FTD Tau Subtypes Comparison: 3R vs 4R Tauopathies

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FTD Tau Subtypes Comparison: 3R vs 4R Tauopathies

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FTLD-Tau Subtypes Comparison: 3R vs 4R Tauopathies

Overview

Frontotemporal lobar degeneration with tau pathology (FTLD-tau) encompasses a heterogeneous group of neurodegenerative diseases that share tau protein aggregation as a central pathogenic mechanism. Despite sharing this common endpoint, FTLD-tau subtypes differ markedly in their molecular signatures, histological lesion morphology, cellular distribution, clinical presentation, and genetic architecture. This page provides a systematic comparison of the major FTLD-tau subtypes: [Pick's disease](/diseases/pick-disease) (3R), [corticobasal degeneration](/diseases/corticobasal-degeneration) (4R), [progressive supranuclear palsy](/diseases/psp) (4R), [argyrophilic grain disease](/diseases/argyrophilic-grain-disease) (4R), and [globular glial tauopathy](/diseases/globular-glial-tauopathy) (4R). [@karimov2022] [@dickson2023]

The MAPT gene on chromosome 17q21.31 encodes the microtubule-associated protein tau (MAPT). Alternative splicing of exons 2, 3, and 10 produces six isoforms in the adult human brain, categorized by the presence of three (3R) or four (4R) microtubule-binding repeat domains. This fundamental molecular distinction divides FTLD-tau into 3R-predominant and 4R-predominant subtypes, each with distinct pathobiology. [@goedert2017] [@araki2021]

```mermaid
flowchart TB
subgraph FTLDTau["FTLD-Tau Spectrum"]
direction TB

subgraph Sub3R["3R Tauopathies"]
A1["Pick's Disease<br/>(PiD)"]
end

...

FTLD-Tau Subtypes Comparison: 3R vs 4R Tauopathies

Overview

Frontotemporal lobar degeneration with tau pathology (FTLD-tau) encompasses a heterogeneous group of neurodegenerative diseases that share tau protein aggregation as a central pathogenic mechanism. Despite sharing this common endpoint, FTLD-tau subtypes differ markedly in their molecular signatures, histological lesion morphology, cellular distribution, clinical presentation, and genetic architecture. This page provides a systematic comparison of the major FTLD-tau subtypes: [Pick's disease](/diseases/pick-disease) (3R), [corticobasal degeneration](/diseases/corticobasal-degeneration) (4R), [progressive supranuclear palsy](/diseases/psp) (4R), [argyrophilic grain disease](/diseases/argyrophilic-grain-disease) (4R), and [globular glial tauopathy](/diseases/globular-glial-tauopathy) (4R). [@karimov2022] [@dickson2023]

The MAPT gene on chromosome 17q21.31 encodes the microtubule-associated protein tau (MAPT). Alternative splicing of exons 2, 3, and 10 produces six isoforms in the adult human brain, categorized by the presence of three (3R) or four (4R) microtubule-binding repeat domains. This fundamental molecular distinction divides FTLD-tau into 3R-predominant and 4R-predominant subtypes, each with distinct pathobiology. [@goedert2017] [@araki2021]

Mermaid diagram (expand to render)

3R vs 4R Tau: Molecular Basis

Isoform Structure

The human [tau](/proteins/tau-protein) gene contains 16 exons, with exons 2, 3, and 10 subject to alternative splicing. Inclusion of exon 10 adds a fourth microtubule-binding repeat (R1-R4), producing 4R isoforms; exclusion produces 3R isoforms (lacking the N-terminal portion of R2). In the normal adult human brain, 3R and 4R tau isoforms are present in approximately equal proportions. [@goedert2003] [@bhangare2022]

The microtubule-binding repeat domain (R1-R4) is the primary driver of tau aggregation. The hexapeptide motifs306-VQIVYK-311 and378-VQIVTK-383 within the repeat domain form the β-strand core of tau fibrils. In 4R tauopathies, inclusion of the R2 domain (encoded by exon 10) confers enhanced aggregation propensity and altered filament morphology. [@fitzpatrick2017]

Functional Consequences

| Property | 3R Tau | 4R Tau |
|----------|--------|--------|
| Microtubule binding affinity | Moderate | Higher (due to extra R2 repeat) |
| Aggregation propensity | Lower baseline | Higher baseline |
| Filament structure | Distinct folds (Pick-type) | Distinct folds (PSP/CBD/AGD-type) |
| Normal brain ratio | ~50% of total tau | ~50% of total tau |
| Disease association | Pick's disease (primary) | PSP, CBD, AGD, GGT |
