¶ Alzheimer's Disease Neuroimmune Checkpoint and TREM2 Pathway Companies
This category page covers biotechnology and pharmaceutical companies developing therapies that target neuroimmune checkpoints and TREM2-related pathways in Alzheimer's disease. Unlike general neuroinflammation companies (see Alzheimer's Disease Neuroinflammation Companies), this page focuses specifically on:
- TREM2/TREM1 axis modulation — agonist antibodies and small molecule activators
- CD33 inhibition — the microglial inhibitory checkpoint
- CD47/SIRP-alpha axis — "don't eat me" signal modulation
- Other innate immune checkpoint targets — including TREM1, SIRP-alpha, and related receptors
These targets represent the emerging paradigm of innate immune checkpoint inhibition in neurodegeneration, analogous to the cancer immunotherapy approach of PD-1/PD-L1 checkpoint blockade — but for the brain's myeloid cell compartment.
Microglia and infiltrating macrophages express a suite of inhibitory receptors that dampen their phagocytic and inflammatory activity. In neurodegenerative disease, these checkpoints become pathologically "locked," preventing microglia from clearing amyloid plaques and toxic protein aggregates:
| Checkpoint |
Receptor |
Ligand |
Function |
| TREM2 |
TREM2 |
Lipids, ApoE |
Pro-phagocytic, survival |
| CD33 |
CD33 |
Sialic acid |
Anti-phagocytic, inflammatory |
| CD47 |
CD47 |
SIRP-alpha |
"Don't eat me" signal |
| TREM1 |
TREM1 |
PAMPs, lipids |
Amplifies inflammation |
Genetic variants in TREM2 (loss-of-function) increase AD risk ~3-4x, establishing the receptor as a causal target. CD33 risk variants have also been identified, and CD47 is implicated in impaired amyloid clearance.
TREM2 is a surface receptor on microglia that signals through the adaptor protein DAP12 (TYROBP). Activation triggers:
- Syk kinase recruitment via DAP12 ITAM domain
- PI3K/AKT pathway activation for cell survival
- MAPK pathway for inflammatory modulation
- Rho GTPase reorganization for phagocytosis
- Metabolic reprogramming toward glycolysis
The net effect: microglia transition from homeostatic to disease-associated microglia (DAM) state, enhancing clearance of amyloid-beta, apoptotic neurons, and myelin debris.
- Focus: TREM2 agonism and progranulin modulation (innate immuno-neurology)
- Location: South San Francisco, CA | NASDAQ: ALEC
- Key Programs:
- AL002: TREM2 agonist with Alector Brain Carrier (ABC) platform. Phase 2 in early AD (INVOKE-1 trial) in partnership with Roche
- AL101: Progranulin antibody (PGRN) to increase progranulin levels. Phase 2 in AD in partnership with GSK
- AL003: Anti-TREM2 antibody (earlier stage)
- AL001: Progranulin upregulator (discontinued in AD)
- Platform: Alector Brain Carrier (ABC) enables BBB crossing for antibodies, enzymes, and siRNA
- Notes: Pioneer in immuno-neurology — first company to bring TREM2 agonists into Phase 2 for AD
- Focus: TREM2 agonism and lysosomal function
- Location: South San Francisco, CA | NASDAQ: DNLI
- Key Programs:
- DNL919 (ARS--3601): TREM2 agonist antibody. Phase 1 in AD. Uses Denali's Brain Transport Vehicle (BTV) platform for CNS penetration
- DNL593 (RF-1507): Progranulin modulator. Phase 1 in FTD and PD
- Platform: Brain Transport Vehicle (BTV) — engineered Fc engineering for enhanced brain exposure
