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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 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 APP717mutation 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.

There are standardized criteria to assist in the diagnosis of Alzheimer's disease (AD), a disorder that lacks unique clinical, morphologic, or biochemical features. Diagnostic reliability of single groups of investigators using these criteria is moderate to substantial. In this study, seven clinicians at separate sites established a criteria-based diagnosis in 42 consecutive memory disorder patients participating in a national genetic epidemiologic study using a quantitative multiaxis AD rating scale (ADRS) that incorporates NINCDS/ADRDA criteria, reliability of information, and comorbidity. Reliability, measured by a generalized kappa statistic for more than two raters, was substantial (0.63 ± 0.13) when the subjects were grouped as “AD” (probable or possible) versus “not AD,” but somewhat lower (0.52 ± 0.10) when subjects were classified as probable AD, possible AD, or not AD. There was unanimous agreement for two-thirds of the subjects using a dichotomous classification scheme. These findings suggest that the ADRS is a useful diagnostic instrument for multicenter studies.