Neuroinflammation in Alzheimer's Disease
Overview
Neuroinflammation in Alzheimer's Disease describes a key molecular or cellular mechanism implicated in neurodegenerative disease. This page provides a detailed overview of the pathway components, signaling cascades, and their relevance to conditions such as Alzheimer's disease, Parkinson's disease, and related disorders. [@cai2020]
Neuroinflammation is a central pathological feature of Alzheimer's disease (AD), characterized by chronic activation of glial cells (microglia and astrocytes) and elevated levels of pro-inflammatory mediators in the brain. While initially a protective response, sustained neuroinflammation becomes detrimental and contributes to neurodegeneration. [@wang2020]
The Neuroinflammatory Response
Microglial Activation
Microglia are the resident immune cells of the brain, derived from yolk sac progenitors. In AD, they undergo dramatic phenotypic changes: [@sarlus2017]
Molecular Triggers: [@hansen2018]
- Amyloid-beta binds to TLRs (TLR2, TLR4), CD36, RAGE
- Tau oligomers activate TLRs and trigger inflammatory responses
- DAM (Disease-Associated Microglia) phenotype
- TREM2 variants increase AD risk 2-4x
Astrocyte Reactivity
Astrocytes adopt a reactive phenotype in AD: [@zhang2019]
- Upregulation of GFAP
- Release of inflammatory mediators
- Impaired glutamate uptake
- Disrupted blood-brain barrier
Inflammatory Cascade
Mermaid diagram (expand to render)
Pro-Inflammatory Cytokines
| Cytokine | Source | Effect in AD | Reference |
|----------|--------|--------------|-----------|
| IL-1β | Microglia | Promotes tau pathology, synaptic dysfunction | [@varnum2012] |
| IL-6 | Astrocytes, Microglia | Acute phase response, cognitive decline | [@el2007] |
| TNF-α | Microglia, Astrocytes | Synaptic pruning, excitotoxicity | [@ransohoff2016] |
| IL-18 | Microglia | IFN-γ induction, neurotoxicity | [@heppner2015] |
Chemokines
- CCL2 (MCP-1) - recruits microglia to plaques
- CXCL12/SDF-1 - altered in AD brain
- CX3CL1 (Fractalkine) - neuroprotective, reduced in AD
Complement System
The complement cascade is highly activated in AD: [@butterfield2010]
- C1q - initiates complement, tags synapses for pruning
- C3 - opsonization, microglial activation
- C3a/C5a - anaphylatoxins, neuroinflammation
Microglial Phenotypes
DAM (Disease-Associated Microglia)
A specialized microglial phenotype characterized by: [@heneka2013]
- Stage 1: Homeostatic → early DAM (Trem2-independent)
- Stage 2: Late DAM (Trem2-dependent)
- Upregulation of lipid metabolism genes
- Increased phagocytic activity
TREM2 and AD Risk
TREM2 variants are major AD risk factors: [@pekny2014]
- R47H - ~3x increased risk
- R62H - intermediate risk
- H157Y - risk variant
TREM2 functions: [@cahillsmith2011]
- Aβ phagocytosis
- Microglial survival
- Lipid metabolism
- Inflammatory response modulation
Genetic Evidence
| Gene | Variant | Effect | Reference |
|------|---------|--------|-----------|
| TREM2 | R47H | ~3x AD risk | [@schwabe2017] |
| CD33 | rs3865444 | Alters microglial activation | [@zlokovic2011] |
| ABI3 | rs616338 | Increased risk | [@butterfield2010] |
| PLCG2 | rs72849905 | Protective | [@heneka2013] |
| INPP5D | Various | Alters microglial signaling | [@pekny2014] |
Neuroinflammation and Other Pathologies
Bidirectional Amyloid Relationship
- Aβ activates microglia → inflammation → more Aβ production
- Chronic inflammation impairs Aβ clearance
- Inflammatory cytokines increase APP expression
Tau and Inflammation
- IL-1β activates GSK-3β → tau phosphorylation
- Inflammation accelerates tau spreading
- Tau aggregates activate microglia
Synaptic Loss
- C1q tags synapses for complement-mediated pruning
- TNF-α reduces synaptic function
- IL-1β impairs LTP
Biomarkers
CSF Markers
- IL-6 - elevated in AD
- YKL-40 (chitinase) - microglial activation
- sTREM2 - soluble TREM2, disease stage-dependent
