The 4-repeat (4R) tauopathies represent a spectrum of neurodegenerative disorders characterized by the predominant accumulation of 4R tau isoforms. While all five major 4R-tauopathies share pathological tau accumulation, they exhibit distinct regional patterns of neurodegeneration that define their clinical phenotypes. Understanding these spreading patterns is critical for differential diagnosis, biomarker development, and therapeutic intervention[@arendt2018][@baumann2022].
This page provides a comprehensive comparison of tau propagation patterns across:
- Progressive Supranuclear Palsy (PSP)
- Corticobasal Degeneration (CBD)
- Argyrophilic Grain Disease (AGD)
- Globular Glial Tauopathy (GGT)
- Frontotemporal Dementia with Parkinsonism-17 (FTDP-17)
| Feature |
PSP |
CBD |
AGD |
GGT |
FTDP-17 |
| Primary Pattern |
Subcortical-brainstem |
Cortical-subcortical |
Limbic |
White matter-glial |
Mutation-dependent |
| Tau in Neurons |
++ |
++ |
+ |
+ |
++ |
| Tau in Glia |
++ (tufted astrocytes) |
++ (astrocytes) |
+ (grains) |
+++ (oligodendrocytes) |
Variable |
| Asymmetry |
Symmetric |
Asymmetric |
Symmetric |
Variable |
Variable |
| Staging System |
NINDS-SPSP |
Distribution-based |
Braak-like AGD |
None standardized |
Mutation-specific |
| Key Regions |
GP, STN, SN, midbrain |
Motor cortex, putamen |
Amygdala, hippocampus |
White matter tracts |
Variable |
PSP demonstrates a characteristic subcortical-to-cortical progression that begins in the brainstem and basal ganglia, spreading upward to involve the cortex in later stages[@williams2009][@dickson2012].
Early Stage (Braak-like I-II):
- Subthalamic nucleus (STN)
- Globus pallidus internus (GPi)
- Midbrain periaqueductal gray
- Oculomotor nuclei (riMLF, INC)
Intermediate Stage (Braak-like III-IV):
- Substantia nigra pars compacta (SNc)
- Red nucleus
- Pontine base
- Dentate nucleus of cerebellum
Late Stage (Braak-like V-VI):
- Frontal cortex
- Parietal cortex
- Motor cortex
PSP has its own staging system based on the distribution of neurofibrillary tangles (NFTs):
- Stage 1-2: Limited to subcortical structures (GP, STN, SN)
- Stage 3-4: Brainstem involvement extends to midbrain and pons
- Stage 5-6: Cortical involvement, particularly frontal regions
flowchart TD
A["4R Tau Aggregation"] --> B["Brainstem Nuclei"]
B --> C["Basal Ganglia GPi/STN"]
C --> D["Substantia Nigra"]
D --> E["Midbrain/Pons"]
E --> F["Frontal Cortex"]
B --> G["Tufted Astrocytes"]
G --> H["Glial Propagation"]
F --> I["Cortical NFT Formation"]
I --> J["Cognitive Decline"]
style A fill:#fff9c4
style B fill:#ff7777
style C fill:#ff5555
style D fill:#ff3333
style E fill:#ff1111
style F fill:#cc0000
The propagation follows the ascending reticular activating system and basal ganglia output pathways, explaining the characteristic vertical gaze palsy and postural instability[@he2022].
CBD exhibits an asymmetric cortical-subcortical pattern that typically begins in one hemisphere and spreads to the contralateral side[@kouri2014][@armstrong2013].
Early Stage:
- Primary motor cortex (Betz cells)
- Premotor cortex
- Posterior putamen
- Globus pallidus
Intermediate Stage:
- Somatosensory cortex
- Prefrontal cortex
- Substantia nigra
- Red nucleus
Late Stage:
- Contralateral motor cortex
- Temporal parietal regions
- Brainstem structures
CBD shows significant heterogeneity with multiple patterns:
- CBS-CBD: Cortical pattern with asymmetric motor involvement
- PSD-CBD: Parkinsonism-predominant
- NFLE-CBD: Non-fluent aphasia variant
flowchart TD
A["4R Tau in Motor Cortex"] --> B["Asymmetric Onset"]
B --> C["Contralateral Spread"]
C --> D["Basal Ganglia Involvement"]
D --> E["Brainstem Extension"]
E --> F["Bilateral Cortical"]
A --> G["Astrocytic Plaques"]
G --> H["Glial Network Spread"]
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CBD tau shows distinct strain characteristics from PSP, with more heterogeneous filament populations including twisted ribbons and paired helical filaments[@shi2021].
AGD demonstrates a limbic-predominant pattern that primarily affects the medial temporal lobe and spreads through limbic circuits[@tolnay2000][@saito2004].
