APBB2 gene encodes for β-amyloid precursor protein-binding family B member 2, (APBB2, FE65-like, FE65L1), an adaptor protein binding to the cytoplasmatic domain of β-amyloid precursor protein (βAPP). Over-expression of APBB2 promotes formation of β-amyloid (Aβ), the main constituent of senile plaques. Polymorphisms within APBB2 gene have been proposed as candidate risk factors for Alzheimer's disease. However, their association with longevity has never been investigated. Here we present the first attempt to analyze APBB2 polymorphisms in centenarians. We used a PCR-RFLP method to analyze two intronic nucleotide substitutions: hCV1558625 (rs17443013) and rs13133980. We found no differences in genotype or allele distribution between centenarians and young controls. After stratification of centenarians upon their cognitive performance, the APBB2 rs13133980 G allele was over-represented in centenarians with severe cognitive impairment compared to individuals without this disability. Also the hCV1558625-rs13133980 AG haplotype increased relative risk for severe cognitive impairment in centenarians. Our results support the concept of APBB2 polymorphism association with cognitive performance in the oldest age.