Table 2.
Reported MAPT genetic findings in tauopathies and synucleinopathies
| Disease | Causative variants | Risk variants and haplotypes | Phenotype-genotype correlations | References |
|---|---|---|---|---|
| FTD | Numerous causative variants reported; see figure 1. | p.A152T is a risk variant. Role of MAPT haplotype is unclear. | Earlier age of onset, higher prevalence of movement disorder, and lower prevalence of language disorder compared to other genetic causes of FTD. Earlier AAO compared to sporadic cases of FTD. H2: possibly earlier AAO. See figure 1 for phenotypes associated with reported causative variants. |
66–68,70–73,75–78,194,221 |
| PSP | Numerous causative variants reported; see figure 1. | H1c: increased risk. H2: decreased risk. H1d, H1g, and H1o: increased risk (one large study). H1b and H1q: increased risk (one small study each). |
H1c: better cognitive performance (one study), more severe pathological phenotype (one study). H1: earlier AAO (one study). |
82–84,93–95,99,193,222 |
| CBD | Numerous causative variants reported; see figure 1. | H1c: increased risk. H2: decreased risk. |
No correlation between tau pathology burden and MAPT haplotype (one study). | 99 |
| PiD | Numerous causative variants reported; see figure 1. | MAPT haplotype are not associated with PiD risk. | See FTD. | 41,43,50 |
| CTE | None. | No significant association found (one study) | None reported. | 105 |
| PART | None. | H1 overrepresented in two small studies. | None reported. | 107,108 |
| AD | p.R406W mutation and 17q21.31 microduplication have shown AD-like phenotype but lack Aβ pathology. | H1 and H1c: increased risk. H2: decreased risk. Unclear association with pA152T variant rs393152: increased risk with A allele |
H1: faster cognitive decline, decreased NFTs and Aβ burden, lower prevalence of symptoms among those that met AD pathological criteria (one study each). Conflicting results for genotype associated with CSF tau levels. |
68,69,88,123,125–134,190,192 |
| PD | None. | H1: increased risk. H2: decreased risk. |
H1: decreased cognitive performance, increased risk of PD dementia (mixed results), non-tremor dominant phenotype, hallucinations. H1p: PD dementia (one study). H1h: non-tremor dominant PD (one study). Intronic MAPT SNPs (rs2435207 and rs11079727): later onset of motor symptoms in LRRK2-associated PD. Mixed genotype-pathology findings. |
88,138.148–162,168,169,195,224–226 |
| DLB | None. | p.A152T, H1/H1 diplotype, and H1g subhaplotype are potential risk factors (mixed results). | H1: Increased alpha-synuclein deposition, particularly in brainstem regions (one small cohort). | 171–173,177,178 |
| MSA | None. | H1, H1j and H1x: increased risk. H1e and H2: reduced risk. (one study each) |
No association between genotype and AAO (one study). | 180,181,186 |
Abbreviations: FTD: frontotemporal dementia; AAO: age at onset; FTLD: frontotemporal lobar degeneration; PSP: progressive supranuclear palsy; CBD: corticobasal degeneration; PiD: Pick’s disease; CTE: chronic traumatic encephalopathy; PART: primary age-related tauopathy; AD: Alzheimer’s disease; NFTs: neurofibrillary tangles; Aβ: amyloid beta; CSF: cerebrospinal fluid; PD: Parkinson’s disease; DLB: dementia with Lewy bodies; MSA: multiple system atrophy