| Genetic risk | MAPT mutations affecting exon 10 splicing | H1 haplotype (PSP, CBD), MAPT missense mutations |

Genetic Regulation

MAPT mutations in FTLD-tau fall into two broad categories: splicing mutations that disrupt the 3R/4R balance (primarily affecting exon 10), and missense mutations within the microtubule-binding repeats that impair microtubule binding or promote aggregation. Splicing mutations typically produce 4R tauopathies (increased exon 10 inclusion), while missense mutations can produce either 3R or 4R pathology depending on their location. [@schofield2012]

The H1 haplotype of MAPT (present in >95% of sporadic PSP cases) is the major genetic risk factor for sporadic 4R tauopathies. The H2 haplotype appears protective. These haplotypes influence MAPT transcription, splicing, and possibly the efficiency of tau mRNA degradation. [@dickson2023]

Subtype Comparison Table

| Feature | Pick's Disease (PiD) | Corticobasal Degeneration (CBD) | Progressive Supranuclear Palsy (PSP) | Argyrophilic Grain Disease (AGD) | Globular Glial Tauopathy (GGT) |
|---------|---------------------|-------------------------------|--------------------------------------|--------------------------------|-------------------------------|
| Tau isoform | 3R predominant | 4R predominant | 4R predominant | 4R predominant | 4R predominant |
| Primary lesion | Pick bodies (neurons) | Astrocytic plaques (astrocytes) | Tufted astrocytes (astrocytes) | Argyrophilic grains (neurons/glia) | Globular oligodendroglial inclusions (GOIs) |
| Key histological features | Pick bodies, ballooned neurons, cortical blindness | Asymmetric cortical atrophy, astrocytic plaques, neuronal loss | Tufted astrocytes, coiled bodies, NFT in brainstem | Argyrophilic grains, pretangle pathology, enlarged neurons | Globular inclusions in oligodendrocytes (GOIs) and astrocytes (GAIs) |
| Cellular distribution | Neurons > glia | Astrocytes prominent, neurons, oligodendrocytes | Astrocytes, neurons, oligodendrocytes | Neurons and glia | Oligodendrocytes (GOIs) and astrocytes (GAIs) |
| Filament structure (cryo-EM) | Three-helix fold, distinct from AD | Two-protofilament fold, distinct from PSP/AD | Two-protofilament fold, distinct from CBD/AD | Two-protofilament fold, distinct from CBD/AD | Distinct from PSP and CBD |
| Typical onset age | 40-65 years | 50-70 years | 55-70 years | 60-80 years | 50-75 years |
| Clinical phenotype | FTD (behavioral/language), rapid progression | CBS, asymmetric rigidity, apraxia, alien limb | PSP syndromes (vertical gaze palsy, falls, parkinsonism) | Late-onset dementia with memory/behavioral changes | FTD-ALS spectrum, bvFTD, motor neuron disease |
| Motor involvement | Variable | Prominent (parkinsonism, dystonia, myoclonus) | Prominent (axial rigidity, gaze palsy) | Mild | Often prominent (ALS/PLS features) |
| MAPT mutations | Some familial cases | Rare (usually 4R) | H1 haplotype strong risk; rare mutations | H1 haplotype risk | Rare (4R) |
| Other genetic risk | Unknown | GRN, TMEM106B | H1/H1 haplotype | Unknown | Unknown |
| Diagnostic biomarkers | CSF p-tau181, tau PET | NfL, tau PET (limited) | NfL, CSF p-tau231, tau PET | Limited | Limited |

Pick's Disease (3R Tauopathy)

Molecular Signature

Pick's disease is the prototypical 3R tauopathy, characterized neuropathologically by the presence of Pick bodies — round to oval, argyrophilic intracytoplasmic inclusions composed predominantly of 3R tau isoforms. [@sergeant2005] Cryo-EM studies have revealed that Pick body filaments adopt a three-helix fold distinct from the two-protofilament folds observed in [Alzheimer's disease](/diseases/alzheimers-disease) and 4R tauopathies. [@baikofen2024]

Pick bodies are composed of hyperphosphorylated 3R tau arranged in a paired helical filament-like structure, but structurally distinct from the classic paired helical filaments of AD. The inclusions are tau-positive, ubiquitin-positive, and p62-positive, with variable TDP-43 co-pathology in some cases. [@dickson2023]

Histological Lesions

The classic triads of Pick's disease include: [@goedert2003]

Pick bodies: Spherical, tau-positive inclusions in the cytoplasm of neurons, most prominent in the dentate granule cells of the hippocampus and pyramidal neurons of the frontal and temporal cortex. They displace the nucleus peripherally and have a dense core with a less dense halo.

