Association of genetic risk factors in Alzheimer's disease and a novel mutation in the predicted TM2 domain of the presenilin-2 gene in late-onset AD

The major risk factors for suffering AD include age, a family history of AD , and the inheritance of a series of potential genetic defects and/or a spe cific AD-related genotype. In population studies, a family history of AD ap pears in 40-65% of the cases, but this frequency varies depending upon the AD-genotype present in a particular family. The frequencies of the most com mon AD-related genotypes in AD patients are the following: APOE-3/3, 40.2%; APOE-3/4, 42.7%; APOE-4/4, 12.2%; PS-1/1, 34.14%; PS1-1/2, 46.34%; PS1-2/2 , 19.51%; PS2-, 54.87%; PS2+, 43.9%; c-FOS-/-, 78.04%; c-FOS+/-, 19.51%; an d c-FOS+/+, 2.44%. The association of APOE-4/4 and PS1-1/1, as well as the association of APOE-4/4 and PS2+, tend to induce an anticipation of the dis ease onset of approximately 10 years. However, mutations in the PS1 and PS2 loci are present in both early- and late-onset AD cases. Mutations in the PS2 gene are less frequent than mutations in the PS1 gene. Most mutations ( > 30) described in the PS1 gene were found in early-onset AD patients, and two missense mutations have been described in the PS2 locus in some AD pedi grees. We have analyzed the TM2 and TM5 domains of the PS2 gene in Spanish AD patients and in a group of age-matched healthy controls and found one pa tient with late-onset AD with a novel missense mutation consisting of a gua nine-to-adenine substitution on exon 5 of the PS2 gene, which results in a Val to Ile substitution at codon 148 within the predicted TM2 domain of the PS2 protein. This is the third mutation described in the PS2 gene and the first presenilin mutation detected in a Spanish AD patient. Both the N141I mutation and the V148I mutation described here are located within the predi cted TM2 domain and both were found in late-onset AD kindreds, whereas the mutation within the predicted TM5 domain was found in an early-onset AD ped igree. Carriers of mutations within the TM2 domain of the PS1 gene have a m ean age at onset of 40 years, while the other mutations in the PS1 locus oc cur in families with a mean age at onset of 47 years. These results seem to indicate that both specific mutations in the PS1 and PS2 loci and the asso ciation of genetic defects in the PS genes with the APOE-4/4 genotype are r isk factors of maximum vulnerability for neurodegeneration and the early ph enotypic expression of AD clinical symptoms.