We investigated three separate families (designated D, F and G) with frontotemporal dementia that have the same molecular mutation in exon 10 of the tau gene (P301L). The families share many clinical characteristics, including behavioural aberrations, defective executive functions, language deficits, relatively preserved constructional abilities and frontotemporal atrophy on imaging studies. However, Family D has an earlier mean age of onset and shorter duration of disease than Families F and G (49.0 and 5.1 years versus 61-64 and 7.3-8.0 years, respectively). Two members of Families D and F had neuropathological studies demonstrating lobar atrophy, but the brain from Family D had prominent and diffuse circular, intraneuronal, neurofibrillary tangles not seen in Family F. The brain from Family F had ballooned neurons typical of Pick's disease type B not found in Family D. A second autopsy from Family D showed neurofibrillary tangles in the brainstem with a distribution similar to that found in progressive supranuclear palsy. These three families demonstrate that a missense mutation in the exon 10 microtubule-binding domain of the tau protein gene can produce severe behavioural abnormalities with frontotemporal lobar atrophy and microscopic tau pathology. However, the findings in these families also emphasize that additional unidentified environmental and/or genetic factors must be producing important phenotypic variability on the background of an identical mutation. Apolipoprotein E genotype does not appear to be such a factor influencing age of onset in this disease.

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Five families are described in which autopsy-confirmed presenile Alzheimer's disease (AD) has occurred in men and women over multiple generations consistent with autosomal dominant inheritance. All 5 families are descendants of a group of immigrants known as the Volga Germans who came to the United States between 1870 and 1920. Their ancestors moved from Germany to the southern Volga region of Russia in the 1760s. All 5 American families are descendants of persons originally living in two small adjacent Volga German villages and share several surnames known to have been present in the census records of those villages. Although a single affected common ancestor cannot be identified, it is likely that the AD in these families represents an autosomal dominant gene inherited from one ancestor (the founder effect). This information is of importance in the genetic study of AD in these families because it greatly increases the probability of genetic homogeneity. There are more than 300,000 American descendants of the Volga Germans, and the prevalence of AD has never been studied in this population.