Tauopathy

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Tauopathy

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Tauopathy

Pathway Diagram

```mermaid
flowchart TD
Tauopathy["Tauopathy"]
style Tauopathy fill:#006494,stroke:#4fc3f7,stroke-width:3px,color:#e0e0e0
Alzheimer["Alzheimer"]
Tauopathy -->|"associated with"| Alzheimer
Neurodegeneration["Neurodegeneration"]
Tauopathy -->|"associated with"| Neurodegeneration
Tauopathy -->|"activates"| Alzheimer
Tauopathy -->|"activates"| Neurodegeneration
Tauopathy -->|"activates"| Tauopathy
Tauopathy -->|"associated with"| Tauopathy
Autophagy["Autophagy"]
Tauopathy -->|"activates"| Autophagy
Tauopathy -->|"expressed in"| Tauopathy
MICROGLIA["MICROGLIA"]
MICROGLIA -->|"activates"| Tauopathy
NEURODEGENERATIVE_DISEASES["NEURODEGENERATIVE DISEASES"]
NEURODEGENERATIVE_DISEASES -->|"activates"| Tauopathy
ALZHEIMER_S_DISEASE["ALZHEIMER'S DISEASE"]
ALZHEIMER_S_DISEASE -->|"activates"| Tauopathy
NEURODEGENERATION["NEURODEGENERATION"]
NEURODEGENERATION -->|"activates"| Tauopathy
TAU["TAU"]
TAU -->|"activates"| Tauopathy
NEURODEGENERATION -->|"associated with"| Tauopathy
ALZHEIMER_S_DISEASE -->|"associated with"| Tauopathy
TAU -->|"associated with"| Tauopathy
style Alzheimer fill:#ef5350,stroke:#4fc3f7,color:#e0e0e0
style Neurodegeneration fill:#ef5350,stroke:#4fc3f7,color:#e0e0e0
style Autophagy fill:#5d4400,stroke:#4fc3f7,color:#e0e0e0
style MICROGLIA fill:#1b5e20,stroke:#4fc3f7,color:#e0e0e0
style NEURODEGENERATIVE_DISEASES fill:#1b5e20,stroke:#4fc3f7,color:#e0e0e0
style ALZHEIMER_S_DISEASE fill:#1b5e20,stroke:#4fc3f7,co

...

Tauopathy

Pathway Diagram

Mermaid diagram (expand to render)

Overview

Tauopathy refers to a class of neurodegenerative disorders characterized by the accumulation of hyperphosphorylated tau protein within neurons and glial cells[@ballard2005]. These disorders include Alzheimer's disease (AD), progressive supranuclear palsy (PSP), corticobasal syndrome (CBD), Pick's disease, and chronic traumatic encephalopathy (CTE)[@goedert2017]. The tau protein, encoded by the MAPT (Microtubule-Associated Protein Tau) gene, plays essential roles in microtubule stabilization, axonal transport, and synaptic function[@mandelkow2012].

The fundamental pathology in tauopathies involves the aggregation of tau into insoluble fibrils that form neurofibrillary tangles (NFTs), neuropil threads, and dystrophic neurites. These aggregates disrupt neuronal function through multiple mechanisms including microtubule destabilization, impaired axonal transport, synaptic dysfunction, and eventual neuronal death[@arendt2016].

Tau Protein Biology

Structure and Isoforms

The human MAPT gene located on chromosome 17q21.31 encodes the tau protein through alternative splicing of exon 10. Six tau isoforms are expressed in the adult brain, distinguished by the presence of 3 or 4 microtubule-binding repeats (3R or 4R tau) and 0, 1, or 2 N-terminal inserts[@goedert1989]:

3R tau isoforms: Exclude exon 10, contain 3 microtubule-binding repeats
4R tau isoforms: Include exon 10, contain 4 microtubule-binding repeats

In the normal adult brain, the ratio of 3R to 4R tau is approximately 1:1, reflecting balanced splicing regulation[@sultan2011]. This balance is critical, as dysregulation toward 4R predominance is a hallmark of PSP and CBD, while 3R predominance characterizes Pick's disease.

Tau Isoform Functions

Tau performs several essential neuronal functions:

Microtubule stabilization: The microtubule-binding repeats (R1-R4) bind to and stabilize microtubules, enabling axonal transport[@weingarten1975].

Axonal transport regulation: Tau modulates the function of motor proteins (kinesin, dynein) that transport cargo along microtubules[@stamer2002].

