The genetics of frontotemporal dementia and related disorders

Recent advances in genetics have revolutionized our understanding of dementia. In the most common of the human dementing illnesses-Alzheimer's disease (AD)mutations in three major genes causing rare dominantly inherited AD (APP, PS1 and PS2), and other contributory genetic risk factors, such as APOE have been identified. Although neurofibrillary tangles composed of tau protein filaments are a diagnostic feature of AD, tau mutations have not been described in AD. Frontotemporal dementia (FTD) encompasses a group of non-Alzheimer's degenerative dementias affecting mainly the frontal and temporal neocortex. In contrast to AD, approximately 50% of FTD cases are inherited and linkage of families with FTD to loci on chromosomes 17 (FTDP-17) and 3 has been demonstrated. Mutations in the microtubule-associated protein tau cause most cases of chromosome 17-linked FTD, demonstrating for the first time that tau dysfunction can play a primary role in neurodegeneration. However, tau mutations have been identified in only 10-20% of familial FTD cases and have not been demonstrated in sporadic FTD. Thus, the etiology of sporadic FTD remains unknown. Association studies have also suggested a role for tau in progressive supranuclear palsy (PSP), with tau mutations reported in two families, confirming previous pathological evidence of tau abnormalities in PSP. The results of linkage disequilibrium studies between tau and Parkinson's disease (PD), AD and other neurodegenerative disorders are more controversial. In this review, we summarize the relevant genetic aspects of FTD and related neurodegenerative disorders, focusing on studies of linkage analysis and tau mutations.