Login Register Cart 0
Generic placeholder image

Current Alzheimer Research

Editor-in-Chief

ISSN (Print): 1567-2050
ISSN (Online): 1875-5828

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Screening for Genetic Mutations Associated with Early-Onset Alzheimer’s Disease in Han Chinese

Author(s): Cuicui Liu, Lin Cong, Min Zhu, Yongxiang Wang, Shi Tang, Xiaojuan Han, Qinghua Zhang, Na Tian, Keke Liu, Xiaoyan Liang, Wenxin Fa, Nan Wang, Tingting Hou* and Yifeng Du*

Volume 19, Issue 10, 2022

Published on: 21 November, 2022

Page: [724 - 733] Pages: 10

DOI: 10.2174/1567205020666221028112915

Price: $65

Abstract

Background: Early-onset Alzheimer’s disease (EOAD) is highly influenced by genetic factors. Numerous mutations in amyloid precursor protein (APP) and presenilin 1 and 2 (PSEN1 and PSEN2) have been identified for EOAD, but they can only account for a small proportion of EOAD cases.

Objective: This study aimed to screen genetic mutations and variants associated with EOAD among Han Chinese adults.

Methods: This study included 34 patients with EOAD and 26 controls from a population-based study and neurological ward. We first sequenced mutations in APP/PSENs and then performed whole-exome sequencing in the remaining patients with negative mutations in APP/PSENs to screen for additional potential genetic variants. Among patients who were negative in genetic screening tests, we further evaluated the risk burden of genes related to the Aβ metabolism-centered network to search for other probable causes of EOAD.

Results: We identified 7 functional variants in APP/PSENs in 8 patients, including 1 APP mutation (p. Val715Met), 3 PSEN1 mutations (p. Phe177Ser; p. Arg377Met; p. Ile416Thr), and 3 PSEN2 mutations (p. Glu24Lys; p. Gly34Ser; p. Met239Thr). Of the remaining 26 EOAD cases without mutations in APP/PSENs, the proportion of carrying rare variants of genes involved in Aβ and APP metabolism was significantly higher than that of controls (84.6% vs. 73.1%, P=0.042). Thirty-one risk genes with 47 variants were identified in 22 patients. However, in 26 normal subjects, only 20 risk genes with 29 variants were identified in 19 subjects.

Conclusions: Our findings demonstrate the role of APP/PSENs mutations in EOAD, identifying a new PSEN2 missense mutation, and further offer valuable insights into the potential genetic mechanisms of EOAD without APP/PSENs mutations among Han Chinese.