Synaptic function: Tau localizes to synapses where it participates in neurotransmitter release and synaptic plasticity[@tai2012].

Signal transduction: Tau interacts with various signaling molecules, including Src family kinases and phosphatases[@lee2011].

Molecular Mechanisms of Tauopathies

Tau Hyperphosphorylation

Hyperphosphorylation is the primary modification that converts tau from a functional microtubule-stabilizing protein into a pathological aggregation-prone species[@hanger2009]. Over 45 serine, threonine, and tyrosine residues can be phosphorylated on tau, with specific phosphorylation patterns correlating with disease progression.

Key kinases regulating tau phosphorylation:

| Kinase | Primary Sites | Role in Tauopathy |
|--------|---------------|-------------------|
| GSK-3β | Ser202, Thr205, Ser396, Ser404 | Primary tau kinase, hyperactive in AD |
| CDK5 | Ser202, Thr205, Ser235 | Activated in neurodegeneration |
| PKA | Ser262, Ser356, Ser214 | Promotes microtubule detachment |
| DYRK1A | Thr212 | Elevated in AD brain |
| MAPK | Ser396, Ser404 | Stress-activated |

Key phosphatases:

PP2A: The major phosphatase dephosphorylating tau; its activity is reduced in tauopathies[@sontag2014]

Tau Aggregation

The aggregation of tau into fibrils follows a nucleation-dependent polymerization model[@soto2008]:

Nucleation: Formation of oligomeric tau species requires overcoming an energy barrier. This is accelerated by:

Hyperphosphorylation at specific sites (Thr231, Ser396)
Conformational changes exposing hydrophobic hexapeptide motifs (^306^VQIVYK^311^, ^378^VQIVLK^383^)
Interaction with seeding-competent tau fibrils

Elongation: Addition of monomeric tau to growing fibrils. 4R tau aggregates faster than 3R due to additional hexapeptide motifs in the fourth repeat.

Maturation: Formation of stable, protease-resistant fibrils with cross-β sheet architecture.

Tau Strain Diversity

Distinct tau fibril structures (strains) characterize different tauopathies, as revealed by cryo-electron microscopy[@fitzpatrick2017]:

Alzheimer's disease:

Paired helical filaments (PHFs)
Straight filaments (SFs)
3R and 4R tau combined in filaments

Progressive supranuclear palsy:

Three-layered helical structure
C-shaped cross-section
4R tau predominant

Corticobasal syndrome:

Four-layered structure
More compact conformation
Variable filament morphologies

Pick's disease:

Distinct filament architecture
3R tau predominant

Classification of Tauopathies

Primary Tauopathies (4R)

These disorders feature predominant 4R tau accumulation:

Progressive Supranuclear Palsy (PSP): Characterized by Richardson's syndrome, parkinsonism, vertical gaze palsy, and frontal cognitive deficits[@litvan1996]
Corticobasal Syndrome (CBS): Features asymmetric parkinsonism, apraxia, alien limb phenomenon, and cortical sensory loss[@riley1994]
Argyrophilic Grain Disease (AGD): Late-onset dementia with argyrophilic grains

Primary Tauopathies (3R)

Pick's Disease: Frontotemporal dementia with behavioral changes and language impairment[@dickson2012]

Mixed Isoform Tauopathies

Alzheimer's Disease: Both 3R and 4R tau in neurofibrillary tangles
Chronic Traumatic Encephalopathy: CTE shows 3R and 4R tau pathology, often with distinctive perivascular tau at the depths of sulci

Tauopathy Mechanisms in Neurodegeneration

Microtubule Dysfunction

Hyperphosphorylated tau loses its ability to bind and stabilize microtubules, leading to:

Impaired axonal transport
Cargo accumulation in axons
Synaptic vesicle depletion
Ultimately, axonal degeneration[@cash2003]

Axonal Transport Impairment

Tau pathology disrupts both anterograde (kinesin-dependent) and retrograde (dynein-dependent) transport:

Kinesin binding to tau competes with microtubule binding
Tau accumulation leads to "traffic jams" in axons
Mitochondria and other organelles cannot reach synaptic terminals[@mandelkow2003]

Synaptic Dysfunction

Tau aggregates at synapses contribute to:

Presynaptic vesicle depletion
Impaired neurotransmitter release
Postsynaptic receptor mislocalization
Early cognitive deficits before neuronal loss[@tai2014]

Neuronal Death Mechanisms

Multiple pathways lead to tauopathy-associated neuronal death:

Apoptosis: Intrinsic pathway activation in tau-bearing neurons
Necroptosis: RIPK1/3-mediated cell death in some tauopathies
Autophagic cell death: Failed autophagy leading to aggregation
Oxidative stress: Mitochondrial dysfunction and ROS accumulation

Genetic Factors in Tauopathies

MAPT Mutations

The MAPT gene on chromosome 17q21.31 encodes tau and numerous mutations cause or predispose to tauopathies[@rademakers2005]. Over 50 pathogenic MAPT mutations have been identified:

Splicing mutations (alter tau isoform ratios):

P301L/S: Most common, causes frontotemporal dementia with parkinsonism (FTDP-17)
exon 10 + 16: Causes 4R tau predominance
exon 10 - 2: Causes 3R tau predominance

Aggregation-promoting mutations:

K280: Increases tau filament formation
S305S: Affects exon 10 splicing
Q336H: Enhances aggregation propensity

H1 Haplotype

The H1 haplotype of MAPT (a 500 kb inversion polymorphism) is strongly associated with PSP, CBD, and AGD[@pike2021]. The H1c sub-haplotype specifically increases risk for PSP with an odds ratio of approximately 5.5. This haplotype influences MAPT expression and alternative splicing, favoring 4R tau production.

