A novel mutation in the predicted TMIII domain of the PSEN2 gene in an Italian pedigree with atypical Alzheimer's disease.

Alzheimer's disease (AD) is characterized by accumulation of toxic amyloid-beta (Abeta) in the brain, with neuronal death, and an associated increased Abeta(42/40) ratio. Several mutations in presenilin 1 (PSEN1), presenilin 2 (PSEN2), and amyloid-beta precursor protein are involved in the etiology of familial AD (FAD); these mutations alter the Abeta(42/40) ratio and promote apoptosis. We describe an Italian pedigree linked to a novel mutation (S175C) at the third transmembrane domain of PSEN2. Clinical phenotype in these individuals is characterized by fast cognitive decline with progressive memory impairment, early involvement of executive functions, behavioral disturbances, and extrapyramidal signs.