Genetic Analyses Of Early-onset Familial Alzheimer’s Disease In Han Chinese Of Yunnan

Alzheimer’s disease (AD) is a common neurodegenerative characterized by impairment of cognitive functions, changes in behavior and personality and mainly affects individuals over 65 years of age. AD is by far the most common form of dementia with 4.4% prevalence.Early-onset familial Alzheimer’s disease (EOFAD) is characterized by onset of progressive dementia symptoms before 65 years old, positive family history and has more aggressive course than late onset sporadic AD. The amyloid precursor protein (APP), the presenilin 1 (PSEN1), and the presenilin 2 (PSEN2) are three well-known EOFAD causative genes. To date, more than 260 mutations have been identified in these three genes, with PSEN1 the most common mutated gene. Mutations in PSEN1, PSEN2 or APP are supposed to share a common pathogenic mechanism resulting in abnormal Aβ42/Aβ40 ratios. EOFAD though rare, EOFAD provides unique opportunities to gain special insights into the pathogenesis and phenotypes of AD. So far, genetic analyses for EOFAD in Han Chinese are very insufficient. There still have no researches of EOFAD in Han Chinese of Yunnan Province.Therefore we carried out screening mutation in Han Chinese EOAD families of Yunnan Province.In this study, we screened mutations of the three AD causal genes in four three-generation Han Chinese EOAD families of Yunnan Province. We aim to investigate mutations and to characterize phenotypes in EOFAD families. Detailed clinical assessments, neuropsychological assessment and genetic screening for mutations in PSEN1, PSEN2, APP and APOE gene were carried out in the four EOFAD families. Two PSEN1 mutations (p.R352C and p.M233L) were identified in two EOFAD families, respectively. Mutation p.R352C was identified for the first time. Conservation analysis and structural modeling indicated that both mutations may lead to a damaging effect on the structure and function of PSEN1. Mutation p.M233L was associated with prominent very early-onset, rapidly progressive dementia and neurological symptoms, whereas p.R352C was associated with progressive dementia, psychiatric syndrome and chronic disease course. Our results showed that the two mutations are associated with cognitive impairment and quite different clinical spectrum. The two mutations enrich the human AD gene mutation spectrum.We identified two novel mutations of the PSEN1 gene in 2 families, whereas there were remaining EOFAD families with no known AD pathogenic mutations identified, indicating that additional genes may contribute to EOFAD risk. In order to identify new pathogenic genes/mutations, we carried out whole-exome sequencing in 2 EOFAD families. We identified 26 potential pathogenic mutations in the proband of EOFAD-3. Further expression analysis showed that most of these mutations were at a gene co-expression network, this indicate that they may be involved in the same pathogenic pathway and these mutations together with APOE,ε4/ε4 promote the early-onset of the proband of EOFAD-3.Recent evidence supports some role of mitochondria dysfunction and oxidative stress in the development of the neurodegenerative process. Mutation in the mitochondrial genome can impair normal metabolic function in the central nervous system where cellular energy demand is high. Primary mitochondrial DNA(mtDNA) mutations have been linked to several mitochondrial disorders that have comorbid psychiatric, neurologic, and cognitive sequelae.In this study, we recruited 4 pedigrees with seemingly maternally inherited EOFAD of Han Chinese population from Yunnan Province. We sequenced the entire mtDNA genome of the probands with EOFAD. Four non-synonymous mutations were identified in 2 probands of EOFAD. A potentially pathogenic mutations, m.8978T>C, were identified by using a phylogenetic method. Further functional assays are needed to validate the pathogenic role of m.8978T>C. Our study on EOFAD mtDNA mutation may provide aessential information to understand the association between mtDNA mutation and AD.In conclusion, the current thesis performed mutation screening of known causal genes, potentially new pathogenic genes, and mtDNA in Chinese early onset familial AD pedigree to investigate the potential genetic basis underlying EOFAD. Our study will be helpful for genetic counseling, prevention and intervention in EOFAD patients and their relatives.