GWAS Findings

Genome-wide association studies have identified multiple tauopathy risk loci[@ferrari2014]:

MAPT: Strongest association (H1 haplotype)
MOBP: Myelin-associated oligodendrocyte basic protein
DUSP10: Dual specificity phosphatase 10
SLCO1A2: Solute carrier organic anion transporter
STX6: Syntaxin 6

Epigenetic Regulation in Tauopathy

DNA Methylation

Tauopathy is associated with widespread DNA methylation changes[@de2019]:

Global hypomethylation in AD brain tissue
Gene-specific changes at tau-related genes
Age-related methylation drift exacerbates tau pathology
APP promoter methylation affects amyloid processing

Histone Modifications

Histone acetylation and methylation patterns are altered in tauopathies:

Reduced H3K9ac at synaptic genes correlates with cognitive decline
Increased H3K27me3 at tau kinase promoters
HDAC inhibitor therapy shows promise in preclinical models

Non-Coding RNAs

MicroRNAs (miRNAs) regulate tau pathology[@siedleckiwullich2019]:

miR-124: Reduced in AD; restores neuronal glutamate transport
miR-132: Downregulated in tauopathy; regulates tau phosphorylation
miR-219: Targets GSK3β mRNA
miR-146a: Upregulated in AD; promotes inflammation

Long non-coding RNAs (lncRNAs):

MALAT1: Altered in AD; regulates synaptic plasticity
NEAT1: Promotes tau aggregation

Metabolic Dysfunction in Tauopathy

Glucose Metabolism

Tauopathy is closely linked to metabolic dysfunction[@butterfield2019]:

Brain glucose hypometabolism precedes clinical symptoms in AD
Insulin signaling impairment exacerbates tau pathology
Type 2 diabetes increases AD risk 1.5-2 fold

Key mechanisms:

IRS-1 serine phosphorylation disrupts insulin signaling
Akt/mTOR pathway dysregulation affects protein synthesis
AMPK reduced activation impairs energy homeostasis

Mitochondrial Dysfunction

Mitochondria are severely affected in tauopathies:

Reduced complex IV activity in AD and PSP
Increased mtDNA mutations with age
Impaired mitochondrial dynamics (fusion/fission)
Tau accumulation in mitochondria disrupts function

Therapeutic implications:

Mitochondrial antioxidants (MitoQ, CoQ10) being studied
PGC-1α activators promote mitochondrial biogenesis

Insulin Signaling

Brain insulin resistance is a key feature[@kellar2020]:

Intranasal insulin improves memory in AD trials
GLP-1 agonists reduce tau phosphorylation in models
SGLT2 inhibitors may provide neuroprotective effects

Sleep Disorders and Tauopathy

Bidirectional Relationship

Sleep disruption and tauopathy have a bidirectional relationship[@ju2017]:

Sleep deprivation increases CSF tau levels by 30-50%
Tau pathology disrupts sleep-wake cycles
Orexin system dysregulation contributes to sleep fragmentation

Circadian Rhythm Disruption

The suprachiasmatic nucleus is affected in tauopathies:

BMAL1 clock gene expression reduced in AD
Peripheral clock genes show altered rhythms
Melatonin secretion declines with age and tauopathy

Therapeutic Implications

Sleep interventions may benefit tauopathy:

Sleep hygiene improves tau clearance via glymphatic system
Orexin antagonists (suvorexant) being studied
Continuous positive airway pressure (CPAP) for sleep apnea improves cognition

Advanced Diagnostic Approaches

Tau PET Imaging

Tau PET ligands enable in vivo visualization of tau pathology[@leuzy2019]:

FDA-approved ligands:

Flortaucipir (AV-1451): Binds to PHF tau in AD
PI-2620: Detects 3R and 4R tau

Emerging ligands:

APN-1608: Superior off-target binding profile