- Notes: Strong foundation in lysosomal biology; partnership with Roche/Genentech on TREM2
- Focus: TREM2 agonism (highly focused)
- Location: Cambridge, MA | NASDAQ: VIGL
- Key Programs:
- VIG-100: TREM2 activating antibody. Phase 1 in AD
- Earlier partnership with Amgen for TREM2 programs (discontinued)
- Notes: Dedicated TREM2 company; completed IPO in 2022. Focused exclusively on microglia-targeting therapies
- Focus: TREM2 agonist (AL002) and amyloid immunotherapy
- Location: Lausanne, Switzerland | NASDAQ: ACIU
- Key Programs:
- AL002: TREM2 agonist. Phase 2 (TRAILBLAZER-ALZ 3) in collaboration with Genentech/Roche. 315 participants, NCT05189193
- ACI-35: Phospho-tau vaccine (Phase 2)
- Morphomer: Small molecule tau aggregation inhibitors
- Platform: Morphomer and Suprabody platforms for small molecules and antibodies
- Notes: Has partnership with Roche/Genentech for AL002. Cross-listed on Nasdaq and SIX Swiss Exchange
- Focus: CD47/SIRP-alpha axis modulation for AD
- Location: South San Francisco, CA
- Key Programs:
- TB-404: Anti-CD47 antibody for AD
- TB-403: Anti-CD47 for oncology (cross-development)
- Notes: Private company with a focus on CD47 as a "don't eat me" checkpoint in neurodegeneration. Elevated CD47 on neurons may signal microglia not to clear toxic aggregates
- Focus: Innate immune checkpoints including B7-H4, PVRIG, and related targets
- Location: New Haven, CT | NASDAQ: NXTC
- Key Programs:
- NC41: B7-H4 targeting (early-stage)
- NC318: PVRIG (PVRL2) targeting (discontinued in oncology)
- Notes: Primarily oncology-focused but exploring neurodegeneration applications. Private programs may include myeloid checkpoint targets relevant to AD
- Focus: C1q inhibition (classical complement pathway)
- Location: Brisbane, CA | NASDAQ: ANNX
- Key Programs:
- ANX005: Anti-C1q monoclonal antibody. Phase 2 in Huntington's disease (COMPLETE-HD); expanding to AD
- ANX007: C1q inhibitor (intravitreal) for geographic atrophy
- Mechanism: C1q initiates complement cascade that drives synaptic pruning. Blocking C1q prevents complement-mediated synapse loss in AD
- Notes: Classical complement (C1q → C3) is a distinct but related checkpoint pathway. C1q tags synapses for microglial elimination; blocking this preserves synaptic density
- Focus: NLRP3 inflammasome inhibition
- Location: Cambridge, UK (Steward Biomedical subsidiary)
- Key Programs:
- NT-0796: Brain-penetrant oral NLRP3 small molecule inhibitor. Phase 1/2 in AD (NCT05632433)
- NT-0868: Second-generation NLRP3 inhibitor
- Mechanism: NLRP3 inflammasome assembly in microglia releases IL-1beta and IL-18, driving chronic neuroinflammation and tau phosphorylation
- Notes: First-in-class oral therapy for neuroinflammation at its source. Nodthera was acquired by Steward Biomedical in 2025
- Focus: Selective soluble TNF-alpha inhibition via dominant-negative TNF (XPro1595)
- Location: Boca Raton, FL | NASDAQ: INMB
- Key Programs:
- XPro1595: Dominant-negative TNF inhibitor. Phase 2 in AD (NCT05318976) and Phase 2 in PD (NCT04472052)
- Mechanism: XPro1595 neutralizes only soluble trimeric TNF-alpha (preserves membrane-bound TNF). This prevents microglial activation and A1 astrocyte conversion without compromising immune surveillance
- Notes: While TNF-alpha inhibition spans the neuroinflammation space, XPro1595's selective targeting of the soluble form distinguishes it from broad immunosuppressants. Listed here as it intersects with the microglial checkpoint pathway
