Conference: AAIC 2026 | Dates: July 12-15, 2026 | Location: Excel London, UK
Glial cells—microglia and astrocytes—have emerged as central players in Alzheimer's disease pathogenesis and represent promising therapeutic targets. AAIC 2026 features extensive research on glial biology, reflecting the field's recognition that neurodegenerative processes involve complex non-neuronal interactions[@aao2026].
Disease-associated microglia represent a distinct microglial activation state observed in Alzheimer's disease and other neurodegenerative conditions[@deczkowska2023]:
flowchart TD
A["Homeostatic Microglia"] --> B["Stage 1 DAM: TREM2-independent"]
B --> C["Stage 2 DAM: TREM2-dependent"]
C --> D["Neurodegeneration Associated"]
A -->|"Aging, Aβ"| B
B -->|"TREM2 activation"| C
C -->|"Chronic inflammation"| D
style A fill:#e1f5fe,stroke:#01579b
style B fill:#fff3e0,stroke:#e65100
style C fill:#ffebee,stroke:#c62828
style D fill:#fce4ec,stroke:#ad1457
Key DAM Characteristics:
- Stage 1 DAM: Initial response to amyloid pathology; TREM2-independent
- Stage 2 DAM: Requires TREM2 signaling; enhanced phagocytic capacity
- Stage 3 DAM: Associated with neurodegeneration; may become maladaptive
DAM Markers:
TREM2 (Triggering Receptor Expressed on Myeloid Cells 2) is a critical regulator of microglial function:
flowchart LR
subgraph Extracellular
A["Aβ plaques / Lipid ligands"] --> B["TREM2"]
end
subgraph Signaling
B --> C["TYROBP / DAP12"]
C --> D["Syk kinase"]
D --> E["PI3K/Akt"]
D --> F["ERK1/2"]
D --> G["NF-κB"]
end
subgraph Outcomes
E --> H["Phagocytosis / Migration"]
F --> I["Survival / Proliferation"]
G --> J["Inflammatory Response"]
end
style B fill:#b3e5fc,stroke:#0277bd
style C fill:#b3e5fc,stroke:#0277bd
TREM2 Variants and AD Risk:
| Variant |
Risk Effect |
Functional Impact |
| R47H |
3-4x increased |
Impaired lipid sensing |
| R62H |
2-3x increased |
Reduced ligand binding |
| T96I |
1.5-2x increased |
Altered signaling |
TREM2-Targeting Therapies at AAIC 2026:
| Program |
Company |
Mechanism |
Stage |
| AL002 |
Alector/GSK |
TREM2 agonist |
Phase II |
| PY314 |
Pyroneer |
TREM2 agonist |
Phase I |
| SAR-443122 |
Sanofi |
TREM2 inverse agonist |
Phase I |
See TREM2 Microglia Pathway for detailed mechanism.
Microglial priming describes the sensitization of microglia to produce exaggerated inflammatory responses:
Priming Factors:
- Aging
- APOE4 allele carriage
- Previous neuroinflammatory events
- Systemic infection
Primed Microglia Characteristics:
- Enhanced baseline cytokine production
- Exaggerated response to secondary challenges
- Impaired surveillance function
CSF1R (Colony Stimulating Factor 1 Receptor) regulates microglial survival and proliferation:
flowchart TD
A["CSF1 / IL-34"] --> B{"CSF1R"}
B --> C["Microglial Survival"]
B --> D["Proliferation"]
B --> E["Differentiation"]
F["CSF1R antagonist: PLX5622 / Pexidartinib"] --> B
F -.->|"Block"| C
F -.->|"Block"| D
F -.->|"Block"| E
style F fill:#ffcdd2,stroke:#c62828
Clinical Considerations:
- CSF1R blockade reduces microglial numbers
- Risk of impairing beneficial surveillance functions
- May need cell-type specific targeting
The complement system mediates synaptic elimination by microglia:
flowchart TD
A["Aβ or tau pathology"] --> B["Microglial activation"]
B --> C["C1q initiation"]
C --> D["C3b opsonization"]
D --> E["CR3-mediated phagocytosis"]
E --> F["Synaptic loss"]
C --> G["C3a inflammation"]
G --> H["Enhanced neuroinflammation"]
style F fill:#ffcdd2,stroke:#c62828
| Target |
Drug |
Company |
Status |
| C1q |
ANX007 |
Annexon |
Phase II |
| C3 |
Pegcetacoplan |
Apellis |
Phase II |
| C5 |
Eculizumab |
Alexion |
Pilot |
See Complement-Mediated Synapse Loss.