Early Stage (Braak AGD I-II):
- Amygdala (particularly the corticomedial nucleus)
- Entorhinal cortex
- Transentorhinal cortex
Intermediate Stage (Braak AGD III-IV):
- Hippocampus (CA1, subiculum)
- Dentate gyrus
- Hypothalamus
Late Stage (Braak AGD V-VI):
- Limbic cortex
- Orbitofrontal cortex
- Temporal pole
AGD follows a Braak-like staging distinct from Alzheimer's disease:
- Stage I: Amygdala-predominant
- Stage II: Amygdala + entorhinal cortex
- Stage III: Add hippocampus
- Stage IV: Add hypothalamic nuclei
- Stage V-VI: Extend to isocortex
flowchart TD
A["4R Tau in Amygdala"] --> B["Entorhinal Cortex"]
B --> C["Hippocampal Formation"]
C --> D["Limbic Circuit"]
D --> E["Hypothalamus"]
E --> F["Orbitofrontal Cortex"]
A --> G["Argyrophilic Grains"]
G --> H["neuritic Loop Spread"]
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AGD is characterized by argyrophilic grains - spindle-shaped tau inclusions in dendrites - which spread through the limbic system circuit[@duyckaerts2009].
GGT exhibits a unique white matter-predominant pattern with 4R tau primarily accumulating in glial cells, particularly oligodendrocytes[@kovacs2011][@ferrer2018].
Early Stage:
- White matter of frontal lobes
- Deep white matter tracts
- Corpus callosum
- Internal capsule
Intermediate Stage:
- Subcortical white matter expansion
- Pyramidal tracts
- Cerebellar white matter
Late Stage:
- Extensive white matter involvement
- Gray matter infiltration
- Brainstem white matter
GGT is unique among 4R-tauopathies in that:
- Primary pathology is in glial cells (oligodendrocytes > astrocytes)
- Globular inclusions in oligodendrocytes and astrocytes
- Minimal neuronal involvement compared to other 4R-tauopathies
- White matter tract degeneration is prominent
flowchart TD
A["4R Tau in Oligodendrocytes"] --> B["White Matter Tracts"]
B --> C["Corpus Callosum"]
C --> D["Internal Capsule"]
D --> E["Pyramidal Tracts"]
E --> F["Cerebellar White Matter"]
B --> G["Glial Network"]
G --> H["Myelin-Mediated Spread"]
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The propagation follows white matter tracts, spreading via oligodendrocyte networks and myelin-mediated transport[@lloyd2013].
FTDP-17 shows mutation-dependent spreading patterns based on the specific MAPT mutation[@goedert2000][@rizzini2000].
Splicing Mutations (e.g., +3, +16, N279K):
- Early: Frontotemporal cortex
- Pattern resembles PSP
- Subcortical involvement prominent
Aggregation Mutations (e.g., P301L, P301S):
- Early: Frontal cortex and limbic system
- Rapid progression
- Severe neuronal loss
Missense Mutations (e.g., R406W):
- More variable pattern
- Hippocampal involvement prominent
- Resembles AD in some cases
| Mutation Type |
Primary Region |
Secondary Region |
Phenotype |
| +3 splice |
Frontotemporal |
Subcortical |
PSP-like |
| N279K |
Brainstem |
Basal ganglia |
PSP-like |
| P301L |
Frontotemporal |
Limbic |
CBD-like |
| R406W |
Limbic |
Cortex |
AD-like |
flowchart TD
A["MAPT Mutation"] --> B{"Direct Effects"}
B --> C["Splicing Dysregulation"]
B --> D["Aggregation Enhancement"]
C --> E["4R Tau Overproduction"]
E --> F["PSP-like Pattern"]
D --> G["Seed-Competent Tau"]
G --> H["CBD/AD-like Pattern"]
F --> I["Network Propagation"]
H --> I
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style I fill:#ff33ff
All 4R-tauopathies follow the principle of prion-like propagation along neural networks[@jucker2018]:
- Template-Directed Misfolding: Pathological tau seeds induce misfolding of endogenous tau
- Trans-synaptic Transport: Tau travels along axons to connected regions
- Activity-Dependent Release: Synaptic activity promotes tau release
- Recipient Neuron Uptake: Connected neurons take up extracellular tau
Cryo-EM studies have revealed disease-specific tau strains[@schweighauser2020]:
| Disease |
Filament Type |
Core Structure |
Protofilaments |
| PSP |
Straight filaments |
3-layer C-shaped |
2 |
| CBD |
Twisted ribbons |
4-layer compact |
2-4 |
| AGD |
PHFs |
3R/4R mixture |
2 |
| GGT |
Straight filaments |
Variable |
2 |
| FTDP-17 |
Mutation-dependent |
Variable |
Variable |
Glial cells play different roles in each disease:
- PSP: Tufted astrocytes (highly specific marker)
- CBD: Astrocytic plaques, coiled bodies
- AGD: Argyrophilic grains in neurons and glia
- GGT: Primary oligodendroglial and astrocytic involvement
- FTDP-17: Variable glial pathology