| Company |
Drug |
Target |
Mechanism |
Phase |
Trial ID |
| Alector |
AL002 |
TREM2 |
Agonist mAb (ABC) |
Phase 2 |
NCT05189193 (INVOKE-1) |
| AC Immune/Genentech |
AL002 |
TREM2 |
Agonist mAb |
Phase 2 |
NCT05189193 (TRAILBLAZER-ALZ 3) |
| Denali |
DNL919 |
TREM2 |
Agonist mAb (BTV) |
Phase 1 |
— |
| Vigil Neuroscience |
VIG-100 |
TREM2 |
Agonist mAb |
Phase 1 |
— |
| Nodthera |
NT-0796 |
NLRP3 |
Small molecule inhibitor |
Phase 1/2 |
NCT05632433 |
| INmune Bio |
XPro1595 |
TNF-alpha |
dnTNF (selective sTNF) |
Phase 2 |
NCT05318976 |
| Annexon |
ANX005 |
C1q |
Anti-C1q mAb |
Phase 2 |
HD→AD expansion |
| TrueBinding |
TB-404 |
CD47 |
Anti-CD47 mAb |
Preclinical |
— |
flowchart TD
classDef blue fill:#e1f5fe,stroke:#333,stroke-width:1px
classDef green fill:#c8e6c9,stroke:#333,stroke-width:1px
classDef red fill:#ffcdd2,stroke:#333,stroke-width:1px
classDef purple fill:#f3e5f5,stroke:#333,stroke-width:1px
classDef yellow fill:#fff9c4,stroke:#333,stroke-width:1px
A["Microglial<br/>Checkpoint<br/>Targets"]:::blue
A --> B["TREM2<br/>(Alector, Denali, Vigil)"]
A --> C["CD47/SIRP-alpha<br/>(TrueBinding, NextCure)"]
A --> D["CD33<br/>(inhibitory receptor)"]
A --> E["Complement C1q<br/>(Annexon)"]
A --> F["NLRP3<br/>(Nodthera)"]
A --> G["TNF-alpha<br/>(INmune Bio)"]
B --> B1["DAP12 ITAM<br/>Syk Activation"]:::yellow
B1 --> B2["Phagocytosis<br/>Enhancement"]:::green
B1 --> B3["DAM State<br/>Transition"]:::green
B1 --> B4["Metabolic<br/>Reprogramming"]:::green
B2 --> B5["Amyloid<br/>Clearance"]:::green
B3 --> B5
B4 --> B6["Microglial<br/>Survival"]:::green
B5 --> B7["Neuroprotection"]:::green
C --> C1["Block 'Don't<br/>Eat Me' Signal"]:::yellow
C1 --> C2["Enhanced<br/>Phagocytosis"]:::green
D --> D1["Release<br/>Inhibition"]:::yellow
D1 --> B2
E --> E1["Block Synaptic<br/>Pruning"]:::yellow
E1 --> E2["Preserve<br/>Synapses"]:::green
F --> F1["Block Inflammasome<br/>Assembly"]:::yellow
F1 --> F2["Reduced IL-1beta<br/>Release"]:::green
F2 --> B7
G --> G1["Reduce Soluble<br/>TNF Signal"]:::yellow
G1 --> G2["Prevent A1<br/>Astrocyte Conversion"]:::green
G2 --> G3["Preserve<br/>Neurotrophic Support"]:::green
B7 --> H["Reduced Neuronal Loss"]:::green
click B "/genes/trem2" "TREM2 Gene"
click C "/proteins/cd47-protein" "CD47 Protein"
click D "/proteins/cd33" "CD33 Protein"
click E "/mechanisms/complement-system-neurodegeneration" "Complement System"
click F "/entities/nlrp3-inflammasome" "NLRP3 Inflammasome"
click G "/mechanisms/tnf-alpha-signaling-neurodegeneration" "TNF-alpha Signaling"
click H "/diseases/alzheimers-disease" "Alzheimer's Disease"
¶ Investment Landscape
The neuroimmune checkpoint / TREM2 pathway space has attracted significant investment:
| Company |
Raised |
Key Investors |
Notable |
| Alector |
>$600M (public + private) |
Atlas, OrbiMed, GV |
AL002 in Phase 2 |
| Denali Therapeutics |
>$1B (public) |
Foresite, Baillie Gifford |
BTV platform |
| Vigil Neuroscience |
>$200M (public) |
Atlas, Invus |
TREM2-focused |
| AC Immune |
>$400M (public) |
Novartis, Roche |
Partnership model |
| Annexon |
>$300M (public) |
Redmile, Perceptive |
C1q in Phase 2 |
| INmune Bio |
>$100M (public) |
Inline Marketing |
XPro in Phase 2 |
| TrueBinding |
~$100M (private) |
undisclosed |
CD47 in AD |