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Heterozygous missense and splice-site mutations in the tau gene have been previously identified in familial frontotemporal dementia with autosomal dominant inheritance. Here we report a Spanish kindred in which two brothers born from a third-degree consanguineous marriage were both affected with atypical progressive supranuclear palsy. A homozygous deletion at codon 296 (delN296) was identified in one of the affected siblings. Among the heterozygous carriers, two members with probable Parkinson's disease were identified, but none of heterozygotes developed atypical parkinsonism. The delN296 mutation lies in the sequence corresponding to the second tubulin-binding repeat of tau protein and affects one asparagine residue absolutely conserved in other species. This finding indicates that homozygous mutations in the tau gene may also cause hereditary tauopathies.

Many studies have demonstrated a strong association between the presence of one or two epsilon 4 alleles and Alzheimer's disease (AD), although few data are available on the apolipoprotein E (APOE) epsilon 4 frequencies at the preclinical stages of AD. Thus, with a view to determining whether APOE genotyping could be useful in the early detection of AD, we determined the Apoe allele frequencies in patients with memory complaints without dementia (age-related memory decline, ARMD). We found an APOE epsilon 4 allele frequency of 0.315 in the ARMD group, similar to 0.293 in the AD group, in contrast to 0.057 in the control group. Significant differences (t=-2.91, df=25, p=0.008) were found between the Alzheimer's Disease Assessment Scale (ADAS) total scores in the ARMD patients with at least one epsilon 4 allele (mean=24.2) compared with the ARMD patients without the epsilon 4 allele (mean=14.7). Our results suggest that the patients with memory complaints, a high ADAS score, and the presence of one or two APOE-4 alleles could be at high risk for developing AD. Thus, we propose that genotyping in conjunction with the ADAS scale may prove useful as diagnostic markers of AD in the presymptomatic stages.