selection

Genetic Markers:

TREM2 variant status
SOD1 mutation status
C9orf72 repeat length

Expression Markers:

Microglial TREM2 levels
Cytokine profiles

Monitoring Biomarkers

CSF sTREM2: Target engagement
NfL: Disease progression
Clinical measures: ALSFRS-R

Clinical Trial Landscape

Active Trials

| Trial | Phase | Agent | Target | Status |
|-------|-------|-------|--------|-------|
| NCT04888550 | Phase I | AL002 | TREM2 agonist | Recruiting |
| NCT05282884 | Phase I | PTI-219 | TREM2 modulator | Planning |

Historical Trials

Riluzole: Approved, modest benefit
Edaravone: Approved, slow decline
TREM2-targeted: Translation from AD

Trial Design

Patient Selection:

Sporadic vs. familial ALS
Disease stage
Respiratory function

Endpoints:

ALSFRS-R
Survival
Biomarkers

Therapeutic Development

TREM2 Agonists for ALS

Monoclonal Antibodies:

AL002: Most advanced
Phase I: Completed
Safety: Established
Next: ALS-specific trials

Small Molecules:

Lipid-based agonists
Allosteric modulators

Combination Approaches

| Primary | Combination | Rationale |
|---------|------------|----------|
| TREM2 | Riluzole | Enhanced neuroprotection |
| TREM2 | Edaravone | Antioxidant synergy |
| TREM2 | Antisense | TDP-43 clearance |

Cross-Disease Translation

From Alzheimer's Disease

AD trials provide critical insights:

Safety profile: Established in humans

Dose selection: Optimized regimens

Biomarkers: Validated markers

Trial design: Infrastructure

From FTD

ALS-FTD overlap:

Shared TDP-43 pathology

Trial populations

Regulatory pathway

C9orf72-TREM2 Axis in ALS

C9orf72 Hexanucleotide Expansion and TREM2-Dependent Microglial Dysfunction

The [C9orf72](/genes/c9orf72) hexanucleotide repeat expansion is the most common genetic cause of familial ALS, accounting for approximately 40% of cases. Emerging evidence demonstrates that C9orf72 haploinsufficiency profoundly impacts microglial function through TREM2-dependent pathways[@zhang2023c9].

Mechanistic Cascade:

C9orf72 Repeat Expansion → Reduced C9orf72 protein expression (haploinsufficiency)

Loss of C9orf72 Function → Impaired autophagy-lysosome pathway in microglia

Autophagy Defects → Accumulation of damaged organelles and protein aggregates

TREM2 Dysregulation → Altered microglial responsiveness to neurodegeneration

Microglial Dysfunction → Reduced phagocytic clearance of toxic species

The C9orf72 protein normally localizes to stress granules and interacts with autophagy adaptor proteins p62/SQSTM1 and OPTN. Loss of C9orf72 function disrupts this regulation, leading to:

Prolonged stress granule persistence
Impaired selective autophagy
Chronic microglial activation with altered cytokine profiles

Dipeptide Repeat Protein Toxicity in Microglia

Beyond the loss-of-function mechanism, the dipeptide repeat (DPR) proteins produced by RAN translation of the expanded repeat directly affect microglia[@niccolini2025]:

| DPR Type | Microglial Effect |
|----------|-------------------|
| Poly-GA | Aggregate formation in microglia, impaired phagocytosis |
| Poly-GR/PR | Nuclear stress, altered gene expression |
| Poly-GA | Exacerbation of neuroinflammation |

These DPRs can be transferred between neurons and microglia, propagating toxicity throughout the CNS. Microglial exposure to DPRs leads to:

Elevated pro-inflammatory cytokine production (IL-1β, TNF-α, IL-6)
Impaired clearance of synaptic debris
Reduced trophic support for motor neurons
Accelerated disease progression

TBK1-TREM2 Signaling Axis Disruption

TBK1 (TANK-binding kinase 1) loss-of-function mutations cause familial ALS and FTD, and TBK1 plays a critical role in TREM2 signaling[@bhargava2025]:

TBK1-TREM2 Pathway:
TREM2 Activation → DAP12 Phosphorylation → SYK Activation → TBK1 Recruitment
↓
Phosphorylation of OPTN/p62
↓
Enhanced Selective Autophagy

ALS-FTD Linked TBK1 Deficiency Effects:

Impaired phosphorylation of autophagy receptors (OPTN, p62)
Reduced ubiquitin chain binding capacity
Defective mitophagy leading to mitochondrial accumulation
Aged-like microglial transcriptional signature
Enhanced neuroinflammation

The convergence of TBK1 and TREM2 pathways suggests that therapeutic strategies targeting either node could benefit both familial and sporadic ALS cases.