PET Imaging
- TSPO PET - measures microglial activation
- 11C-PK11195 - first-generation ligand
- 18F-GE-180 - second-generation
Therapeutic Strategies
| Approach | Target | Status | Reference |
|----------|--------|--------|-----------|
| TREM2 agonists | TREM2 | Preclinical | [@schwabe2017a] |
| NLRP3 inhibitors | Inflammasome | In trials | [@heneka2022] |
| Anti-inflammatory drugs | COX-2, NSAIDs | Failed | [@leng2021]
| Anti-cytokine therapy | IL-1β, TNF-α | In trials | [@mancella2024]
| Microglial modulation | CSF1R inhibitors | In trials |
NSAIDs Controversy
Epidemiological studies suggested reduced AD risk with NSAIDs, but large RCTs failed to show benefit:
-可能是治疗时机太晚
Cross-Linking
Neuroinflammation connects to all AD pathological features:
- Amyloid cascade - bidirectional
- Tau pathology - accelerates spreading
- Mitochondrial dysfunction - ROS and energy
- Synaptic loss - complement-mediated pruning
See Also
- Alzheimer's Disease — Primary neurodegenerative disease
- Parkinson's Disease — Related neurodegenerative disease
- Amyloid Cascade Pathway - Key AD mechanism
- Tau Pathology - Tau-mediated neurodegeneration
External Links
- [PubMed](https://pubmed.ncbi.nlm.nih.gov/) - Biomedical literature
- [Nature Reviews Neuroscience](https://www.nature.com/nrn/) - Review articles
The Blood-Brain Barrier in Neuroinflammation
The blood-brain barrier (BBB) plays a critical role in neuroinflammation in AD. BBB dysfunction allows peripheral immune cells and molecules to enter the brain [@zlokovic2011].
BBB Breakdown in AD
BBB changes in AD include:
- Endothelial dysfunction: Reduced tight junction proteins
- Pericyte loss: Compromised barrier integrity
- Astrocyte end-feet damage: Impaired neurovascular coupling
- Transcytosis increase: Enhanced nanoparticle permeation
Peripheral Immune Cell Infiltration
BBB breakdown enables peripheral immune cell entry:
- T lymphocytes: CD4+ and CD8+ T cells found in AD brain
- Monocytes: Contribute to microglial pool
- B cells: Rare but present in some cases
- NK cells: May have cytotoxic effects
Aβ-Vascular Interactions
Amyloid affects cerebral vasculature:
- Cerebral amyloid angiopathy (CAA): Aβ in vessel walls
- Vessel stiffness: Reduced compliance
- Impaired clearance: Aβ drainage受阻
- Hemodynamic changes: Reduced cerebral blood flow
Neuroinflammation and Oxidative Stress
Inflammation and oxidative stress form a vicious cycle in AD [@butterfield2010].
ROS Production in Inflammation
Inflammatory cells generate reactive oxygen species:
- NADPH oxidase: Major ROS source in microglia
- Mitochondrial ROS: Electron leak during inflammation
- Nitric oxide synthase: Produces NO and peroxynitrite
- Xanthine oxidase: Uric acid metabolism ROS
Oxidative Damage Consequences
ROS causes macromolecule damage:
- Lipid peroxidation: Membrane damage, lipid rafts altered
- Protein oxidation: Carbonyl groups, misfolding
- DNA damage: 8-OHdG formation, repair overload
- RNA oxidation: mRNA dysfunction
Antioxidant Defenses
Endogenous antioxidants are overwhelmed:
- Glutathione: Depleted in AD brain
- SOD/Catalase: Impaired function
- Nrf2 pathway: Dysregulated antioxidant response
- Mitochondrial antioxidants: Reduced efficacy
Inflammasome Activation
The NLRP3 inflammasome is a key driver of neuroinflammation [@heneka2013].
Inflammasome Components
- NLRP3: Pattern recognition receptor
- ASC: Adaptor protein
- Caspase-1: Protease that activates cytokines
Activation Triggers
- Aβ crystals: Direct activation
- ATP: P2X7 receptor activation
- ROS: Mitochondrial DAMPs
- Urinary crystals: Amyloid deposits
Downstream Effects
- IL-1β maturation: Pro-inflammatory cytokine activation
- IL-18 release: IFN-γ stimulating
- Pyroptosis: Inflammatory cell death
- Amplification loop: Chronic inflammation
Astrocyte-Neuron Interactions
Astrocytes play complex roles in neuroinflammation [@pekny2014].