Reactive astrocytes adopt distinct phenotypes in neurodegeneration[@liddelow2017]:
flowchart TD
subgraph Neurotoxic
A["Microglia: IL-1α, TNF, C1q"] --> B["A1 Astrocyte"]
B --> C["Neurotoxic"]
B --> D["Synaptic dysfunction"]
B --> E["Complement production"]
end
subgraph Neuroprotective
F["Injury / Ischemia"] --> G["A2 Astrocyte"]
G --> H["Neuroprotective"]
G --> I["Tissue repair"]
G --> J["Growth factor release"]
end
style C fill:#ffcdd2,stroke:#c62828
style H fill:#c8e6c9,stroke:#2e7d32
A1 Astrocyte Markers:
A2 Astrocyte Markers:
Neurotoxic Effects:
- Impaired glutamate homeostasis (reduced EAAT1/2)
- Release of pro-inflammatory cytokines
- Complement component production
Therapeutic Implications:
- Block A1-inducing factors (IL-1α, TNF, C1q)
- Promote A2 phenotype conversion
- Enhance astrocyte support functions
flowchart LR
subgraph Microglia
A["Activated Microglia"]
end
subgraph Signaling
B["IL-1α / TNF / C1q"]
C["IL-10 / TGF-β"]
end
subgraph Astrocytes
D["Reactive Astrocytes"]
end
A -->|"Pro-inflammatory"| B
B -->|"Induces"| D
A -->|"Anti-inflammatory"| C
C -->|"Promotes"| D
style A fill:#b3e5fc,stroke:#0277bd
style D fill:#fff3e0,stroke:#e65100
Gut-Brain Axis:
- Microbiome-derived SCFAs modulate glial function
- Leaky gut increases systemic LPS triggering CNS inflammation
- Microbiome signatures differ in AD vs. controls
Peripheral Immune System:
| Strategy |
Target |
Approach |
Stage |
| TREM2 agonism |
TREM2 |
Enhance phagocytosis |
Phase II |
| CSF1R inhibition |
CSF1R |
Reduce DAM |
Preclinical |
| Complement inhibition |
C1q, C3 |
Prevent synapse loss |
Phase II |
| Astrocyte modulation |
A1→A2 shift |
Reprogram phenotype |
Preclinical |
- Microglial replacement: Bone marrow transplant approaches
- Glial progenitor targeting: Induced pluripotent stem cell-derived glia
- Gene therapy: Modulate glial gene expression in vivo
| Biomarker |
Source |
Significance |
| sTREM2 |
CSF/Plasma |
TREM2 shedding, disease progression |
| YKL-40 |
CSF/Plasma |
Astrocyte activation |
| IBA1 |
Tissue |
Microglial activation marker |
| Biomarker |
Source |
Significance |
| GFAP |
Plasma |
Reactive astrogliosis |
| S100B |
CSF/Plasma |
Astrocyte damage |
- "Microglia in Alzheimer's Disease: From Biology to Therapeutics"
- "Astrocyte Reactivity: Good, Bad, or Both?"
- "Complement-Mediated Synaptic Loss: New Therapeutic Targets"
- "Glial Cell Models for Drug Discovery"
- "In Vivo Imaging of Glial Activation"
- Wang S, et al., Microglia in Alzheimer's disease: from pathogenesis to therapeutic targeting. Signal Transduct Target Ther. 2023 (2023)
- Deczkowska A, et al., Disease-associated microglia: A universal target for neurodegeneration. Cell. 2023 (2023)
- Liddelow SA, et al., Neurotoxic reactive astrocytes are induced by activated microglia. Nature. 2017 (2017)