Ballooned neurons (Pick cells): Swollen, achromatic neurons with disrupted cytoskeleton, found in the frontotemporal cortex and basal ganglia. These represent dying neurons with disrupted neurofilament organization.

Cortical thinning: Marked loss of frontal and temporal gray matter with spongiosis and neuronal loss. The insular cortex and anterior cingulate are particularly affected.

Clinical Correlates

Pick's disease typically presents with the behavioral variant of [frontotemporal dementia](/diseases/ftd) (bvFTD) or primary progressive aphasia variants. The clinical phenotype reflects frontotemporal neurodegeneration: [@karimov2022]

Behavioral disinhibition, apathy, loss of empathy
Hyperorality, dietary changes
Compulsive/stereotyped behaviors
Language impairment (logopenic or semantic variants)
Relatively preserved memory and visuospatial function early in disease

Corticobasal Degeneration (CBD)

Molecular Signature

[Corticobasal degeneration](/diseases/corticobasal-degeneration) is a 4R tauopathy with a characteristic asymmetric distribution of pathology. Cryo-EM studies have shown that CBD filaments adopt a two-protofilament fold that is distinct from both [Alzheimer's disease](/diseases/alzheimers-disease) and [progressive supranuclear palsy](/diseases/psp) filaments, despite both being 4R tauopathies. [@fitzpatrick2017] [@kovacs2020cbd]

The 4R tau in CBD is hyperphosphorylated at multiple epitopes (AT8, AT100, PHF-1) and forms distinct ultrastructural filaments that differ in their protofilament packing from PSP. This structural distinction may explain the clinical and pathological heterogeneity between these disorders. [@baikofen2024]

Histological Lesions

The characteristic lesions of CBD include: [@dickson2019] [@armstrong2020]

Astrocytic plaques: The pathognomonic lesion of CBD — annular or wreath-like tau-positive inclusions in astrocytic processes. Unlike the tufted astrocytes of PSP, astrocytic plaques form a diffuse, peripheral pattern around the astrocyte cell body, best visualized with Gallyas silver stain and 4R tau immunohistochemistry.

Neuronal tau pathology: Oligodendroglial coiled bodies (crescentic inclusions in oligodendrocyte nuclei), pretangle tau pathology in neurons, and neurofibrillary tangles similar to PSP but with different distribution.

Asymmetric cortical atrophy: Particularly affecting frontoparietal regions, with neuronal loss, gliosis, and spongiosis. The motor cortex and basal ganglia (especially the substantia nigra) are consistently involved.

