CLINICOPATHOLOGICAL FEATURES OF FAMILIAL ALZHEIMERS-DISEASE ASSOCIATED WITH THE M139V MUTATION IN THE PRESENILIN-1 GENE - PEDIGREE BUT NOT MUTATION SPECIFIC AGE AT ONSET PROVIDES EVIDENCE FOR A FURTHER GENETIC-FACTOR

Sixteen affected individuals are described from two families with earl y onset autosomal dominant familial Alzheimer's disease. A mutation at codon 139 in the presenilin 1 gene on chromosome 14 results in a meth ionine to valine substitution which cosegregates with the disease in t hese families. Onset of dementia tvas before the age of 50 years in al l individuals. The ages at onset within each family were tightly clust ered but were significantly different between the families; this diffe rence could not be accounted for by apolipoprotein E status and sugges ts the existence of a further genetic factor that modifies age at dise ase onset. The pattern of cognitive decline was similar in both famili es: early memory loss (initially selective for verbal memory in some i ndividuals) was followed soon after by loss of arithmetic skills while naming and object perception skills were relatively preserved. A spee ch production deficit was observed in three members of one family but not in the other. Seizures were common and usually predated by myoclon ic jerks by a number of years. Serial MRIs showed progressive cortical atrophy with periventricular white matter change appearing 3-4 years into the disease. PET revealed parieto-temporal hypometabolism in all individuals scanned. The diagnosis of Alzheimer's disease was confirme d with typical histopathology in one individual from each family.