Frontotemporal Lobar Degeneration with tau proteinopathy (FTLD-tau) represents the second most common pathological subgroup of frontotemporal dementia, accounting for approximately 40-45% of all FTD cases. This group encompasses several distinct clinicopathological entities characterized by the accumulation of abnormal tau protein within neurons and glia.
Unlike FTLD-TDP, which primarily involves TDP-43 proteinopathy, FTLD-tau disorders are linked to mutations in the MAPT gene and share overlapping features with other 4R tauopathies including corticobasal degeneration and progressive supranuclear palsy.
| Subtype |
Primary Tau Species |
Key Pathology |
Clinical Correlates |
| Pick's disease |
3R tau |
Pick bodies, ballooned neurons |
bvFTD, svPPA |
| Corticobasal degeneration |
4R tau |
astrocytic plaques, oligodendroglial coils |
CBS, PSP phenotypes |
| Progressive supranuclear palsy |
4R tau |
globose NFTs, tufted astrocytes |
PSP syndrome |
| MAPT mutation-associated |
3R/4R mixed |
variable inclusions |
bvFTD, nfvPPA, parkinsonism |
| Argyrophilic grain disease |
4R tau |
argyrophilic grains, coiled bodies |
bvFTD, amnestic syndromes |
flowchart TD
A["FTLD-tau"] --> B["3R Tauopathies"]
A --> C["4R Tauopathies"]
A --> D["Mixed 3R/4R"]
B --> B1["Pick's Disease"]
B --> B2["3R+4R Mix"]
C --> C1["CBD"]
C --> C2["PSP"]
C --> C3["AGD"]
D --> D1["MAPT Mutations"]
B1 --> E1["Pick Bodies<br/>Ballooned Neurons"]
C1 --> E2["Astrocytic Plaques<br/>Oligodendroglial Coils"]
C2 --> E3["Globose NFTs<br/>Tufted Astrocytes"]
D1 --> E4["Variable Pattern<br/>Perivacuolar Lesions"]
style A fill:#e8f5e9,stroke:#333,stroke-width:2px
style B fill:#c8e6c9,stroke:#333
style C fill:#a5d6a7,stroke:#333
style D fill:#81c784,stroke:#333
Pick's disease is characterized by progressive behavioral and language changes that typically present in the 5th-7th decade. The clinical presentation often overlaps with bvFTD, with prominent features including:
- Behavioral disinhibition and loss of social conduct
- Apathy and reduced initiative
- Compulsive behaviors and ritualistic movements
- Hyperorality and dietary changes
- Language impairment that may progress to mutism
- Pick bodies: spherical, argyrophilic inclusions composed of 3R tau isoforms
- Ballooned neurons (Pick cells): swollen, achromatic neurons
- Cortical atrophy predominantly affecting frontal and anterior temporal lobes
- Neuronal loss and gliosis in affected regions
- Typically sporadic, though familial cases occur
- MAPT mutations can produce Pick-like pathology
- No specific gene definitively linked to classic Pick's disease
CBD presents with a spectrum of motor and cognitive symptoms:
- Asymmetric parkinsonism with rigidity and bradykinesia
- Cortical sensory loss (astereognosis, tactile neglect)
- Ideomotor apraxia and alien limb phenomena
- Cognitive impairment ranging from executive dysfunction to frank dementia
- Speech impairment including nonfluent/agrammatic patterns
- Astrocytic plaques: distinctive tau-positive astrocytic processes
- Oligodendroglial coiled bodies: tau inclusions in oligodendrocytes
- Neuronal loss and gliosis in basal ganglia, brainstem
- 4R tau predominance in all inclusions
MAPT H1 haplotype is a significant risk factor
Specific MAPT mutations (e.g., P301S, R5H) associated with CBD-like pathology
Recent evidence suggests GRN mutations can also produce CBD pathology
PSP typically presents in the 6th-7th decade:
- Vertical supranuclear gaze palsy (downgaze > upgaze)
- Postural instability with backward falls
- Akinetic-rigid parkinsonism with axial rigidity
- Cognitive impairment including executive dysfunction and behavioral changes
- Speech disturbances ranging from dysarthria to mutism
- Globose neurofibrillary tangles: tau inclusions in brainstem nuclei
- Tufted astrocytes: characteristic astrocytic tau pathology
- Neuronal loss in substantia nigra, globus pallidus
- 4R tau isoform predominance
MAPT H1 haplotype is the major genetic risk factor
MAPT mutations can cause PSP-like pathology
Rare cases linked to C9orf72 expansions
AGD is increasingly recognized as a common cause of late-onset behavioral changes:
- Behavioral variant FTD features in many cases
- Amnestic presentations mimicking Alzheimer's disease
- Late-onset psychosis and hallucinations
- Slow progression compared to other FTLD subtypes
- Argyrophilic grains: spindle-shaped tau inclusions in neuronal processes
- Coiled bodies: oligodendroglial tau inclusions
- 4R tau in all pathology
- Often co-exists with AD-type pathology
| Mutation |
Primary Phenotype |
Pathology |
Tau Isoforms |
| P301L |
bvFTD, PSP |
Mixed 3R/4R |
3R + 4R |
| P301S |
CBD |
4R predominant |
4R |
| R406W |
AD-like |
Mixed |
3R + 4R |
| G272V |
bvFTD |
3R predominant |
3R |
| ΔN296 |
PSP-like |
4R |
4R |
MAPT mutations lead to tau dysfunction through:
- Impaired microtubule binding and stabilization
- Enhanced aggregation propensity
- Altered splicing patterns leading to isoform imbalances
- Dysregulated post-translational modifications
¶ FTLD-tau and FTLD-TDP Overlap
flowchart LR
subgraph FTLD
A["FTLD-tau"] --- B["FTLD-TDP"]
end
subgraph FTLD-tau
A1["Pick's"] --- A2["CBD"] --- A3["PSP"]
end
subgraph FTLD-TDP
B1["Type A (GRN)"] --- B2["Type B (C9orf72)"] --- B3["Type C (svPPA)"]
end
A1 --> C["bvFTD"]
A2 --> D["CBS"]
A3 --> E["PSP"]
B1 --> C
B2 --> F["FTD-ALS"]
B3 --> G["svPPA"]
style A fill:#e8f5e9
style B fill:#e3f2fd
| Clinical Syndrome |
Most Common Pathology |
| bvFTD |
FTLD-tau (Pick's) or FTLD-TDP (type A/B) |
| svPPA |
FTLD-TDP type C |
| nfvPPA/CBS |
FTLD-tau (CBD) or FTLD-TDP (type A) |
| PSP syndrome |
FTLD-tau (PSP) |
| FTD-ALS |
FTLD-TDP type B |
Anti-tau therapies in development:
- Antibodies targeting tau aggregation: Longeveron, ABBV-0805
- Small molecule tau aggregation inhibitors: Methylene blue derivatives
- Tau kinase inhibitors: GSK-3β, CDK5 inhibitors
- Microtubule stabilizers: Davunetide, TPI-287
- Pathological heterogeneity requires biomarker-based patient selection
- MAPT mutation carriers may benefit from genotype-specific approaches
- Combination therapies targeting both tau and complementary pathways (e.g., neuroinflammation) show promise