Association Between the Extended tau Haplotype and Frontotemporal Dementia

Background Recent studies have shown an association between an extended tau haplotype (H1) that covers the entire human tau gene and progressive supranuclear palsy or, more inconsistently, other neurodegenerative disorders, such as corticobasal degeneration, Parkinson disease, Alzheimer disease, and frontotemporal dementia (FTD). In addition, disease-causing mutations in the tau gene on chromosome 17 have been detected in some families with autosomal dominant FTD and parkinsonism. In FTD, the pathological accumulation of the microtubule-associated protein tau suggests that the tau gene may be a genetic risk factor for this disorder. Objective To confirm or refute the association between the H1 haplotype or the H1H1 genotype of the tau gene and FTD. Design Case-control study. Setting Neurology departments of 12 French university hospitals. Participants One hundred unrelated patients with FTD and 79 controls. Methods Tau genotype (contiguous polymorphisms in exons 1, 7, and 13 and in intron 9 used to reconstruct the extended haplotypes H1 and H2). Clinical examination, psychometric testing, laboratory tests, computed tomography and magnetic resonance imaging, single-photon emission computed tomography, and electroencephalography for patients with FTD. Results The H1H1 genotype was significantly overrepresented in patients with FTD compared with controls (62% vs 46%; P = .01, 1-sided; odds ratio adjusted for age and sex, 1.95). After stratification according to apolipoprotein E ( APOE ) genotype, we found a significant interaction between APOE and tau genotypes ( P = .03). Conclusions This study of the largest series of patients with FTD confirms the primary role of tau in FTD and establishes that the H1 haplotype of the tau gene and the E2 allele of APOE interact by an unknown mechanism that increases the risk of FTD.