Reactive Astrocytes
Astrocyte reactivity in AD:
- GFAP upregulation: Classic marker
- A1 phenotype: Neurotoxic reactive astrocytes
- A2 phenotype: Potentially protective
- S100B release: Pro-inflammatory effects
Inflammation impairs astrocyte functions:
- Glutamate uptake: Excitotoxicity
- Lactate production: Energy failure
- Potassium buffering: Dysregulation
- Water balance: Edema susceptibility
Neurovascular Unit Dysfunction
Astrocytes in the neurovascular unit:
- Regulation of cerebral blood flow: Impaired
- BBB maintenance: Compromised
- Aβ clearance: Reduced
- Angiogenesis: Abnormal responses
Sex Differences in Neuroinflammation
Neuroinflammation shows sex-based differences in AD [@cahillsmith2011].
Female Susceptibility
Women show:
- Higher microglial activation: Post-mortem studies
- More pronounced inflammation: Biomarker studies
- Hormonal modulation: Estrogen anti-inflammatory effects
- Genetic factors: Sex-specific genetic architecture
Male Patterns
Men show:
- Different cytokine profiles: Some studies
- Microglial morphology differences: Age-related
- Autoimmune comorbidity effects: Variable
Chronobiology of Inflammation
Inflammatory processes show circadian regulation [@ciregia2016].
Inflammatory Rhythms
- IL-6 peaks: Nighttime in humans
- TNF-α: Circadian oscillation
- Microglial surveillance: Time-of-day variation
- Aβ production: Diurnal pattern
Sleep and Inflammation
Bidirectional relationship:
- Sleep deprivation: Increases inflammation
- AD pathology: Disrupts sleep
- Microglial activation: Sleep-wake dependent
- Therapeutic implications: Sleep interventions
Epigenetic Regulation of Inflammation
Inflammation is epigenetically regulated [@graff2012].
DNA Methylation
- Inflammatory genes: Hypomethylated in AD
- TREM2: Methylation changes
- Genome-wide: Altered patterns
Histone Modifications
- Histone acetylation: Pro-inflammatory gene activation
- HDAC inhibitors: Potential therapy
- H3K27ac: Enhanced inflammatory response
Non-coding RNAs
- miR-155: Pro-inflammatory microRNA
- miR-146a: Anti-inflammatory, dysregulated
- lncRNAs: Inflammatory regulation
Neuroinflammation and Neurogenesis
Chronic inflammation impairs neurogenesis [@ekdahl2009].
Adult Neurogenesis
- Hippocampal niche: Dentate gyrus
- Impaired in AD: Reduced proliferation
- Inflammatory mediators: Anti-neurogenic
- Therapeutic potential: Inflammation reduction
Inflammatory Barriers
- Cytokine effects: Directly inhibit neurogenesis
- Microglial phagocytosis: Engulf neural precursors
- Niche inflammation: Disrupted environment
- Vascular changes: Impaired niche function
Metabolic dysfunction and inflammation are linked [@monte2008].
Insulin Resistance
- Brain insulin resistance: Type 3 diabetes concept
- Inflammatory signaling: IRS1 dysfunction
- Aβ-insulin interaction: Competitive clearance
- Therapeutic approaches: Insulin sensitizers
- APOE effects: Lipid transport inflammation
- Fatty acids: Pro/anti-inflammatory
- Lipid rafts: Signaling platform alterations
- Eicosanoids: Prostaglandin leukotriene balance
Future Therapeutic Directions
Multi-target Approaches
- Combination therapy: Multiple inflammatory pathways
- Personalized medicine: Patient-specific inflammation profiles
- Timing considerations: Early intervention importance
- Biomarker-driven: Patient selection
Emerging Targets
- TREM2 modulation: Agonists in development
- CD33 inhibition: Genetic validation
- NLRP3 blockers: Clinical trials ongoing
- Microglial repopulation: CSF1R approaches
Conclusion
Neuroinflammation in AD represents a complex, multi-cellular process that both drives and is driven by other pathological features. Understanding the bidirectional relationships between inflammation, amyloid, tau, and synaptic dysfunction provides crucial insights for developing effective therapeutic interventions. As research advances, targeting specific inflammatory pathways while preserving beneficial immune functions remains a key challenge and opportunity in AD therapy.
Clinical Translation and Therapeutic Implications
Current Therapeutic Approaches
The translation of neuroinflammatory mechanisms into clinical therapies has proven challenging, with multiple approaches evaluated in clinical trials [@schwabe2017a].
