The 4R-tauopathies are a family of neurodegenerative disorders characterized by the preferential accumulation of four-repeat (4R) tau isoforms in the brain. This page provides a comprehensive comparison of the genetic architecture across the major 4R-tauopathies: Progressive Supranuclear Palsy (PSP), Corticobasal Degeneration (CBD), Argyrophilic Grain Disease (AGD), Globular Glial Tauopathy (GGT), and Frontotemporal Dementia with Parkinsonism linked to Chromosome 17 (FTDP-17).
The 4R-tauopathies share the common feature of tau protein pathology consisting of 4R-tau isoforms. However, they differ in their genetic risk profiles, with some shared genetic factors and disease-specific mutations. Understanding these genetic similarities and differences provides insight into disease mechanisms and potential therapeutic targets.
The MAPT gene (Microtubule-Associated Protein Tau) located on chromosome 17q21.31 is central to all 4R-tauopathies. The H1 haplotype of MAPT is the major genetic risk factor for sporadic forms of PSP, CBD, and to a lesser extent, AGD[1][2].
The H1 haplotype risk is highest for PSP, followed by CBD, with weaker associations observed in AGD[4].
PSP is the prototypical 4R-tauopathy with the strongest genetic association with MAPT.
| Gene | Variant | Type | Risk/Effect |
|---|---|---|---|
| MAPT | H1/H1 genotype | Risk | OR ≈ 5.5-7.8[5] |
| MAPT | p.A152T | Risk | OR ≈ 2.3[6] |
| MAPT | p.V363I | Protective | Reduces risk[7] |
| STUB1 | Various | Risk | Increases susceptibility[8] |
| MOBP | rs1768208 | Risk | OR ≈ 1.5[9] |
| EIF2AK3 | rs7531528 | Risk | OR ≈ 1.4[10] |
PSP is predominantly sporadic, with only 5-10% of cases showing familial aggregation. The H1 haplotype accounts for the majority of genetic risk in sporadic PSP.
CBD shares significant genetic overlap with PSP, particularly the MAPT H1 haplotype.
| Gene | Variant | Type | Effect |
|---|---|---|---|
| MAPT | H1/H1 genotype | Risk | OR ≈ 4.0[11] |
| MAPT | Various mutations | Familial | 10% of cases |
| GRN | Null mutations | Risk | 5-10% of familial cases[12] |
| LRRK2 | p.G2019S | Risk | Associated with parkinsonian features[13] |
| CBD | 17q21.31 region | Risk | Shared with PSP |
CBD shows greater clinical and genetic heterogeneity than PSP, with approximately 10-20% of cases having a family history.
AGD has the weakest genetic association with MAPT among the 4R-tauopathies.
| Gene | Variant | Population | Effect |
|---|---|---|---|
| MAPT | H1 haplotype | All | Weaker association than PSP/CBD[14] |
| SVIL | rs2413229 | Japanese | Novel risk locus[15] |
| DAPK2 | Transcriptome | Japanese | Candidate causal gene |
A 2025 GWAS in Japanese populations identified SVIL (supervillin) as a novel risk locus, highlighting population-specific genetic architecture[15:1].
GGT is the rarest 4R-tauopathy with limited genetic data.
GGT shares pathological features with PSP and CBD, suggesting shared genetic factors.
FTDP-17 is distinct from other 4R-tauopathies as it is primarily caused by dominant MAPT mutations.
| Mutation | Location | Effect |
|---|---|---|
| P301L | Exon 10 | Most common, ~40% of families[16] |
| P301S | Exon 10 | Early onset |
| G389R | Exon 12 | Variable expressivity |
| R406W | Exon 13 | Late onset, tauopathy |
Over 40 pathogenic MAPT mutations have been identified in FTDP-17 families. These mutations disrupt tau-microtubule binding, promote tau aggregation, and alter the 3R/4R isoform ratio[17].
| Disease | Sporadic % | Familial % | Key Genes |
|---|---|---|---|
| PSP | 90-95% | 5-10% | MAPT (H1) |
| CBD | 80-90% | 10-20% | MAPT, GRN, LRRK2 |
| AGD | ~95% | ~5% | MAPT (weak), SVIL |
| GGT | ~95% | ~5% | MAPT |
| FTDP-17 | <5% | >95% | MAPT (mutations) |
The gradient from nearly all sporadic (PSP, AGD) to nearly all familial (FTDP-17) reflects the underlying genetic architecture. FTDP-17 is unique as a monogenic tauopathy caused by specific MAPT mutations.
Major GWAS have identified multiple risk loci for PSP[18]:
CBD GWAS show significant overlap with PSP:
Understanding the shared and unique genetic architecture of 4R-tauopathies has important therapeutic implications:
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Rizzu P et al. High prevalence of mutations in the microtubule-associated protein tau gene in progressive supranuclear palsy. Am J Hum Genet. 1999. ↩︎
Pittman AM et al. The MAPT H1 haplotype is a risk factor for progressive supranuclear palsy and corticobasal degeneration but not for Alzheimer's disease. J Neurol Neurosurg Psychiatry. 2005. ↩︎
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Genome-wide association study in Japanese population identifies novel risk loci for argyrophilic grain disease. J Hum Genet. 2025. ↩︎ ↩︎ ↩︎
Hutton M et al. FTDP-17: a tauopathy associated with mutations in the tau gene. Ann Neurol. 2000. ↩︎
Ghetti B et al. Tauopathy with MAPT P301L mutations: features and mechanisms. Acta Neuropathol. 2015. ↩︎
Hoglinger GU et al. Identification of two novel loci for progressive supranuclear palsy. Brain. 2021. ↩︎