Lu-AV-145: Longer half-life for production

Limitations:

Off-target binding to monoamine oxidase
Variable binding in different brain regions
Limited sensitivity for non-AD tauopathies

Cerebrospinal Fluid Biomarkers

CSF analysis provides molecular profiling[@blennow2021]:

Tau species:

Total tau (t-tau): Marker of neuronal injury
Phosphorylated tau (p-tau181, p-tau217, p-tau231): Disease-specific
p-tau217/p-tau181 ratio: Differentiates AD from other dementias

Utility:

p-tau217: High accuracy for AD diagnosis (AUC > 0.9)
p-tau231: Tracks disease progression
p-tau181: Predicts cognitive decline

Blood-Based Biomarkers

Emerging blood tests offer accessible diagnostics[@karikari2020]:

Key biomarkers:

p-tau217: Plasma p-tau217 detects early AD
p-tau181: FDA-approved blood test for AD
NfL: Neurofilament light chain for neurodegeneration

Platforms:

Simoa: Ultra-sensitive immunoassay
Mass spectrometry: Precise tau species measurement
IP-MS: Combined p-tau217/total tau ratio

Detailed Therapeutic Pipeline

Immunotherapy

Active vaccination:

AADvac1: Phase 2, targets phospho-tau (Thr231)
ACI-35: Liposome-based, targets phospho-tau (Ser396/404)
Lu AF20513: Designed to induce antibodies to N-terminal tau

Passive immunotherapy:

Gosuranemab (BMS-986168): Anti-N-terminal antibody, failed in PSP
Semorinemab (RG6100): Anti-tau antibody, mixed results in AD
Tilavonemab (ABBV-8E12): Anti-tau antibody, failed in PSP
JAIKE (Lu AF87908): Targets early aggregate tau

Small Molecule Inhibitors

Tau aggregation inhibitors:

Methylthioninium chloride (LMTM): Failed in Phase 3
Davunetide: Peptidyl-prolyl isomerase inhibitor
Nicotinamide: SIRT1 activator

Kinase inhibitors:

Tideglusib: GSK-3β inhibitor, failed in AD
Saracatinib (AZD0530): Fyn inhibitor
AMG-520: CDK5/p25 inhibitor

Microtubule Stabilizers

Paclitaxel derivatives:

TX-2001: CNS-penetrant microtubule stabilizer
NAP (davunetide): Octapeptide fragment of activity-dependent neuroprotective protein

Antisense Oligonucleotides

ASO therapy:

IONIS-MAPTRx: Reduces MAPT mRNA, completed Phase 1/2
ASO targeting exon 10 splicing: Reduce 4R tau

Gene Therapy

Viral vector approaches:

AAV-MAPT: Express therapeutic tau variants
CRISPR-based editing: Correct pathogenic mutations
RNAi: Knockdown mutant tau expression

Animal Models of Tauopathy

Transgenic Models

3xTg-AD mice:

APP, tau, and PS1 mutations
Develops both amyloid and tau pathology
Widely used for therapeutic testing

P301S tau mice:

Express mutant human tau (P301S)
Rapid NFT formation
Used for immunotherapy testing

rTg4510 mice:

Inducible tau expression
Reversible tau pathology
Allows study of tau clearance

Seeding Models

Inoculation studies:

Brain homogenate from AD patients injected into mice
Demonstrates prion-like propagation
Used to study strain characteristics

Tau Propagation Models

Adeno-associated virus (AAV) models:

AAV-tau injected into specific brain regions
Spreads to connected regions
Models tau network progression

Tau Propagation and Prion-Like Spread

Templated Aggregation

Tau exhibits prion-like properties[@frost2009]:

Seed-competent tau templated from patient brains
Conformational templating converts normal tau to pathological forms
Strain fidelity maintained in propagation

Intercellular Transfer

Tau spreads between neurons via:

Synaptic transmission: Tau packaged in synaptic vesicles
Extracellular vesicles: Exosomes carry tau
