Genetic Evidence for a Novel Familial Alzheimer’s Disease Locus on Chromosome 14: Analysis of Candidate Genes

Alzheimer disease (AD) is a common, fatal, degenerative disease of the adult human central nervous system associated with distinctive neuro-pathological features and with progressive cognitive and intellectual decline during mid- to late adult life (Katzman, 1986). In some families AD is inherited as an autosomal dominant trait (St. George-Hyslop et al., 1989), subsequent studies have revealed that the disorder is genetically heterogeneous (St. George-Hyslop et al., 1991). Thus, a small proportion of FAD cases are associated with mutations in the amyloid precursor protein (APP) gene on chromosome 21 (Goate et al., 1991; Karlinsky et al., 1992; Murrell et al., 1991), while some pedigrees segregating senile onset FAD show linkage or association with genetic markers on chromosome 19 (Pericak-Vance et al., 1991). Many FAD pedigrees however have not shown strong evidence for linkage to either chromosome, suggesting the existence of additional FAD genes on other chromosomes. We report here the discovery of a novel FAD locus on chromosome 14 and the analysis of three candidate genes from this chromosome, and we provide preliminary results concerning the clinical application of molecular genetic data.