Clinical comparison of Alzheimer's disease in pedigrees with the codon 717 Val→Ile mutation in the amyloid precursor protein gene

M. Mullan, S. Tsuji, T. Miki, T. Katsuya, S. Naruse, K. Kaneko, T. Shimizu, T. Kojima, I. Nakano, T. Ogihara, T. Miyatake, I. Ovenstone, F. Crawford, A. Goate, J. Hardy, P. Roques, G. Roberts, P. Luthert, P. Lantos, C. ClarkP. Gaskell, B. Crain, A. Roses

Research output: Contribution to journalArticlepeer-review

74 Scopus citations


Alzheimer's disease (AD) is the most common cause of dementia (32). Although the majority of cases of AD are sporadic, the most consistent risk factor detected in several epidemiological studies has been a positive family history of the disease (14,21). In addition, many large pedigrees have been described in which AD appears to be inherited as an autosomal dominant disorder. In one such pedigree (F23) a point mutation within the β-amyloid precursor protein (APP) gene at codon 717 was identified and hypothesized to be pathogenic (10). The mutation results in a valine to isoleucine change in APP (APP717 Val→Ile). Subsequent screening has revealed four other pedigrees, detailed in this study, in which this mutation co-segregates with AD (13,26,37). In addition, one other pedigree (Tor3) with this mutation has been described (15) and detailed clinical, neuropsychological, and neuropathological data are reported. Tor3 is discussed below in comparison to the findings in the families in this study. The five families we report with the mutation were identified in Britain (1 family), the United States (1 family), 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). In all cases, there is complete co-segregation of the APP mutation with early onset AD, providing overwhelming statistical evidence that these mutations are pathogenic. We present the clinical features and limited neuropathology of AD in these families with the APP 717 Val→Ile mutation.

Original languageEnglish (US)
Pages (from-to)407-419
Number of pages13
JournalNeurobiology of aging
Issue number5
StatePublished - 1993
Externally publishedYes


  • Alzheimer's disease
  • Chromosome 21
  • Dementia
  • Human genetics
  • Lewy bodies
  • Neuropathology
  • Neuropsychology

ASJC Scopus subject areas

  • Neuroscience(all)
  • Aging
  • Clinical Neurology
  • Developmental Biology
  • Geriatrics and Gerontology


Dive into the research topics of 'Clinical comparison of Alzheimer's disease in pedigrees with the codon 717 Val→Ile mutation in the amyloid precursor protein gene'. Together they form a unique fingerprint.

Cite this