Tunneling nanotubes: Direct cell-to-cell transfer

Network-Based Spread

Tau pathology follows brain networks:

Connected brain regions show correlated pathology
Vulnerable networks include default mode network
Posterior-to-anterior progression in AD

Implications for Therapy

Therapeutic strategies targeting propagation:

Anti-tau antibodies: Neutralize extracellular tau
Aggregation inhibitors: Prevent seed formation
Synaptic blockers: Inhibit trans-synaptic spread

Neuroinflammation in Tauopathy

Microglial Activation

Microglia play complex roles in tauopathy[@hyman2021]:

Pro-inflammatory (M1-like) microglia:

Release cytokines (IL-1β, TNF-α)
Exacerbate tau pathology
Contribute to neuronal loss

Neuroprotective (M2-like) microglia:

Phagocytose tau aggregates
Release neurotrophic factors
Promote tissue repair

Complement System

The complement cascade is heavily involved:

C1q binds to tau aggregates
C3 knockout reduces tau pathology
CR3 mediates microglial phagocytosis

Cytokine-Mediated Effects

Key cytokines in tauopathy:

IL-1β: Promotes tau phosphorylation via GSK-3β
TNF-α: Disrupts synaptic function
IL-6: Enhances tau aggregation

Therapeutic Targeting

Anti-inflammatory approaches:

Minocycline: Broad microglial inhibitor
TREM2 activation: Shifts microglia to protective phenotype
NLRP3 inflammasome inhibitors: Reduce IL-1β production

Biomarkers

Imaging Biomarkers

Tau PET ligands (Flortaucipir, PI-2620)
MRI atrophy patterns
Diffusion tensor imaging

Fluid Biomarkers

CSF p-tau181, p-tau217, p-tau231
Blood p-tau217, p-tau181

[Alzheimer's Disease Mechanisms](/diseases/alzheimers-disease)
[4R Tauopathies (PSP, CBD) Mechanisms](/mechanisms/4r-tau-cbs)
[Tau Phosphorylation Pathway](/mechanisms/tau-phosphorylation-pathway)
[MAPT Gene](/genes/mapt)
[Neurofibrillary Tangles](/mechanisms/neurofibrillary-tangles)
[Tau Immunotherapy](/therapeutics/tau-immunotherapy)

Vascular Contributions to Tauopathy

Cerebral Amyloid Angiopathy

Cerebral amyloid angiopathy (CAA) frequently co-occurs with tauopathy and contributes to disease progression[@cai2022]. The accumulation of amyloid-beta in cerebral blood vessels not only increases hemorrhage risk but also disrupts vascular clearance pathways for both amyloid and tau. CAA-associated vascular dysfunction impairs the glymphatic system, reducing nocturnal clearance of toxic proteins from the brain interstitium.

Blood-Brain Barrier Breakdown

Tauopathy is associated with progressive blood-brain barrier (BBB) dysfunction[@biglari2022]. Pericyte loss and endothelial tight junction disruption allow peripheral proteins and immune cells to enter the brain, exacerbating neuroinflammation. BBB breakdown correlates with cognitive decline and predicts rapid progression in tauopathies.

Vascular Risk Factors

Hypertension, diabetes, and hyperlipidemia all accelerate tau pathology:

Hypertension: Reduces cerebral blood flow, impairs tau clearance
Diabetes: Promotes tau hyperphosphorylation via insulin signaling dysregulation
Hyperlipidemia: Alters membrane composition, affects tau aggregation kinetics

Metal Ion Dysregulation

Iron Metabolism

Iron accumulation in the aging brain contributes to tau pathology through oxidative stress mechanisms[@lovell2009]. Excess iron catalyzes the formation of reactive oxygen species that promote tau phosphorylation and aggregation. Iron regulatory proteins (IRP1, IRP2) show altered expression in tauopathies, disrupting cellular iron homeostasis.

