Novel amyloid precursor protein mutation in an Iowa family with dementia and severe cerebral amyloid angiopathy

Several mutations in the amyloid precursor protein (APP) gene have been fou nd to associate with pathologic deposition of the beta -amyloid peptide (A beta) in neuritic plaques or in the walls of cerebral vessels. We report a mutation at a novel site in APP in a three-generation Iowa family with auto somal dominant dementia beginning in the sixth or seventh decade of life. T he proband and an affected brother had progressive aphasic dementia, leukoe ncephalopathy, and occipital calcifications. Neuropathological examination of the proband revealed severe cerebral amyloid angiopathy, widespread neur ofibrillary tangles, and unusually extensive distribution of A beta 40 in p laques. The affected brothers shared a missense mutation in APP, resulting in substitution of asparagine for aspartic acid at position 694. This site corresponds to residue 23 of A beta, thus differing from familiar Alzheimer 's disease mutations, which occur outside the A beta sequence. Restriction enzyme analysis of DNA from 94 unrelated patients with sporadic cerebral am yloid angiopathy-related hemorrhage found no other instances of this mutati on. These results suggest a novel site within A beta that may promote its d eposition and toxicity.