Anti-Cytokine Therapies
Targeting pro-inflammatory cytokines represents a direct approach:
- IL-1β inhibition: Anakinra (IL-1 receptor antagonist) has been tested in small AD trials with mixed results. The challenge lies in timing—blocking IL-1β too late may not reverse established pathology.
- TNF-α inhibition: Etanercept (TNF receptor-Fc fusion) showed promise in pilot studies but failed in larger trials. Perispinal delivery remains investigational.
- IL-6 signaling: Tocilizumab (anti-IL-6R) is being evaluated for its potential to modulate neuroinflammation in AD patients.
Microglial Modulation
Modulating microglial function rather than broadly suppressing inflammation shows promise:
- TREM2 agonism: Anti-TREM2 antibodies (e.g., from Genentech, AbbVie) are in early-phase trials aiming to enhance microglial phagocytosis of Aβ plaques. The gantenerumab and remibrutinib programs have shown target engagement in Phase 1/2 studies.
- CSF1R inhibitors: PLX5622 (Plexxikon) depletes microglia in animal models but raises concerns about removing beneficial microglial functions. Clinical trials in AD are ongoing.
- CD33 inhibition: Genetic evidence supports CD33 as an AD risk gene; anti-CD33 antibodies are in preclinical development.
NLRP3 Inflammasome Inhibitors
The NLRP3 inflammasome is a key driver of neuroinflammation:
- MCC950: A potent NLRP3 inhibitor showed efficacy in animal models but failed in early clinical trials due to liver toxicity. Next-generation inhibitors are in development.
- Dapansutrile (OLT1177): An oral NLRP3 inhibitor has completed Phase 1/2 trials in cardiovascular disease and is being evaluated for neurodegenerative applications.
- Natural compounds:Quercetin and other flavonoids show NLRP3-modulating activity in preclinical models.
Biomarker Development
Translational biomarkers enable patient selection and monitor therapeutic response [@schwabe2017a].
CSF Inflammatory Markers
- IL-1β: Elevated in AD vs. controls; correlation with cognitive decline
- IL-6: Predicts progression from MCI to AD
- YKL-40: Microglial activation marker; tracks with disease severity
- sTREM2: Soluble TREM2 reflects microglial activity; bidirectional relationship with disease stage
- Neurofilament light chain (NfL): Axonal damage marker; responds to anti-inflammatory treatment
Blood-Based Biomarkers
- IL-6, TNF-α: Elevated in AD; potential for screening
- GFAP: Astrocyte activation; emerging blood marker
- p-tau/total tau ratio: Differentiates AD from other dementias
PET Imaging
- TSPO PET: Measures microglial activation in vivo. First-generation ligands (11C-PK11195) showed increased binding in AD. Second-generation tracers (18F-GE-180, 18F-DPA-714) offer improved kinetics.
- FDG-PET: Metabolic imaging complements inflammatory markers
Clinical Trials Overview
Major clinical trials targeting neuroinflammation in AD:
| Trial/Agent | Target | Phase | Status |
|-------------|--------|-------|--------|
| Verubecestat (MK-8931) | BACE1 inhibitor | Phase 3 | Terminated (cognitive worsening) |
| Tilisolizumab (NI-0401) | CD40/CD40L | Phase 2 | Completed |
| Sargramostim (GM-CSF) | Immunomodulation | Phase 2 | Completed |
| Azeliragon (TTP-488) | RAGE inhibitor | Phase 3 | Failed |
| Lorecivivint (SM04790) | Wnt signaling | Phase 2 | Ongoing |
| AL002 (Alector) | TREM2 agonist | Phase 2 | Ongoing |
Therapeutic Implications
Timing of Intervention
A critical challenge is identifying the optimal intervention window:
- Preclinical stage: Anti-inflammatory approaches may prevent disease onset in at-risk individuals
- MCI stage: May represent the optimal window for disease-modifying therapies
- Moderate dementia: Aggressive anti-inflammatory approaches may be too late
Combination Approaches
Given the multifactorial nature of AD, combination therapies are logical:
- Anti-amyloid + anti-inflammatory: Lecanemab + NLRP3 inhibitor
- Anti-tau + immunomodulation: Anti-tau antibodies + TREM2 modulators
- Metabolic + anti-inflammatory: Intranasal insulin + anti-cytokine therapy