Zinc and Copper

Divalent metal ions directly influence tau aggregation:

Zinc: Binds to tau at multiple sites, promotes aggregation at physiological concentrations
Copper: Catalyzes oxidative modifications to tau, enhancing its aggregation propensity

Therapeutic Implications

Metal chelation therapy has been explored in tauopathies:

Clioquinol: Copper/zinc chelator showed some cognitive benefit in Phase 2
Deferoxamine: Iron chelator being studied for AD
Novel chelators: CNS-penetrant compounds in development

Network Failure in Tauopathy

Default Mode Network Disruption

The default mode network (DMN) is particularly vulnerable in tauopathies[@harris2020]. Early tau accumulation in the entorhinal cortex and posterior cingulate disrupts DMN connectivity, correlating with episodic memory deficits. Functional connectivity changes precede structural atrophy, providing potential early biomarkers.

Tau and Brain Networks

Tau pathology spreads along connected neural networks:

Connected regions show correlated tau deposition
Synaptic activity promotes trans-synaptic tau spread
Neuronal activity influences tau phosphorylation

Therapeutic Implications

Network-based approaches offer novel therapeutic strategies:

Neural activity modulators: Reducing excitatory activity may slow spread
Network-targeted interventions: Focused ultrasound, TMS
Activity-dependent therapies: Environmental enrichment, cognitive training

Key Proteins and Genes

| Protein/Gene | Function | Disease Link |
|-------------|----------|--------------|
| [MAPT](/genes/mapt) | Microtubule-associated protein tau | All tauopathies |
| [GSK3B](/genes/gsk3b) | Tau kinase | AD, PSP |
| [CDK5R1](/genes/cdk5r1) | CDK5 activator p35 | Neurodegeneration |
| [PPP2CA](/genes/pp2aca) | PP2A catalytic subunit | Tau dephosphorylation |
| [FYN](/genes/fyn) | Src family kinase | Tau phosphorylation |

External Links

[PubMed](https://pubmed.ncbi.nlm.nih.gov/)
[KEGG Pathways](https://www.genome.jp/kegg/pathway.html)

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Pathway Diagram

The following diagram shows the key molecular relationships involving Tauopathy discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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📊 Evidence Profile Foundational

Evidence Balance

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📗 Cite This Artifact

Tauopathy

Tauopathy

Pathway Diagram

Tauopathy

Pathway Diagram

Overview

Tau Protein Biology

Structure and Isoforms

Tau Isoform Functions

Molecular Mechanisms of Tauopathies

Tau Hyperphosphorylation

Tau Aggregation

Tau Strain Diversity

Classification of Tauopathies

Primary Tauopathies (4R)

Primary Tauopathies (3R)

Mixed Isoform Tauopathies

Tauopathy Mechanisms in Neurodegeneration

Microtubule Dysfunction

Axonal Transport Impairment

Synaptic Dysfunction

Neuronal Death Mechanisms

Genetic Factors in Tauopathies

MAPT Mutations

H1 Haplotype

GWAS Findings

Epigenetic Regulation in Tauopathy

DNA Methylation

Histone Modifications

Non-Coding RNAs

Metabolic Dysfunction in Tauopathy

Glucose Metabolism

Mitochondrial Dysfunction

Insulin Signaling

Sleep Disorders and Tauopathy

Bidirectional Relationship

Circadian Rhythm Disruption

Therapeutic Implications

Advanced Diagnostic Approaches

Tau PET Imaging

Cerebrospinal Fluid Biomarkers

Blood-Based Biomarkers

Detailed Therapeutic Pipeline

Immunotherapy

Small Molecule Inhibitors

Microtubule Stabilizers

Antisense Oligonucleotides

Gene Therapy

Animal Models of Tauopathy

Transgenic Models

Seeding Models

Tau Propagation Models

Tau Propagation and Prion-Like Spread

Templated Aggregation

Intercellular Transfer

Network-Based Spread

Implications for Therapy

Neuroinflammation in Tauopathy

Microglial Activation

Complement System

Cytokine-Mediated Effects

Therapeutic Targeting

Biomarkers

Imaging Biomarkers

Fluid Biomarkers

Cross-Links to Related Mechanisms

Vascular Contributions to Tauopathy

Cerebral Amyloid Angiopathy

Blood-Brain Barrier Breakdown

Vascular Risk Factors

Metal Ion Dysregulation

Iron Metabolism

Zinc and Copper

Therapeutic Implications

Network Failure in Tauopathy

Default Mode Network Disruption

Tau and Brain Networks

Therapeutic Implications

Key Proteins and Genes