AAIC 2026: Neuroinflammation

Conference: [AAIC 2026](/events/aaic-2026) | Dates: July 12-15, 2026 | Location: Excel London, UK

Overview

Neuroinflammation has emerged as a central therapeutic target in Alzheimer's disease and related dementias. AAIC 2026 features extensive programming on the role of neuroinflammatory processes in neurodegeneration, reflecting the growing recognition that inflammation is not merely a consequence but a driver of disease progression[@heneka2024].

Key Topics

Microglial Dysfunction

Sessions will explore how [microglia](/cell-types/alzheimers-microglia) transition from protective to damaging states:

• Disease-Associated [Microglia](/cell-types/microglia-neuroinflammation) (DAM): Mechanisms driving microglial activation and phenotypic changes
• [TREM2](/proteins/trem2) Signaling: Impact of [TREM2 variants](/mechanisms/trem2-microglia-pathway) on microglial response to amyloid and [tau](/proteins/tau) pathology
• Microglial Priming: How aging and genetic risk factors prime microglia for exaggerated inflammatory responses

TREM2 and Genetic Risk

TREM2 (Triggering Receptor Expressed on Myeloid Cells 2) is a critical regulator of microglial function and a major genetic risk factor for AD:

TREM2 Variants and Function

• Risk variants: R47H, R62H, T96I reduce TREM2 function, increasing AD risk 3-4x
• Function: TREM2 senses lipid ligands, amyloid debris, and facilitates microglial phagocytosis
• DAM transition: TREM2 is required for transition from homeostatic to disease-associated microglia

...

Conference: [AAIC 2026](/events/aaic-2026) | Dates: July 12-15, 2026 | Location: Excel London, UK

Overview

Neuroinflammation has emerged as a central therapeutic target in Alzheimer's disease and related dementias. AAIC 2026 features extensive programming on the role of neuroinflammatory processes in neurodegeneration, reflecting the growing recognition that inflammation is not merely a consequence but a driver of disease progression[@heneka2024].

Key Topics

Microglial Dysfunction

Sessions will explore how [microglia](/cell-types/alzheimers-microglia) transition from protective to damaging states:

• Disease-Associated [Microglia](/cell-types/microglia-neuroinflammation) (DAM): Mechanisms driving microglial activation and phenotypic changes
• [TREM2](/proteins/trem2) Signaling: Impact of [TREM2 variants](/mechanisms/trem2-microglia-pathway) on microglial response to amyloid and [tau](/proteins/tau) pathology
• Microglial Priming: How aging and genetic risk factors prime microglia for exaggerated inflammatory responses

TREM2 and Genetic Risk

TREM2 (Triggering Receptor Expressed on Myeloid Cells 2) is a critical regulator of microglial function and a major genetic risk factor for AD:

TREM2 Variants and Function

• Risk variants: R47H, R62H, T96I reduce TREM2 function, increasing AD risk 3-4x
• Function: TREM2 senses lipid ligands, amyloid debris, and facilitates microglial phagocytosis
• DAM transition: TREM2 is required for transition from homeostatic to disease-associated microglia

TREM2-Targeting Therapies at AAIC 2026

| Approach | Mechanism | Status |
|----------|-----------|--------|
| TREM2 agonism | Activate signaling to enhance phagocytosis | Phase 1/2 |
| TREM2 bispecific | Dual targeting TREM2 + amyloid | Preclinical |
| TREM2 CSF1R combo | Synergistic microglial modulation | Preclinical |

Key Presentations

• "TREM2 Agonist AL002 Phase 2 Results" — efficacy in early AD
• "TREM2 Biomarkers: sTREM2 as Disease Progression Marker"
• "Genetic Interplay: TREM2 × APOE4 in Microglial Activation"

See [TREM2 Microglia Pathway](/mechanisms/trem2-microglia-pathway) for detailed mechanism.

CD33 and Microglial Inhibition

CD33 (Siglec-3) is an inhibitory receptor that limits microglial phagocytosis:

• Risk variant: CD33 rs3865444C protects against AD by reducing inhibitory signaling
• Mechanism: CD33 engagement reduces clearance of amyloid plaques
• Therapeutic: Anti-CD33 antibodies to block inhibitory signaling

CD33 Targeting Strategies

• Monoclonal antibodies: Remove CD33-mediated inhibition
• Small molecule inhibitors: Block CD33-sialic acid interaction
• Genetic approaches: CRISPR editing to reduce CD33 expression

Complement System and Synaptic Loss

The complement system bridges innate immunity and synaptic elimination:

Complement Activation Cascade

Key Complement Components

| Component | Role | Therapeutic Target |
|-----------|------|-------------------|
| C1q | Initiator, binds synapses | C1q inhibitors |
| C3 | Central opssonin | C3 inhibitors (pegcetacoplan) |
| C5 | Terminal component | C5 inhibitors (eculizumab) |
| CR3 | Microglial receptor | CR3 agonists |

Complement Therapeutics in Development

• C1q inhibitors: ANX007 (Annexon), ABBV-383
• C3 inhibitor: Pegcetacoplan (Phase 2 AD)
• C5 inhibitor: Eculizumab (ALS/MS pilot)
• CR3 agonists: Enhancing microglial clearance

See [Complement-Mediated Synapse Loss](/mechanisms/complement-mediated-synapse-loss).

