Gene Mutations In A Han Chinese Alzheimer's Disease Cohort

BackgroundAlzheimer's disease(AD)is a neurodegenerative disease characterized by cognitive,behavioral and neuropsychiatric changes that impair social function and activities of daily living(ADLs)with the pathologic hallmarks of amyloid beta(A?)peptides,neurofibrillary tangles,neuronal loss and gliosis.It's the most common cause of dementia,affecting approximately 36 million people worldwide,accounting for 60%-80% of all dementia cases.According to the age of disease onset,AD is classified into two types,early-onset AD(EOAD)and late-onset AD(LOAD).EOAD means the age of disease onset younger than 65 years,making up about 4% to 6% of all AD cases.Late-onset AD(LOAD),which is the most common form,occurs in individuals over the age of 65 years.Generally,AD is considered to be a polygenic disease resulting from complex interactions between environmental factors and multiple genes.Three common causative genes were reported to be associated with AD,including the amyloid precursor protein(APP)gene,and the presenilin 1(PSEN1)and presenilin 2(PSEN2)genes.However,some rare frontotemporal lobar degeneration(FTLD)mutations have also been described in clinical AD cohorts or in families with AD clinical phenotypea,such as progranulin(GRN),C9orf72 and microtubulin-associated protein tau(MAPT)genes.Considering that AD sharessimilar clinical features with other neurodegenerative diseases and the clinical and genetic diversity of AD patients,it is easy to be misdiagnosed.Therefore,for patients with clinical diagnosis of AD,especially those with an early-onset age or a family history of dementia,detecting other dementia-related genes is necessary.ObjectiveThe present study aimed to identify the clinical and genetic characteristics in a Han Chinese AD cohort with an early onset age and a family history.MethodsCollecting AD patients diagnosed in People's Hospital of Zhengzhou University between January 2016 to May 2018.Next-generation sequencing in all dementia related genes were performed in 40 AD probands who with an early onset age or an AD family history to catch the target region and sanger sequencing were used to detect DNA sequence variants.ResultsPSEN1 p.L226 R was found in an early-onset AD(EOAD)family,characterized by language impairment at disease onset,a novel probably pathogenetic variant(p.D534H)was identified in a Frontal-temporal dementia gene,TANK-binding kinase1(TBK1),with a typical AD phenotype in a late-onset AD(LOAD)family,a PSEN2 p.H169N mutation and two probably benign MAPT(p.Q230 R and p.V48L)mutations were detected in three EOAD patients.Conclusions1)We found five genetic mutations in the Han Chinese AD population with an early onset age or with an AD family history,of which three were probably pathogenetic variants,two were probably benign mutations.2)There may be genetic mutations in the FTD in patients with clinical manifestations of AD.