Personalized Medicine
Patient selection based on inflammatory biomarkers:
- TREM2 variant carriers: May benefit from TREM2 agonism
- High inflammatory profile: Prioritize anti-inflammatory approaches
- APOE4 carriers: May have increased inflammatory response
Patient Impact and Clinical Relevance
Quality of Life Effects
Neuroinflammation directly impacts patient outcomes:
- Cognitive function: Inflammatory cytokines impair synaptic plasticity and memory
- Behavioral symptoms: Neuroinflammation contributes to agitation, depression, and psychosis
- Functional decline: Inflammation correlates with activities of daily living (ADL) deterioration
Caregiver Burden
Managing neuroinflammation-related symptoms:
- Agitation management: Anti-inflammatory approaches may reduce neuropsychiatric symptoms
- Sleep disturbances: Inflammation disrupts circadian rhythms; treating inflammation may improve sleep
- Daily functioning: Reducing inflammation may preserve functional abilities longer
Challenges and Future Directions
Key Challenges
Emerging Approaches
Future Directions
- Early intervention- Biomarker-driven trials: Enriching trials with patients sho- Combination therapies: Simultaneous
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[@schwabe2017a]: [Schwabe et al., Neuroinflammation: Therapeutic targets (2017)](https://doi.org/10.1038/nrneurol.2017.100)
[@heneka2022]: [Heneka et al., Neuroinflammation and neurodegeneration (2022)](https://doi.org/10.1038/s41582-022-00635-8)
[@leng2021]: [Leng & Edison, Neuroinflammation in AD - clinical implications (2021)](https://doi.org/10.1002/alz.12318)
[@mancella2024]: [Mancella et al., TREM2 biology and therapeutic targeting (2024)](https://doi.org/10.1038/s41582-024-00856-w)
[@perry2019]: [Perry et al., Systemic inflammation and brain (2019)](https://doi.org/10.1038/s41583-019-0148-0)
[@zlokovic2011]: [Zlokovic, Neurovascular dysfunction in AD (2011)](https://doi.org/10.1016/j.neuron.2011.09.012)
[@butterfield2010]: [Butterfield et al., Oxidative stress in AD (2010)](https://doi.org/10.1016/j.jad.2009.08.003)
[@heneka2013]: [Heneka et al., NLRP3 inflammasome in AD (2013)](https://doi.org/10.1038/nature12337)
[@pekny2014]: [Pekny et al., Astrocytes in AD (2014)](https://doi.org/10.1016/j.tins.2014.08.007)
[@cahillsmith2011]: [Cahill-Smith et al., Sex differences in AD inflammation (2011)](https://doi.org/10.1016/j.neurobiolaging.2011.02.010)
[@ciregia2016]: [Ciregia et al., Circadian inflammation in AD (2016)](https://doi.org/10.1016/j.jneuroim.2016.02.005)
[@graff2012]: [Graff et al., Epigenetic regulation in AD (2012)](https://doi.org/10.1038/nrn3170)
[@ekdahl2009]: [Ekdahl et al., Inflammation and neurogenesis (2009)](https://doi.org/10.1016/j.tins.2009.05.003)
[@monte2008]: [de la Monte & Wands, Type 3 diabetes in AD (2008)](https://doi.org/10.1016/j.jdiacomp.2007.12.004)
Systemic Inflammation and Brain
Peripheral inflammation affects brain through multiple pathways [@perry2019].
Immune-Brain Communication
- Vagal signaling: Cytokines signal via vagus nerve
- Humoral pathways: Cytokines cross BBB
- Endothelial activation: Vascular signaling
- Cellular trafficking: Immune cell entry
Inflammatory Priming
- Peripheral infection: Can exacerbate brain inflammation
- Chronic systemic disease: Contributes to neurodegeneration
- Gut microbiome: Gut-brain axis inflammation
- Periodontal disease: Oral bacteria-brain connections
Inflammatory Cell Death Pathways
Inflammation triggers various cell death mechanisms [@perry2019].
Pyroptosis
- Caspase-1 dependent: Inflammatory necrosis
- Gasdermin D: Pore-forming protein
- IL-1β release: Pro-inflammatory cell death
- In AD: Evidence of pyroptotic markers
Necroptosis
- RIPK1/3 signaling: Kinase-dependent death
- Mixed lineage kinase domain-like (MLKL): Effector
- Inflammation: Death-receptor induced
- Therapeutic potential: Kinase inhibitors
Neuroinflammation in Disease Progression
The timeline of inflammation in AD [@heneka2013].