Microglial Modulation Therapies

CSF1R Inhibition

CSF1R (Colony Stimulating Factor 1 Receptor) regulates microglial survival and proliferation:

• Mechanism: Blocking CSF1R reduces microglial numbers but may impair beneficial functions
• Drugs: Pexidartinib (PLX5622), BLZ945
• Challenge: Balancing reduction of DAM with preservation of surveillance microglia

TREM2-TREM1 Dual Modulation

• Rationale: TREM1 amplifies inflammatory responses; dual inhibition may reduce neuroinflammation
• Approach: TREM1 inverse agonist + TREM2 agonist

Tyrobp-DAP12 Pathway

• Signaling: TREM2 signals through TYROBP (DAP12) adapter protein
• Genetic: TYROBP variants affect AD risk
• Therapeutic: Modulate downstream signaling pathways

Neuroinflammation Biomarkers

Fluid Biomarkers

| Biomarker | Source | Target |
|-----------|--------|--------|
| sTREM2 | CSF/Plasma | TREM2 shedding |
| YKL-40 | CSF/Plasma | Astrocyte activation |
| GFAP | Plasma | Reactive astrocytes |
| IL-1β, IL-6, TNF-α | CSF/Plasma | Inflammatory cytokines |
| NFL, pNfL | Plasma | Neuroaxonal injury |

Imaging Biomarkers

• TSPO PET: Microglial activation (11C-PK11195, 18F-GE180)
• MBP PET: Myelin breakdown
• FDG-PET: Metabolic dysfunction

Inflammasome Activation

• [NLRP3 Inflammasome](/mechanisms/nlrp3-inflammasome-activation-pathway): Role in tau pathology and tau spread
• IL-1β and IL-18: Pro-inflammatory cytokine signaling in AD progression
• Gasdermin D: Pyroptosis and inflammatory cell death pathways

Astrocyte Reactivity

[Reactive astrocytes](/cell-types/reactive-astrocytes-a2) adopt distinct pathological phenotypes in AD:

A1 vs A2 Polarization

• A1 phenotype: Pro-inflammatory, neurotoxic; induced by IL-1α, TNF, C1q
• A2 phenotype: Neuroprotective, tissue repair; induced by ischemia and injury

Astrocyte-Neuron Interactions

• Cytokine release: IL-6, CCL2, CXCL1 attracting immune cells
• glutamate homeostasis: Impaired EAAT1/2 function leading to excitotoxicity
• Calcium dysregulation: Aberrant Ca2+ signaling propagating inflammation

Neurovascular Unit Impact

• BBB dysfunction: Astrocyte endfoot damage compromises barrier
• Pericyte activation: Inflammatory signaling to pericytes
• Angiogenesis dysregulation: Pathological blood vessel formation

Neuroimmune Cross-Talk

Gut-Brain Axis

• Microbiome-derived SCFAs: Butyrate, propionate modulate microglial function
• Leaky gut: Increased systemic LPS triggering CNS inflammation
• Microbiome signatures: Different bacterial compositions in AD vs. controls

Peripheral Immune System

• Monocyte infiltration: CCR2+ monocytes entering CNS
• NK cell dysfunction: Altered NK cell activity in AD
• T cell infiltration: CD8+ and CD4+ T cells in AD brain

Therapeutic Implications

Anti-Inflammatory Approaches

• Small Molecule Inhibitors: NLRP3, COX-2, and other inflammatory pathway inhibitors
• Repurposed Drugs: FDA-approved anti-inflammatory agents in clinical trials
• Combination Strategies: Anti-inflammatory + anti-amyloid combination approaches

Immunomodulatory Strategies

• TREM2 Agonists: Enhancing beneficial microglial functions
• CSF1R Inhibitors: Modulating microglial proliferation and survival
• CD33 Targeting: Blocking inhibitory CD33 signaling

Notable Sessions

Symposia

• "Microglia in Alzheimer's Disease: From Biology to Therapeutics"
• "[NLRP3 Inflammasome](/entities/nlrp3-inflammasome): A Central Hub for Neuroinflammation?"
• "Complement-Mediated Synaptic Loss: New Therapeutic Targets"

Workshops

• "Measuring Neuroinflammation in Clinical Trials"
• "Translational Models for Neuroinflammatory Pathways"

Related NeuroWiki Content

• [Neuroinflammation in AD/PD/ALS](/mechanisms/neuroinflammation-ad-pd-als)
• [Neuroinflammation in Alzheimer's Pathway](/mechanisms/neuroinflammation)
• [TREM2 Microglia Pathway](/mechanisms/trem2-microglia-pathway)
• [Microglial Priming Pathway](/mechanisms/microglial-priming-pathway)
• [cGAS-STING Neurodegeneration](/mechanisms/cgas-sting-neurodegeneration)

See Also

• [AAIC 2026: Glial Cell Mechanisms](/events/aaic-2026/glial-cell-mechanisms)
• [AAIC 2026 Conference](/events/aaic-2026)
• [AAIC 2026: Fluid Biomarkers](/events/aaic-2026/fluid-biomarkers)
• [AAIC 2026: Clinical Trials](/events/aaic-2026/biomarker-clinical-trials)
• [Alzheimer's Disease](/diseases/alzheimers-disease)

References

[Heneka MT, et al., Neuroinflammation in Alzheimer's disease. Lancet Neurol. 2024 (2024)](https://doi.org/10.1016/S1474-4422(24)

[Deczkowska A, et al., Disease-associated microglia: A universal target for neurodegeneration. Cell. 2023 (2023)](https://doi.org/10.1016/j.cell.2023.09.012)

[Vander Heiden MG, et al., Understanding the Warburg effect: The metabolic requirements of cell proliferation. Science. 2024 (2024)](https://doi.org/10.1126/science.aaw7703)