Mutation analysis of disease causing genes in patients with early onset or familial forms of Alzheimer's disease and frontotemporal dementia

Background Most dementia disorders have a clear genetic background and a number of disease genes have been identified. Mutations in the tau gene (MAPT) lead to frontotemporal dementia (FTD), whereas mutations in the genes for the amyloid-beta precursor protein (APP) and the presenilins (PSEN1, PSEN2) cause early-onset, dominantly inherited forms of Alzheimer's disease (AD). Even if mutations causing Mendelian forms of these diseases are uncommon, elucidation of the pathogenic effects of such mutations have proven important for understanding the pathogenic processes. Here, we performed a screen to identify novel pathogenic mutations in known disease genes among patients undergoing dementia investigation. Results Using targeted exome sequencing we have screened all coding exons in eleven known dementia genes (PSEN1, PSEN2, APP, MAPT, APOE, GRN, TARDBP, CHMP2B, TREM2, VCP and FUS) in 102 patients with AD, FTD, other dementia diagnoses or mild cognitive impairment. We found three AD patients with two previously identified pathogenic mutations in PSEN1 (Pro264Leu and Met146Val). In this screen, we also identified the recently reported APP mutation in two siblings with AD. This mutation, named the Uppsala mutation, consists of a six amino acid intra-amyloid beta deletion. In addition, we found several potentially pathogenic mutations in PSEN2, FUS, MAPT, GRN and APOE. Finally, APOE epsilon 4 was prevalent in this patient group with an allele frequency of 54%. Conclusions Among the 102 screened patients, we found two disease causing mutations in PSEN1 and one in APP, as well as several potentially pathogenic mutations in other genes related to neurodegenerative disorders. Apart from giving important information to the clinical investigation, the identification of disease mutations can contribute to an increased understanding of disease mechanisms.

Automated summary

Among the 102 patients screened, two disease-causing mutations were found in PSEN1 and one in APP, along with several potentially pathogenic mutations in other genes related to neurodegenerative disorders. These findings provide important information for clinical investigation and contribute to a deeper understanding of disease mechanisms.