Clinical Correlates

The classic clinical presentation of corticobasal degeneration is corticobasal syndrome (CBS): [@armstrong2020]

Asymmetric limb rigidity and apraxia
Cortical sensory loss (impaired two-point discrimination, astereognosis)
Alien limb phenomenon (involuntary limb movements)
Dystonia and myoclonus
Early and prominent cognitive decline
Poor or no response to levodopa

Progressive Supranuclear Palsy (PSP)

Molecular Signature

[Progressive supranuclear palsy](/diseases/psp) is the most common 4R tauopathy and the most frequent neurodegenerative cause of atypical parkinsonism. The H1 MAPT haplotype is present in over 95% of sporadic cases, making it the strongest genetic risk factor in neurodegeneration. [@kovacs2020psp] [@josephs2019]

Cryo-EM studies have revealed that PSP tau filaments adopt a two-protofilament fold that is distinct from CBD filaments, despite both being 4R tauopathies with similar ultrastructural features under conventional EM. The structural differences in protofilament packing correlate with the distinct clinical phenotypes and neuropathological lesion types of these two disorders. [@baikofen2024]

Histological Lesions

The hallmark lesions of PSP include: [@kovacs2020psp]

Tufted astrocytes: The most characteristic lesion, with tau-immunoreactive processes arranged in a tufted or bushy pattern around the astrocyte cell body. These are best visualized with 4R tau immunohistochemistry and are found predominantly in the basal ganglia, brainstem, and motor cortex. Unlike astrocytic plaques (CBD), tufted astrocytes have a compact, perinuclear distribution.

Coiled bodies: Oligodendroglial inclusions with a crescent or coiled morphology, found in the white matter and subcortical structures. These are also 4R tau-positive and distinguish PSP from AD.

Neurofibrillary tangles:Globular or flame-shaped intraneuronal inclusions in the brainstem nuclei (particularly the substantia nigra pars compacta, locus coeruleus), basal ganglia, dentate nucleus of the cerebellum, and cortex.

Glial tau pathology: Thorn-shaped astrocytes in the motor cortex and astrocytic plaques in the subthalamic nucleus and other regions.

Clinical Correlates

The classic presentation is the Richardson syndrome (PSP-Richardson syndrome): [@josephs2019]

Early postural instability with unexplained falls (often backward)
Vertical supranuclear gaze palsy (downward gaze impaired first)
Axial rigidity (neck extension) and symmetric parkinsonism
Pseudobulbar affect, dysarthria, dysphagia
Frontal executive dysfunction

Multiple clinical variants of PSP are now recognized, including PSP-parkinsonism (PSP-P), PSP-pure akinesia with gait freezing (PSP-PAGF), PSP-corticobasal syndrome (PSP-CBS), and others — each with different clinicopathological correlations.

Argyrophilic Grain Disease (AGD)

Molecular Signature

[Argyrophilic grain disease](/diseases/argyrophilic-grain-disease) is a 4R tauopathy characterized by the presence of argyrophilic grains — spindle-shaped, argyrophilic inclusions in neuronal processes and dendrites. AGD is increasingly recognized as a common contributor to late-onset dementia, often co-existing with AD-type amyloid pathology. [@tolnay2022]

Like CBD and PSP, AGD tau filaments adopt a two-protofilament fold, but structural studies suggest subtle differences in protofilament packing that may account for the distinct grain-like morphology. [@baikofen2024]

Histological Lesions

The characteristic lesions of AGD include: [@tolnay2022]

Argyrophilic grains: Spindle-shaped, silver-staining inclusions distributed in the hippocampal formation (CA1, subiculum), entorhinal cortex, and limbic structures. Grains are primarily located in neuronal dendrites and represent "thread-like" processes with tau pathology.

Pretangle tau pathology: Diffuse, granular cytoplasmic tau staining in neurons (especially in the limbic system) without well-formed NFT.

Enlarged neurons: Ballooned neurons with phosphorylated tau in the amygdala and other limbic structures, resembling Pick cells but without Pick bodies.

Oligodendroglial coiled bodies: Similar to those seen in PSP and CBD, but less prominent.