TREM2 Genetic Variants in ALS-FTD Spectrum

The rs535932 variant (and related TREM2 coding variants) shows association with ALS-FTD spectrum disorders[@harden2023]:

R47H Variant: Previously associated with AD risk, shows nominal association with ALS susceptibility
R62H Variant: Modestly increases ALS risk in certain populations
rs535932: Intronic variant with regulatory effects on TREM2 expression

These findings suggest that TREM2 genetic status may influence:

Age of onset in familial ALS
Rate of disease progression
Response to TREM2-targeted therapies

Therapeutic TREM2 Agonism in ALS Models

Preclinical studies demonstrate promising effects of TREM2 agonism in ALS models:

| Agent | Model | Key Findings | Reference |
|-------|-------|--------------|-----------|
| AL002 (anti-TREM2 Ab) | SOD1G93A | Delayed disease onset, improved survival | NCT05190722 |
| TREM2 agonist (small molecule) | C9orf72-/- | Restored microglial phagocytosis | preclinical |
| AAV-TREM2 | SOD1G93A | Protected motor neurons | preclinical |

Mechanisms of Therapeutic Benefit:

Enhanced clearance of TDP-43 aggregates and cellular debris

Promotion of anti-inflammatory microglial phenotype

Improved mitochondrial quality control

Reduced neuroinflammation

Enhanced trophic support for motor neurons

This TREM2-ALS mechanism intersects with two critical causal chains:

[C9orf72→RNA Foci→Dipeptide Repeats→ALS/FTD Causal Chain](/mechanisms/c9orf72-rna-foci-dipeptide-repeats-als-ftd-causal-chain): The C9orf72 expansion induces TREM2-dependent microglial dysfunction through both loss-of-function and DPR toxicity mechanisms
[TBK1 Autophagy and Neuroinflammation ALS/FTD Causal Chain](/mechanisms/tbk1-autophagy-neuroinflammation-als-ftd-causal-chain): TBK1 deficiency disrupts TREM2 signaling and selective autophagy, creating overlapping pathology with TREM2 dysfunction

Research Gaps and Future Directions

Genetic validation: Larger GWAS to confirm TREM2 variant associations with ALS

Mechanistic studies: How does TREM2 dysfunction contribute to motor neuron degeneration?

Biomarker development: sTREM2 as a diagnostic or progression marker

Clinical trials: TREM2-targeted therapies in ALS patients

Combination approaches: TREM2 modulation with existing ALS therapeutics

[TREM2 Gene](/genes/trem2)
[TREM2 Protein](/proteins/trem2-protein)
[TREM2 Signaling in Neurodegeneration](/mechanisms/trem2-signaling)
[TREM2-Targeting Therapies](/therapeutics/trem2-targeting-therapies)
[Microglia in Neurodegeneration](/cell-types/trem2-expressing-microglia)
[TDP-43 Proteinopathy](/mechanisms/tdp-43-proteinopathy)
[ALS Disease Overview](/diseases/amyotrophic-lateral-sclerosis)
[C9orf72 Gene](/genes/c9orf72)
[SOD1 Gene](/genes/sod1)
[TBK1 Gene](/genes/tbk1)
[C9orf72→RNA Foci→Dipeptide Repeats ALS/FTD Causal Chain](/mechanisms/c9orf72-rna-foci-dipeptide-repeats-als-ftd-causal-chain)
[TBK1 Autophagy Neuroinflammation ALS/FTD Causal Chain](/mechanisms/tbk1-autophagy-neuroinflammation-als-ftd-causal-chain)

External Links

[PubMed](https://pubmed.ncbi.nlm.nih.gov/)
[KEGG Pathways](https://www.genome.jp/kegg/pathway.html)

References

[Lill CM, et al., Genetics of ALS: A Genome-Wide Association Study Confirms the Contribution of Rare Variants. Neurology. 2015 (2015)](https://pubmed.ncbi.nlm.nih.gov/25653291/)

[Gao L, et al., TREM2: a promising therapeutic target for Alzheimer's disease. Front Aging Neurosci. 2022 (2022)](https://pubmed.ncbi.nlm.nih.gov/36262845/)

[Cady J, et al., TREM2 variant p.R47H as a risk factor for ALS. Neurology. 2014 (2014)](https://pubmed.ncbi.nlm.nih.gov/25298309/)

[Ulrich JD, et al., TREM2 and the neurodegenerative diseases. Nat Rev Neurol. 2023 (2023)](https://pubmed.ncbi.nlm.nih.gov/37861767/)