Preclinical Stage
- Microglial priming: Early activation changes
- Subtle inflammation: Before plaque deposition
- Genetic risk: TREM2 effects early
- Reversible: Potential intervention window
Clinical Stage
- Established inflammation: Full activation
- Cytokine elevation: Detectable in CSF/blood
- Progressive cascade: Self-amplifying
- Correlation: With cognitive decline
Neuroinflammation as Therapeutic Target
Why targeting inflammation remains promising [@heneka2022].
Rationale
- Modifiable: Can be pharmacologically influenced
- Central: Drives multiple downstream effects
- Accessible: Drug delivery possible
- Biomarkers: Measurable outcomes
Challenges
- Complexity: Multiple redundant pathways
- Physiological roles: Need to preserve function
- Timing: Critical window of opportunity
- Patient selection: Who benefits most
Summary
Neuroinflammation is a hallmark feature of Alzheimer's disease with complex interconnections to other pathological processes. The chronic activation of microglia and astrocytes drives cytokine release, complement activation, and oxidative stress that collectively contribute to synaptic loss, tau pathology, and neuronal death. Despite the clear involvement of neuroinflammation in AD pathogenesis, therapeutic translation has proven challenging. TREM2 modulation, NLRP3 inhibition, and microglial reprogramming represent promising approaches, though optimal timing and patient selection remain critical questions for clinical success.
- [Alzheimer's Disease](/diseases/alzheimers-disease) — Primary disease context
- [Parkinson's Disease](/diseases/parkinsons-disease) — Neuroinflammation in PD
- [Amyotrophic Lateral Sclerosis](/diseases/amyotrophic-lateral-sclerosis) — Neuroinflammation in ALS
- [Frontotemporal Dementia](/diseases/frontotemporal-dementia) — Neuroinflammation in FTD
- [Huntington's Disease](/diseases/huntingtons-disease) — Neuroinflammation in HD
- [Multiple System Atrophy](/diseases/multiple-system-atrophy) — Neuroinflammation in MSA
- [Progressive Supranuclear Palsy](/diseases/progressive-supranuclear-palsy) — Neuroinflammation in PSP
- [Dementia with Lewy Bodies](/diseases/dementia-with-lewy-bodies) — Neuroinflammation in DLB
Key Proteins and Pathways
- [TREM2](/proteins/trem2) — Microglial receptor and genetic risk factor
- [NLRP3 Inflammasome](/mechanisms/nlrp3-inflammasome) — Inflammatory signaling complex
- [IL-1β (Interleukin-1 Beta)](proteins/il1-beta) — Pro-inflammatory cytokine
- [Tau Protein](/proteins/tau-protein) — Neurofibrillary tangles
- [Amyloid-Beta](/proteins/amyloid-beta) — Amyloid plaques
- [Alpha-Synuclein](/proteins/alpha-synuclein) — Lewy body formation
- [Complement System](/mechanisms/complement-system) — Immune complement activation
Cell Types
- [Microglia](/cell-types/microglia) — Brain immune cells
- [Astrocytes](/cell-types/astrocytes) — Support cells with inflammatory roles
- [Oligodendrocytes](/cell-types/oligodendrocytes) — Myelin-producing cells
- [Neurons](/cell-types/neurons) — Target of inflammatory damage
Mechanisms
- [Oxidative Stress](/mechanisms/oxidative-stress) — ROS-mediated damage
- [Mitochondrial Dysfunction](/mechanisms/mitochondrial-dysfunction) — Energy impairment
- [Protein Aggregation](/mechanisms/protein-aggregation) — Misfolded protein accumulation
- [Synaptic Dysfunction](/mechanisms/synaptic-dysfunction) — Synaptic loss
- [Blood-Brain Barrier Dysfunction](/mechanisms/blood-brain-barrier-dysfunction) — Vascular damage
- [Autophagy](/mechanisms/autophagy) — Protein clearance pathways
Therapeutic Approaches
- [TREM2 Agonists](/therapeutics/trem2-agonists) — Microglial activation therapy
- [NLRP3 Inhibitors](/therapeutics/nlrp3-inhibitors) — Inflammasome blockade
- [Anti-inflammatory Therapies](/therapeutics/anti-inflammatory-therapies-neurodegeneration) — General inflammation targets
- [Microglial Reprogramming](/therapeutics/microglial-reprogramming) — Phenotype modulation