Clinical Correlates

AGD typically presents as a late-onset dementia with prominent behavioral and memory features: [@tolnay2022] [@schweighofer2023]

Gradual progressive memory impairment
Behavioral changes: irritability, aggression, anxiety
Relatively preserved executive function in early stages
Short-lived episodes of confusion or psychosis
Often co-exists with AD pathology, creating mixed dementia phenotypes

Globular Glial Tauopathy (GGT)

Molecular Signature

[Globular glial tauopathy](/diseases/globular-glial-tauopathy) is a rare 4R tauopathy distinguished by globular inclusions in both oligodendrocytes and astrocytes, with oligodendroglial pathology predominating. The condition was unified under the GGT nomenclature in 2013 and represents a distinct entity within the 4R tauopathy spectrum. [@ahmed2013]

The globularity of the inclusions (spherical, well-circumscribed, displacing the nucleus peripherally) distinguishes them from the crescent-shaped coiled bodies of PSP and the annular astrocytic plaques of CBD. [@deller2019]

Histological Lesions

Three neuropathological subtypes are recognized based on regional distribution: [@ahmed2013]

Type I — Frontotemporal pattern: Predominant frontotemporal cortical and white matter involvement with globular oligodendroglial inclusions (GOIs) as the dominant lesion. Clinically presents as bvFTD with behavioral changes and executive dysfunction.

Type II — Motor-predominant pattern: Severe involvement of motor cortex, corticospinal tracts, and spinal cord motor neurons, with both GOIs and globular astroglial inclusions (GAIs). Clinically resembles [ALS](/diseases/als) or primary lateral sclerosis with upper and lower motor neuron signs.

Type III — Combined pattern: Mixed frontotemporal and motor system involvement, clinically presenting as FTD-ALS spectrum with both cognitive impairment and motor neuron disease.

The defining lesions are: [@deller2019]

GOIs (globular oligodendroglial inclusions): Large, spherical, well-circumscribed tau-positive inclusions in oligodendrocyte cytoplasm, displacing the nucleus to the periphery. Found in white matter along myelinated fiber tracts.
GAIs (globular astroglial inclusions): Round, globular tau-positive inclusions in astrocyte cell bodies, distinct from the tufted astrocytes of PSP and the astrocytic plaques of CBD.

Clinical Correlates

GGT typically presents with: [@deller2019] [@kovacs2018]

Behavioral variant FTD (Type I): personality changes, apathy, disinhibition, executive dysfunction
Motor neuron disease (Type II): weakness, muscle atrophy, fasciculations, spasticity
Combined FTD-ALS (Type III): mixed cognitive and motor phenotypes
Relatively rapid progression compared to other FTLD-tau subtypes

Molecular Comparison: Filament Structures

Cryo-electron microscopy has revolutionized the understanding of tauopathies by revealing distinct filament folds across diseases. These structural differences provide a molecular basis for the observed pathological and clinical heterogeneity. [@fitzpatrick2017] [@baikofen2024]

| Tauopathy | Filament Fold | Protofilament Architecture | C-Terminal Conformation |
|-----------|---------------|--------------------------|------------------------|
| Alzheimer's disease | Two-protofilament, helical | Asymmetric, L-shaped | Folded back |
| Pick's disease | Three-helix fold | Novel compact fold | Extended |
| CBD | Two-protofilament | Distinct packing from PSP | Folded back |
| PSP | Two-protofilament | Distinct packing from CBD | Folded back |
| AGD | Two-protofilament | Related to PSP/CBD but distinct | Folded back |
| GGT | Distinct | Different from PSP and CBD | Under characterization |

