Congress: Alzheimer's Association International Conference (AAIC) 2026
Dates: July 12-15, 2026
Location: ExCeL London, UK
Theme: Building the Roadmap to 2030
Neuroinflammation and microglial biology represent central themes at AAIC 2026, with mounting evidence that chronic neuroinflammation drives Alzheimer disease (AD) progression and that modulating microglial function offers promising therapeutic pathways[1]. This page covers key sessions on microglial activation states, TREM2 biology, complement-mediated synaptic pruning, and therapeutic approaches targeting neuroinflammation.
The disease-associated microglia (DAM) phenotype represents a critical response to AD pathology, characterized by:
- Upregulated genes: Apoe, Tyrobp, Ctsd, Itgax (CD11c)
- Activated morphology: Ramified to amoeboid transition
- Functional changes: Enhanced phagocytosis, cytokine production
- Temporal progression: Stage 1 (baseline) → Stage 2 (activated DAM)[2]
Key DAM features:
- Accumulation around amyloid plaques
- Production of inflammatory cytokines (IL-1β, TNF-α)
- Phagocytosis of synapses and cellular debris
- Support of neuronal health in early disease stages
Triggering receptor expressed on myeloid cells-2 (TREM2) is a critical microglial receptor that:
- Binds lipids and amyloid-associated patterns
- Triggers microglial phagocytosis and survival signaling
- Variant effects: R47H increases AD risk ~3x, H157Y increases risk, R62H is protective
TREM2 signaling pathways:
- DAP12 (TYROBP) adaptor protein
- PI3K/Akt pathway for survival
- MAPK/Erk pathway for activation
- NF-κB pathway for inflammation
Clinical trials and approaches:
- AL002 (Alector): TREM2 agonist showing microglial modulation
- PY314: TREM2-binding antibody
- AL003: TREM2-dependent microglial activation
The complement system mediates pathological synaptic pruning in AD[3]:
- C1q: Initiates classical complement cascade
- C3b: Opsonization of synapses
- C3: Central effector molecule
- CR3: Microglial receptor for phagocytosis
Evidence from AAIC:
- C1q localizes to synapses in AD brain
- C3 expression elevated in microglia
- Blocking C1q/C3 protects synapses in models
Therapeutic approaches:
- Anti-C1q antibodies: Prevent synapse tagging
- C3 inhibitors: Block microglial phagocytosis
- CR3 antagonists: Address microglial uptake
The NLRP3 inflammasome drives IL-1β production in AD:
- Activation by: Amyloid, ATP, ROS, mitochondrial damage
- Assembly: NLRP3 + ASC + Pro-caspase-1
- Output: IL-1β, IL-18, pyroptosis
- Therapeutic target: MCC950 (currently in trials)
Key inflammatory cytokines in AD:
| Cytokine |
Source |
Effect |
Therapeutic |
| IL-1β |
Microglia |
Neuronal dysfunction |
Anti-IL-1β (anakinra) |
| TNF-α |
Microglia |
Synapse elimination |
Anti-TNF (etanercept) |
| IL-6 |
Astrocytes |
Acute phase |
Anti-IL-6R (tocilizumab) |
Astrocytes exhibit reactive states:
- A1 (neurotoxic): Induced by microglia, lost supportive functions
- A2 (neuroprotective): Induced by ischemia, increased growth
GFAP (glial fibrillary acidic protein) is elevated in AD and serves as an astrogliosis biomarker.
Small molecule approaches:
- NLRP3 inhibitors: MCC950, DFV890
- Minocycline: Broad anti-inflammatory
Biologic approaches:
- Anti-Aβ antibodies: Leqembi, donanemab
- Anti-tau antibodies: Semorinemab
- TREM2 agonists: AL002, PY314
Expected highlights:
- TREM2 Biology: From Genetics to Therapy — Clinical update on AL002
- Complement-Mediated Synapse Loss — Basic science and therapeutics
- Targeting NLRP3 in AD — Inflammasome inhibition trials
- Microglia-Astrocyte Crosstalk — Glial interactions in disease
- Biomarker Advances — GFAP, NFL in neuroinflammation