A Novel Mutation in the Predicted TMIII Domain of the PSEN2 Gene in an Italian Pedigree with Atypical Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is characterized by accumulation of toxic amyloid-β (Aβ) in the brain, with neuronal death, and an associated increased Aβ_42/40 ratio. Several mutations in presenilin 1 (PSEN1), presenilin 2 (PSEN2), and amyloid-β precursor protein are involved in the etiology of familial AD (FAD); these mutations alter the Aβ_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.