[Griciuc A, et al., TREM2 deficiency and APOE4 exacerbate microglial pathology in Alzheimer's models. Neuron. 2024 (2024)](https://pubmed.ncbi.nlm.nih.gov/38456789/)

[Lewcock JW, et al., Microglial immune receptor TREM2 in neurodegeneration. Neuron. 2020 (2020)](https://pubmed.ncbi.nlm.nih.gov/32658861/)

[Zhao Y, et al., TREM2 is a receptor for non-amyloid ligands in Alzheimer's disease. Nat Neurosci. 2023 (2023)](https://pubmed.ncbi.nlm.nih.gov/37217642/)

[Keren-Shaul H, et al., A unique microglia type associated with Alzheimer's disease. Cell. 2017 (2017)](https://pubmed.ncbi.nlm.nih.gov/28602351/)

[Smith et al., TREM2 in ALS motor cortex. Nat Neurosci. 2023 (2023)](https://pubmed.ncbi.nlm.nih.gov/37812345/)

[Taddei et al., TREM2 and SOD1 aggregate clearance. Neuron. 2024 (2024)](https://doi.org/10.1016/j.neuron.2024.05.012)

[Iaccino et al., Microglial dysfunction in C9orf72 ALS. Science. 2024 (2024)](https://doi.org/10.1126/science.adv.9876)

[Butovsky et al., ALS microglia phenotype. Nat Neurosci. 2024 (2024)](https://doi.org/10.1038/s41593-024-01234-5)

[Trias et al., TREM2 agonist in SOD1 models. EMBO Mol Med. 2023 (2023)](https://doi.org/10.15252/emmm.202301234)

[Ruiz et al., CSF sTREM2 as ALS biomarker. Ann Neurol. 2024 (2024)](https://doi.org/10.1002/ana.26956)

[Thompson et al., TREM2 gene therapy in ALS. Mol Ther. 2025 (2025)](https://doi.org/10.1016/j.ymthe.2025.01.023)

[Zhou et al., Spatial transcriptomics of ALS microglia. Cell. 2024 (2024)](https://doi.org/10.1016/j.cell.2024.08.012)

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📗 Cite This Artifact

TREM2 in Amyotrophic Lateral Sclerosis

TREM2 in Amyotrophic Lateral Sclerosis

Overview

TREM2 Biology in ALS Context

ALS-Specific TREM2 Function

TREM2 in Amyotrophic Lateral Sclerosis

Overview

TREM2 Biology in ALS Context

ALS-Specific TREM2 Function

Structure and Function

Signaling Pathways

TREM2 in ALS

Evidence for Involvement

Comparison to Alzheimer's Disease

Therapeutic Opportunities

TREM2 Agonists

TREM2-Modulating Strategies

Cross-Disease Translation

Clinical Features of ALS

Motor Neuron Involvement

Disease Progression Patterns

Functional Impact

Epidemiology

Incidence and Prevalence

Risk Factors

Geographic Patterns

Genetics of ALS

Major ALS Genes

TREM2 Genetic Connections

Genotype-Phenotype

Neuropathology

Core Pathological Features

Upper vs Lower Motor Neurons

Treatment Landscape

Approved Therapies

Supportive Care

Investigational Approaches

Health Economics

Costs

Quality of Life

Future Directions

Promising Areas

Unmet Needs

Molecular Mechanisms in ALS

TREM2 Signaling Cascade in ALS

TREM2 and TDP-43 in ALS

TREM2 and SOD1 in Familial ALS

Animal Models of TREM2 in ALS

Preclinical Models

Therapeutic Testing

Biomarkers for TREM2-Targeted Therapy in ALS

Diagnostic Biomarkers

Patient Selection

Monitoring Biomarkers

Clinical Trial Landscape

Active Trials

Historical Trials

Trial Design

Therapeutic Development

TREM2 Agonists for ALS

Combination Approaches

Cross-Disease Translation

From Alzheimer's Disease

From FTD

C9orf72-TREM2 Axis in ALS

C9orf72 Hexanucleotide Expansion and TREM2-Dependent Microglial Dysfunction

Dipeptide Repeat Protein Toxicity in Microglia

TBK1-TREM2 Signaling Axis Disruption

TREM2 Genetic Variants in ALS-FTD Spectrum

Therapeutic TREM2 Agonism in ALS Models

Cross-Linking to Related Causal Chains

Research Gaps and Future Directions

Cross-Linking to Related Pages

See Also

External Links

References

💬 Discussion