Mutation Arg406Trp in the tau gene (MAPT; MIM# 157140) causes a hereditary tauopathy clinically resembling Alzheimer disease (AD; MIM# 104300)[Reed et al., 2001]. The mutation was first reported in family FTD004, a family from the Midwestern United States with a Danish ancestor [Reed et al., 1997], and family Dutch4 from the Netherlands [van Swieten et al., 1999]. Both families presented with a relatively late-onset and slowly progressive dementia, clearly distinct from FTD with parkinsonism linked to chromosome 17 (FTDP-17). Here, we describe a six-generation Belgian family, family AD/G, segregating Arg406Trp and showing similar clinical characteristics. The proband (IV-5; Fig. 1) was diagnosed with AD and referred to our department for routine DNA diagnostic screening. Mutations in all coding exons of presenilin 1 (PSEN1; MIM# 104311), presenilin 2 (PSEN2; MIM# 600759), and exons 16 and 17 of the amyloid precursor protein gene (APP; MIM# 104760) were excluded. Direct sequencing of MAPTexons revealed the substitution c. 1216C> T in exon 13, corresponding to Arg406Trp. Informed consent was obtained from family members and blood samples were collected for genetic studies. The inheritance pattern in family AD/G is compatible with autosomal dominant transmission (Fig. 1). Analysis of Arg406Trp in 47 available family members using PCR amplification of MAPT exon 13 and restriction digestion with NlaIII showed segregation of the mutation with the disease. The mutation was present in four patients and in 13 out of 24 at-risk individuals (Fig. 1). Patient IV-13, who had symptoms of dementia, did not carry the mutation and most likely represents a phenocopy, especially since patient IV-13’s parent died at 73 years without symptoms of dementia. In family AD/G, mean onset age in mutation carriers was 58.7 7 3.9 years (n= 12, range 54–65), mean age at death was 71.6 7 4.0 years (n= 11, range 65–77), and mean duration of disease was 13.7 7 4.7 years (n= 9, range 7–22). Neurological reports were available for six patients. In each patient, memory impairment was mentioned as the first symptom. In later stages, features compatible with frontal degeneration, like behavioral and speech problems, were found in five out of six patients.

When available, imaging studies consistently showed diffuse cortical atrophy. The diagnosis of AD was given in three patients (IV-2, IV-7, and IV-11) and dementia without further specification was the diagnosis in three other patients (III-2, IV-1, and IV-10). The clinical phenotype of AD with frontal signs in the Belgian family AD/G closely resembles the phenotype observed in families FTD004 and Dutch4 [Reed et al., 1997; van Swieten et al., 1999]. Mean onset age in family AD/G (58.7 years) is similar to that of families FTD004 (55 years) and Dutch4 (59.2 years). In each family, memory impairment was mentioned as the first symptom in all patients. Brain pathology of FTD004 and Dutch4 patients showed abundant neurofibrillary tangles in the absence of amyloid deposition. No autopsy data was available for family AD/G. The clinical presentation in the Belgian family AD/G provides supportive evidence that Arg406Trp presents with a dementia closely resembling AD. This is also confirmed by the development of associative memory deficits in mice expressing Arg406Trp human tau [Tatebayashi et al., 2002]. These data are in contrast with the observation of Saito et al.[2002], who reported a patient with Arg406Trp that first presented with psychiatric symptoms, followed by early-onset rapidly progressing dementia resembling the FTDP-17 phenotype.