Molecular and prospective phenotypic characterization of a pedigree with familial Alzheimer's disease and a missense mutation in codon 717 of the beta-amyloid precursor protein gene.

We present prospective clinical and neuropathologic details of a pedigree segregating familial Alzheimer's disease (FAD) associated with a mutation (G----A substitution) at nucleotide 2149 in exon 17 of the amyloid precursor protein (APP) gene. This mutation, which is predicted to cause the missense substitution of isoleucine for valine at codon 717 of APP, cosegregated perfectly with the FAD trait (lod score = 3.49 at theta = 0.00). The earliest clinical manifestations of the disease relate to deficits in memory function, cognitive processing speed, and attention to complex cognitive sets. These changes occurred in the absence of changes in nonmemory language and visuospatial functions. The neuropathologic features of FAD associated with the APP717 mutation in this family include severe neuronal loss, abundant neurofibrillary tangles, amyloid plaques, and amyloid angiopathy. These results provide independent confirmation that mutations in the APP gene are linked to the FAD trait in some families.