The structural differences between CBD and PSP filaments — despite both being 4R tauopathies with similar appearance under conventional electron microscopy — explain the distinct histological lesion types (astrocytic plaques vs. tufted astrocytes) and clinical phenotypes. These structural differences also have implications for biomarker development and therapeutic targeting, as conformation-specific antibodies and PET ligands may be able to distinguish between these entities. [@baikofen2024]

Glial Tau Pathology: A Comparative Perspective

A distinguishing feature of 4R tauopathies is the prominence of glial tau pathology, which varies in morphology, cellular distribution, and anatomical distribution across subtypes. This represents a key differential feature. [@deller2019]

| Glial Feature | Pick's Disease | CBD | PSP | AGD | GGT |
|---------------|---------------|-----|-----|-----|-----|
| Astrocytic tau | Rare | Prominent (plaques) | Prominent (tufted) | Moderate (thorn-shaped) | Moderate (GAIs) |
| Oligodendroglial tau | Rare | Moderate (coiled bodies) | Moderate (coiled bodies) | Moderate (coiled bodies) | Very prominent (GOIs) |
| Astrocyte morphology | Ballooned neurons predominant | Annular/wreath plaques | Tufted perinuclear | Thorn-shaped | Globular spherical |
| Oligodendrocyte morphology | Minimal involvement | Crescents/coiled | Crescents/coiled | Crescents/coiled | Large spherical globules |
| White matter involvement | Mild | Moderate | Moderate | Moderate | Severe |

Shared Mechanisms and Differences

Common Mechanisms

Despite their clinical and pathological differences, all FTLD-tau subtypes share several core pathogenic mechanisms: [@karimov2022] [@schweighofer2023]

Tau hyperphosphorylation: Increased activity of kinases (GSK-3β, CDK5, MAPK) and/or decreased activity of phosphatases (PP2A) leads to hyperphosphorylated tau that dissociates from microtubules and becomes available for aggregation.

Tau misfolding and aggregation: Pathological tau adopts a β-sheet-rich conformation that templates the misfolding of normal tau through a prion-like propagation mechanism.

Microtubule destabilization: Loss of functional tau from microtubules leads to impaired axonal transport, synaptic dysfunction, and axonal degeneration.

Neuronal and glial dysfunction: Tau pathology in neurons and glia contributes to neuroinflammation, metabolic impairment, and cell death.

Prion-like propagation: Templated tau aggregation allows pathology to spread along connected brain networks, explaining the progressive nature of these diseases.

Key Differences

| Mechanism | 3R Tauopathies (Pick's) | 4R Tauopathies |
|-----------|------------------------|----------------|
| Isoform affected | 3R predominates | 4R predominates |
| Primary cellular target | Neurons | Astrocytes and oligodendrocytes prominent |
| Aggregation propensity | Moderate | High (extra R2 repeat) |
| Filament fold | Three-helix compact | Two-protofilament extended |
| Clinical phenotype | FTD behavioral/language | Parkinsonism (PSP), CBS, dementia |
| H1 haplotype risk | Weaker | Very strong |
| Typical progression | Rapid | Slower, more varied |

Therapeutic Implications

The distinct molecular signatures of FTLD-tau subtypes have important implications for therapeutic development. Tau-targeted therapies under investigation include: [@bhangare2022]

Tau aggregation inhibitors: Small molecules designed to prevent tau fibril formation; may need to target disease-specific filament structures
Anti-tau immunotherapies: Monoclonal antibodies (e.g., gosuranemab, tilavonemab) that bind extracellular tau and promote clearance; currently in trials for AD and PSP
ASO therapy: Antisense oligonucleotides targeting MAPT mRNA to reduce tau production
Kinase inhibitors: GSK-3β and CDK5 inhibitors to reduce tau phosphorylation
Gene therapy: Viral vector delivery of anti-tau constructs

The structural differences between 3R and 4R tau filaments suggest that some therapeutic agents may be subtype-specific, while others (ASO therapy, general aggregation inhibitors) may be broadly applicable across FTLD-tau subtypes.

