Novel PSEN1 (P284S) Mutation Causes Alzheimer's Disease with Cerebellar Amyloid beta-Protein Deposition

Background/Objective: AD-associated PSEN1 mutations exhibit high clinical heterogeneity. The discovery of these mutations and the analysis of their associations with cases such as EOAD should be critical to understanding AD's pathogenesis.Methods: We performed clinical analysis, neuroimaging, target region capture and high-throughput sequencing, and Sanger sequencing in a family of 3 generations. The underlying Alzheimer's pathology was evaluated using biomarker evidence obtained from cerebrospinal fluid (CSF) amyloid testing and F-18-florbetapir (AV-45) PET imaging.Results: Target region capture sequencing revealed a novel heterozygous C to T missense point mutation at the base position 284 (c.850 C > T) located in exon 8 of the PSEN1 gene, resulting in a Proline-to-Serine substitution (P284S) at codon position 850. The mutation was also identified by Sanger sequencing in 2 family members, including proband and her daughter and was absent in the other 4 unaffected family members and 50 control subjects. Cerebrospinal fluid (CSF) amyloid test exhibited biomarker evidence of underlying Alzheimer's pathology. F-18-florbetapir (AV-45) PET imaging indicated extensive cerebral cortex and cerebellar A beta deposition.Conclusions: We discovered a novel PSEN1 pathogenic mutation, P284S, observed for the first time in a Chinese family with early-onset AD.