Neuroinflammation is a central pathological feature of Alzheimer's disease (AD), involving chronic activation of microglia, astrocytes, and the complement system [1]. While neuroinflammation was originally considered a secondary response to amyloid and tau pathology, increasing evidence suggests it plays a primary role in disease progression. This page focuses on microglial-mediated neuroinflammation in AD [2].
Microglia are the resident immune cells of the CNS [3]:
| Function | Mechanism | AD Relevance |
|---|---|---|
| Surveillance | Continuous process extension | Impaired in AD |
| Phagocytosis | Clearance of debris/pathogens | Reduced in AD |
| Synaptic pruning | Complement-mediated | Excessive in AD |
| Cytokine release | Innate immune response | Dysregulated in AD |
Microglia adopt different activation states in AD [4]:
TREM2 (Triggering Receptor Expressed on Myeloid Cells 2) is a microglial receptor critical for AD:
Common AD risk variants in TREM2 [5]:
The complement system is highly activated in AD:
Classical pathway:
Consequences:
C1q marks synapses for elimination:
| Cytokine | Source | Effect in AD |
|---|---|---|
| IL-1β | Microglia, astrocytes | Pro-inflammatory, drives tau pathology |
| TNF-α | Microglia | Neurotoxic, synaptic dysfunction |
| IL-6 | Various | Acute phase, cognitive decline |
| IL-10 | Anti-inflammatory | Often elevated, may be compensatory |
Aβ plaques → Microglial activation → NF-κB activation → Pro-inflammatory cytokine release → Neuronal dysfunction
Astrocytes become reactive in AD:
Cross-talk between astrocytes and microglia:
Tau pathology and neuroinflammation interact:
| Target | Approach | Agent | Status |
|---|---|---|---|
| NSAIDs | COX inhibition | Various | Failed |
| TREM2 | Agonistic antibodies | Anti-TREM2 mAbs | Phase 2 |
| IL-1β | Receptor antagonist | Anakinra | Phase 2 |
| Complement | C1q inhibition | Anti-C1q | Preclinical |
| Strategy | Target | Status |
|---|---|---|
| TREM2 activation | TREM2 | Phase 2 |
| Colony-stimulating factor 1 receptor (CSF1R) antagonism | Microglial depletion | Preclinical |
| PPARγ agonists | Anti-inflammatory | Failed |
| Trial ID | Intervention | Population | Status |
|---|---|---|---|
| NCT01608142 | Anakinra | Mild AD | Completed |
| NCT02474948 | RG7412 (anti-TREM2) | AD | Phase 1 complete |
| NCT05618348 | Tocilizumab | Early AD | Recruiting |
| NCT04881253 | Anti-TREM2 mAb | MCI-AD | Phase 2 |
| Marker | Fluid | Correlation |
|---|---|---|
| YKL-40 | CSF, plasma | Disease progression |
| IL-6 | CSF | Cognitive decline |
| TNF-α | CSF | Disease severity |
| C1q | CSF | Synaptic loss |
| sTREM2 | CSF | TREM2 pathway engagement |
Heneka MT, et al. Neuroinflammation in Alzheimer's disease. Lancet Neurology. 2015. ↩︎
Wang Y, et al. TREM2 lipid sensing sustains the microglial response in an Alzheimer's disease model. Cell. 2015. ↩︎
Hansen DV, et al. Microglia in Alzheimer's disease. Journal of Cell Biology. 2018. ↩︎
Keren-Shaul N, et al. A unique microglia type associated with Alzheimer's disease. Cell. 2017. ↩︎
Guerreiro R, et al. TREM2 variants in Alzheimer's disease. New England Journal of Medicine. 2013. ↩︎