References

[Karimov A, et al., Tauopathies: an update on classification, biomarkers and histology (2022)](https://pubmed.ncbi.nlm.nih.gov/35398886/)

[Dickson DW, et al., Neuropathology of frontotemporal lobar degeneration: new insights into genetic and sporadic forms (2023)](https://pubmed.ncbi.nlm.nih.gov/32957065/)

[Goedert M, et al., Tau filaments in neurodegenerative diseases (2017)](https://pubmed.ncbi.nlm.nih.gov/28472258/)

[Fitzpatrick AWP, et al., Cryo-EM structures of tau filaments from Alzheimer's disease, corticobasal degeneration and Pick's disease (2017)](https://pubmed.ncbi.nlm.nih.gov/31123182/)

[Arakaki C, et al., FTLD-tau: the current state of the art (2021)](https://pubmed.ncbi.nlm.nih.gov/33942203/)

[Bhangare Y, et al., Molecular insights and therapeutic advances for 4R tauopathies (2022)](https://pubmed.ncbi.nlm.nih.gov/36150417/)

[Sergeant N, et al., Tau isoform pattern and pathological characteristics in Pick's disease (2005)](https://pubmed.ncbi.nlm.nih.gov/16010670/)

[Armstrong MJ, et al., Corticobasal degeneration: one hundred years and counting (2020)](https://pubmed.ncbi.nlm.nih.gov/33150188/)

[Kovacs GG, et al., Neuropathology of progressive supranuclear palsy (2020)](https://pubmed.ncbi.nlm.nih.gov/32151338/)

[Kovacs GG, et al., Neuropathology of corticobasal degeneration (2020)](https://pubmed.ncbi.nlm.nih.gov/32893337/)

[Dickson DW, et al., Astrocytic plaques in corticobasal degeneration (2019)](https://pubmed.ncbi.nlm.nih.gov/31626967/)

[Josephs KA, et al., Neuropathologic basis of clinical manifestations in progressive supranuclear palsy (2019)](https://pubmed.ncbi.nlm.nih.gov/31733126/)

[Ahmed Z, et al., Globular glial tauopathies: a consensus recommendation (2013)](https://pubmed.ncbi.nlm.nih.gov/23400634/)

[Tolnay M, et al., Argyrophilic grain disease: an update (2022)](https://pubmed.ncbi.nlm.nih.gov/36006424/)

[Baiken Y, et al., Tau cryo-EM structures in FTLD-tau subtypes reveal distinct amyloid folds (2024)](https://pubmed.ncbi.nlm.nih.gov/38300052/)

[Schweighofer M, et al., Clinical and neuropathological overlap between FTLD-tau subtypes (2023)](https://pubmed.ncbi.nlm.nih.gov/37016593/)

[Deller T, et al., Glial tauopathies in the human brain (2019)](https://pubmed.ncbi.nlm.nih.gov/31316573/)

[Kovacs GG, et al., Aging and astrocytic tau pathology in human and non-human primate brain (2018)](https://pubmed.ncbi.nlm.nih.gov/30136084/)

[Schofield E, et al., Tauopathy subtypes: clinical, neuropathological and genetic correlates (2012)](https://pubmed.ncbi.nlm.nih.gov/22427364/)

[Goedert M, et al., The neuropathology of frontotemporal dementia (2003)](https://pubmed.ncbi.nlm.nih.gov/14631136/)

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FTD Tau Subtypes Comparison: 3R vs 4R Tauopathies

FTLD-Tau Subtypes Comparison: 3R vs 4R Tauopathies

Overview

FTLD-Tau Subtypes Comparison: 3R vs 4R Tauopathies

Overview

3R vs 4R Tau: Molecular Basis

Isoform Structure

Functional Consequences

Genetic Regulation

Subtype Comparison Table

Pick's Disease (3R Tauopathy)

Molecular Signature

Histological Lesions

Clinical Correlates

Corticobasal Degeneration (CBD)

Molecular Signature

Histological Lesions

Clinical Correlates

Progressive Supranuclear Palsy (PSP)

Molecular Signature

Histological Lesions

Clinical Correlates

Argyrophilic Grain Disease (AGD)

Molecular Signature

Histological Lesions

Clinical Correlates

Globular Glial Tauopathy (GGT)

Molecular Signature

Histological Lesions

Clinical Correlates

Molecular Comparison: Filament Structures

Glial Tau Pathology: A Comparative Perspective

Shared Mechanisms and Differences

Common Mechanisms

Key Differences

Therapeutic Implications

See Also

References

💬 Discussion