CLINICAL COMPARISON OF ALZHEIMERS-DISEASE IN PEDIGREES WITH THE CODON-717 VAL-]ILE MUTATION IN THE AMYLOID PRECURSOR PROTEIN GENE

Alzheimer's disease (AD) is the most common cause of dementia (32). Al though the majority of cases of AD are sporadic, the most consistent r isk factor detected in several epidemiological studies has been a posi tive family history of the disease (14,21). In addition, many large pe digrees have been described in which AD appears to be inherited as an autosomal dominant disorder. In one such pedigree (F23) a point mutati on within the beta-amyloid precursor protein (APP) gene at codon 717 w as identified and hypothesized to be pathogenic (10). The mutation res ults in a valine to isoleucine change in APP (APP717 Val-->Ile). Subse quent screening has revealed four other pedigrees, detailed in this st udy, in which this mutation co-segregates with AD (13,26,37). In addit ion, one other pedigree (Tor3) with this mutation has been described ( 15) and detailed clinical, neuropsychological, and neuropathological d ata are reported. Tor3 is discussed below in comparison to the finding s in the families in this study. The five families we report with the mutation were identified in Britain (1 family), the United States (1 f amily), and Japan (3 families). The mutation has not been reported in the general population of any of these countries (3,13,26,33). On this basis alone it seems this mutation is pathogenic. Other APP codon 717 mutations have been identified which co-segregate with the disease (4 ,25). Also, a double mutation in APP at codons 670/671 has been shown to cosegregate with the disease in two large Swedish pedigrees (22). I n all cases, there is complete co-segregation of the APP mutation with early onset AD, providing overwhelming statistical evidence that thes e mutations are pathogenic. We present the clinical features and limit ed neuropathology of AD in these families with the APP 717 Val-->Ile m utation.