Frontotemporal dementia (FTD) and Alzheimer’s disease (AD) are two frequent causes of dementia that share both clinical and neuropathological features. Common to both disorders are the neurofibrillary tangles consisting of aggregations of hyperphosphorylated tau protein. Recently, a number of different pathogenic mutations in the tau gene have been identified in families with FTD and parkinsonism linked to chromosome 17 (FTDP-17). In the present study, a Swedish family with presenile degenerative dementia with bitemporal atrophy was screened for mutations in the tau gene. As a result, the R406W mutation in exon 13 was identified in all affected cases. This mutation has previously been reported in two different FTDP-17 families of Dutch and Midwestern American origin. Common features to these two kindreds and our family are the late age at onset and long duration of the disease. Our pedigree as well as the American one show early memory impairment and pronounced temporal lobar atrophy similar to AD, while the Dutch cases show more FTD features. This further illustrates the large clinical variability among cases with tau mutations and stresses the importance of genetic classification in addition to the traditional clinical classification of neurodegenerative disorders.

This study describes the clinical, neuropsychological, neuroimaging and genetic characteristics in two generations of a Swedish family affected by presenile dementia. The pedigree includes 5 cases (mother and 4 of 5 children) of progressive dementia with onset between 54 and 62 years. The clinical picture is characterized by insidious onset and progressive decline in episodic memory without spatial impairment or dyspraxia, followed by changes in personality and behaviour, with signs of disinhibition, irritability, impulsivity and loss of social awareness. Three siblings, examined after 10 years of duration, showed moderate language deficits but preserved spatial function and praxis. CT and MRI showed progressive bilateral temporal atrophy and moderate frontal white matter changes. Regional cerebral blood flow measurements showed hypoperfusion in temporal areas bilaterally. Quantitative EEG was normal within 5 years after symptom onset and thereafter showed a moderate increase in relative theta power. Sequencing of the tau gene (chromosome 17) revealed the previously described R406W mutation in exon 13 as a likely cause of the disease. This mutation was identified in all affected cases. The clinical picture of this family shows striking similarities not only to frontotemporal dementia but also to Alzheimer’s disease.

Frontotemporal dementia (FTD) is a neurodegenerative disease and next to Alzheimer’s disease and vascular dementia, the third most common cause of early-onset progressive dementia. FTD leads to neurodegeneration in the frontal and temporal neocortex and usually encompasses both sides of the frontal and anterior temporal lobes. Psychologically, FTD is characterized by personality changes such as lack of insight, inappropriate behaviour, disinhibition, apathy, executive disabilities and a decline in cognitive functions, with large clinical and neuropathological variations among cases. Neuropathological characteristics include gliosis or microvacuolation of cortical nerve cells. Inclusions staining for tau protein and/or ubiquitin are also common findings. Both sporadic and hereditary forms of FTD have been identified and 30–50% of the FTD cases have a familial background. So far, at least three genetic loci for FTD have been identified, at human chromosomes 3, 9 and 17 in familial forms of the disease. A large number of the familial forms have been linked to chromosome 17q21 and referred to as frontotemporal dementia and Parkinsonism linked to chromosome 17. In the majority of these families, pathogenic mutations in the tau gene were identified. However, tau mutations seem to be a rare cause of disease in the general FTD population. Thus, other genes and/or environmental factors are yet to be identified, which will give further clues to this complex and heterogeneous disorder.

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