¶ Regional Spreading and Symptoms
| Disease |
Early Symptoms |
Correlation with Spread |
| PSP |
Vertical gaze palsy, falls |
Brainstem → basal ganglia |
| CBD |
Apraxia, alien limb |
Motor cortex → subcortical |
| AGD |
Memory loss, personality change |
Limbic system involvement |
| GGT |
Gait disturbance, parkinsonism |
White matter → cortical |
| FTDP-17 |
Behavioral change, parkinsonism |
Mutation-dependent |
Understanding spreading patterns informs biomarker development:
- CSF tau: Different isoform patterns in each disease
- PET ligands: Region-specific binding patterns
- Blood biomarkers: Disease-specific tau fragments
Anti-tau therapeutic trials targeting tau spreading mechanisms across 4R-tauopathies:
| Agent |
Company |
Target |
Phase |
Trial ID |
Status |
Notes |
| E2814 |
Eisai/Eldridge |
p-tau217, MTBR |
Phase II/III |
NCT05498661 |
Recruiting |
DIAN-TU, PSP/CBS |
| Bepranemab |
UCB |
p-tau231, MTBR |
Phase II |
NCT04134862 |
Completed |
33-58% tau PET slowing |
| Tilavonemab |
Lilly |
N-terminal tau |
Phase II |
NCT02460094 |
Failed |
No clinical benefit |
| Semorinemab |
Roche |
N-terminal tau |
Phase II |
NCT02880956 |
Mixed |
TAURIEL failed, LAURIET partial |
| Prasinezumab |
Roche/Genentech |
p-tau N-terminus |
Phase II |
NCT03100186 |
Failed |
No significant benefit |
| BIIB080 |
Biogen |
MAPT ASO |
Phase II |
NCT03053068 |
Recruiting |
Tau reduction in CSF |
Tau PET Imaging Trials:
CSF Biomarkers for Tau Spreading:
- p-tau181: Elevated in PSP, correlates with disease severity
- p-tau217: High specificity for 4R-tauopathies vs AD
- p-tau231: Early marker for CBD, sensitive to treatment response
- Total tau: Non-specific but indicates neuronal injury
- Neurofilament light chain (NfL): Progression marker
Imaging Biomarkers:
- Tau PET: Regional uptake patterns distinguish 4R-tauopathies
- MR volumetry: Subcortical atrophy progression
- FDG-PET: Hypometabolism patterns correlate with spreading
Blood Biomarkers:
- p-tau181 in plasma: Screening for PSP
- p-tau217: Emerging as sensitive 4R-tau marker
- NfL: General neurodegeneration marker
Therapeutic Implications:
- Early intervention before extensive spreading offers best outcomes
- MTBR-targeting antibodies (E2814, bepranemab) show promise for disease modification
- Combination approaches targeting both intracellular and extracellular tau may be necessary
- Patient selection based on biomarker profile may improve trial success
Clinical Practice Integration:
- Tau PET can identify patients likely to benefit from anti-tau therapy
- CSF biomarker monitoring can track treatment response
- Early identification of spreading pattern guides prognostic counseling
- Network-based spread patterns explain variable clinical presentations
Challenges:
- Blood-brain barrier penetration for anti-tau antibodies
- Optimal timing of intervention (pre-symptomatic vs symptomatic)
- Heterogeneity of 4R-tauopathy subtypes affects treatment response
- Need for disease-specific (not AD-focused) trial designs
- Arendt T, et al., Nat Rev Dis Primers 2018 - Tauopathies (2018)
- Baumann C, et al., J Neuropathol Exp Neurol 2022 - 4R tauopathies classification (2022)
- Williams DR, Lees AJ, Lancet Neurology 2009 - Progressive supranuclear palsy (2009)
- Dickson DW, et al., Acta Neuropathol 2012 - Neuropathology of PSP and CBD (2012)
- He Z, et al., Nat Rev Neurol 2022 - Tau propagation and Braak staging (2022)
- Kouri N, et al., Nat Rev Neurol 2014 - CBS neuropathology (2014)
- Armstrong MJ, et al., Neurology 2013 - CBD diagnostic criteria (2013)
- Shi Y, et al., Neuron 2021 - CBD tau filament structures (2021)
- Tolnay M, Ghetti B, Acta Neuropathol 2000 - Argyrophilic grain disease (2000)
- Saito M, et al., Acta Neuropathol 2004 - AGD staging system (2004)
- Duyckaerts C, et al., Brain 2009 - AGD propagation (2009)
- Kovacs GG, et al., Brain 2011 - GGT classification (2011)
- Ferrer I, et al., Acta Neuropathol 2018 - GGT pathology (2018)
- Lloyd GM, et al., J Neurosci 2013 - Glial tau propagation (2013)
- Goedert M, Spillantini MG, Nat Rev Neurosci 2000 - FTDP-17 and MAPT mutations (2000)
- Rizzini M, et al., Brain 2000 - FTDP-17 tau pathology (2000)
- Jucker M, Walker LC, Nature 2018 - Self-propagation of protein aggregates (2018)
- Schweighauser M, et al., Nature 2020 - Tau filaments from multiple neurodegenerative diseases (2020)