Increased risk for frontotemporal dementia through interaction between tau polymorphisms and apolipoprotein E epsilon4.

The tau gene has an important role in frontotemporal dementia (FTD) as pathogenic mutations have been found in hereditary forms of the disease. Furthermore, a certain extended tau haplotype has been shown to increase the risk for progressive supranuclear palsy, corticobasal degeneration, Parkinson's disease and, in interaction with the apolipoprotein E (apoE) epsilon4 allele, Alzheimer's disease. By microsatellite analysis we investigated an intronic tau polymorphism, in linkage disequilibrium with the extended tau haplotype, in FTD patients (n = 36) and healthy controls (n = 39). No association between any of the tau alleles/genotypes and FTD was seen, but certain tau alleles and apoE epsilon4 interactively increased the risk of FTD (p = 0.006). We thus propose that this extended tau haplotype in combination with apoE epsilon4 is a genetic risk factor for FTD.

Clinic-based cases with frontotemporal dementia show increased cerebrospinal fluid tau and high apolipoprotein E epsilon4 frequency, but no tau gene mutations.

Frontotemporal dementia (FTD) belongs to a group of neurodegenerative disorders known as tauopathies, characterized by intracellular aggregation of hyperphosphorylated tau protein in the brain. Some tauopathies, like Alzheimer's disease (AD), consistently show increased levels of tau protein in cerebrospinal fluid (CSF). However, similar studies in FTD populations have shown variable results, although mutations in the tau gene are identified as causes of disease in certain FTD families. In the present study, a Swedish clinic-based FTD population was investigated with respect to CSF tau levels, apolipoprotein E (APOE) genotype distribution and occurrence of mutations in the tau gene. CSF tau levels were significantly increased among FTD patients (534 +/- 235 pg tau/ml, P < 0.001) (n = 47) compared to controls (316 +/- 137 pg tau/ml) (n = 51). Furthermore, a strong increase in the APOE epsilon4 allele frequency was found in the FTD population, as 52% were epsilon4 carriers, compared to 21% of the controls. However, no mutations in the tau gene were identified. These findings support the present notion of a common pathogenic pathway in the disease processes for several tauopathies, with both APOE epsilon4 and CSF tau being a pathological link between the different disorders. Furthermore, we conclude that mutations in the tau gene are a rare cause of FTD. .