« Previous Next »
[1]
Jia L, Du Y, Chu L, et al. Prevalence, risk factors, and management of dementia and mild cognitive impairment in adults aged 60 years or older in China: A cross-sectional study. Lancet Public Health 2020; 5(12): e661-71.
[http://dx.doi.org/10.1016/S2468-2667(20)30185-7] [PMID: 33271079]
[2]
Bakota L, Brandt R. Tau biology and tau-directed therapies for Alzheimer’s disease. Drugs 2016; 76(3): 301-13.
[http://dx.doi.org/10.1007/s40265-015-0529-0] [PMID: 26729186]
[3]
Li K, Wei Q, Liu FF, et al. Synaptic dysfunction in Alzheimer’s disease: Aβ, Tau, and epigenetic alterations. Mol Neurobiol 2018; 55(4): 3021-32.
[http://dx.doi.org/10.1007/s12035-017-0533-3] [PMID: 28456942]
[4]
Mantzavinos V, Alexiou A. Biomarkers for Alzheimer’s disease diagnosis. Curr Alzheimer's Res 2017; 14(11): 1149-54.
[PMID: 28164766]
[5]
Van Cauwenberghe C, Van Broeckhoven C, Sleegers K. The genetic landscape of Alzheimer’s disease: Clinical implications and perspectives. Genet Med 2016; 18(5): 421-30.
[http://dx.doi.org/10.1038/gim.2015.117] [PMID: 26312828]
[6]
Jia L, Fu Y, Shen L, et al. PSEN1, PSEN2, and APP mutations in 404 Chinese pedigrees with familial Alzheimer’s disease. Alzheimers Dement 2020; 16(1): 178-91.
[http://dx.doi.org/10.1002/alz.12005] [PMID: 31914229]
[7]
Jiang B, Zhou J, Li HL, et al. Mutation screening in Chinese patients with familial Alzheimer’s disease by whole-exome sequencing. Neurobiol Aging 2019; 76: 215.
[http://dx.doi.org/10.1016/j.neurobiolaging.2018.11.024]
[8]
Li XY, Cui Y, Jing D, et al. Novel PSEN1 and PSEN2 mutations identified in sporadic early-onset Alzheimer’s disease and posterior cortical atrophy. Alzheimer Dis Assoc Disord 2021; 35(3): 208-13.
[http://dx.doi.org/10.1097/WAD.0000000000000438] [PMID: 33973882]
[9]
Kunkle BW, Vardarajan BN, Naj AC, et al. Early-onset Alzheimer’s disease and candidate risk genes involved in endolysosomal transport. JAMA Neurol 2017; 74(9): 1113-22.
[http://dx.doi.org/10.1001/jamaneurol.2017.1518] [PMID: 28738127]
[10]
Ramos-Campoy O, Antonell A, Falgàs N, et al. Screening of dementia genes by whole-exome sequencing in Spanish patients with early-onset dementia: Likely pathogenic, uncertain significance and risk variants. Neurobiol Aging 2020; 93: e1-9.
[http://dx.doi.org/10.1016/j.neurobiolaging.2020.02.008] [PMID: 32317127]
[11]
Wang Y, Han X, Zhang X, et al. Health status and risk profiles for brain aging of rural‐dwelling older adults: Data from the interdisciplinary baseline assessments in MIND‐China. Alzheimers Dement 2022; 8(1): e12254.
[http://dx.doi.org/10.1002/trc2.12254] [PMID: 35441085]
[12]
McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on Aging‐Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 2011; 7(3): 263-9.
[http://dx.doi.org/10.1016/j.jalz.2011.03.005] [PMID: 21514250]
[13]
Lanoiselée HM, Nicolas G, Wallon D, et al. APP, PSEN1, and PSEN2 mutations in early-onset Alzheimer disease: A genetic screening study of familial and sporadic cases. PLoS Med 2017; 14(3): e1002270.
[http://dx.doi.org/10.1371/journal.pmed.1002270] [PMID: 28350801]
[14]
Greaves CV, Rohrer JD. An update on genetic frontotemporal dementia. J Neurol 2019; 266(8): 2075-86.
[http://dx.doi.org/10.1007/s00415-019-09363-4] [PMID: 31119452]
[15]
Rovelet-Lecrux A, Charbonnier C, Wallon D, et al. De novo deleterious genetic variations target a biological network centered on Aβ peptide in early-onset Alzheimer’s disease. Mol Psychiatry 2015; 20(9): 1046-56.
[http://dx.doi.org/10.1038/mp.2015.100] [PMID: 26194182]
[16]
Giau VV, Bagyinszky E, Youn YC, An SSA, Kim S. APP, PSEN1, and PSEN2 mutations in Asian patients with early-onset Alzheimer’s disease. Int J Mol Sci 2019; 20(19): 4757.
[http://dx.doi.org/10.3390/ijms20194757] [PMID: 31557888]
[17]
Wu L, Rosa-Neto P, Hsiung GYR, et al. Early-onset familial Alzheimer’s disease (EOFAD). Can J Neurol Sci 2012; 39(4): 436-45.
[http://dx.doi.org/10.1017/S0317167100013949] [PMID: 22728850]
[18]
Mao C, Li J, Dong L, et al. Clinical phenotype and mutation spectrum of Alzheimer’s disease with causative genetic mutation in a Chinese cohort. Curr Alzheimer Res 2021; 18(3): 265-72.
[http://dx.doi.org/10.2174/1567205018666210608120339] [PMID: 34102969]
[19]
Rogaev EI, Sherrington R, Rogaeva EA, et al. Familial Alzheimer’s disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer’s disease type 3 gene. Nature 1995; 376(6543): 775-8.
[http://dx.doi.org/10.1038/376775a0] [PMID: 7651536]
[20]
Finckh U, Alberici A, Antoniazzi M, et al. Variable expression of familial Alzheimer’s disease associated with presenilin 2 mutation M239I. Neurology 2000; 54(10): 2006-8.
[http://dx.doi.org/10.1212/WNL.54.10.2006] [PMID: 10822446]
[21]
Janssen JC, Beck JA, Campbell TA, et al. Early onset familial Alzheimer’s disease: Mutation frequency in 31 families. Neurology 2003; 60(2): 235-9.
[http://dx.doi.org/10.1212/01.WNL.0000042088.22694.E3] [PMID: 12552037]
[22]
Li N, Liu K, Qiu Y, et al. Effect of presenilin mutations on APP cleavage; insights into the pathogenesis of FAD. Front Aging Neurosci 2016; 8: 51.
[http://dx.doi.org/10.3389/fnagi.2016.00051] [PMID: 27014058]
[23]
Papassotiropoulos A, Fountoulakis M, Dunckley T, Stephan DA, Reiman EM. Genetics, transcriptomics, and proteomics of Alzheimer’s disease. J Clin Psychiatry 2006; 67(4): 652-70.
[http://dx.doi.org/10.4088/JCP.v67n0418] [PMID: 16669732]
[24]
Ramirez AL, Acosta-Uribe J, Giraldo MM, et al. Genetic origin of a large family with a novel PSEN1 mutation (Ile416Thr). Alzheimers Dement 2019; 15(5): 709-19.
[http://dx.doi.org/10.1016/j.jalz.2018.12.010] [PMID: 30745123]
[25]
Hausner L, Tschäpe JA, Schmitt HP, Hentschel F, Hartmann T, Frölich L. Clinical characterization of a presenilin 1 mutation (F177S) in a family with very early‐onset Alzheimer’s disease in the third decade of life. Alzheimers Dement 2014; 10(2): e27-39.
[http://dx.doi.org/10.1016/j.jalz.2013.02.006] [PMID: 23850332]
[26]
Gao Y, Ren RJ, Zhong ZL, et al. Mutation profile of APP, PSEN1, and PSEN2 in Chinese familial Alzheimer’s disease. Neurobiol Aging 2019; 77: 154-7.
[http://dx.doi.org/10.1016/j.neurobiolaging.2019.01.018] [PMID: 30822634]
[27]
Jiang B, Bi M, Li J, et al. A pathogenic variant p.Phe177Val in PSEN1 causes early-onset Alzheimer’s disease in a Chinese family. Front Genet 2020; 11: 713.
[http://dx.doi.org/10.3389/fgene.2020.00713] [PMID: 32754199]
[28]
Bai X, Yan C, Yang G, et al. An atomic structure of human γ-secretase. Nature 2015; 525(7568): 212-7.
[http://dx.doi.org/10.1038/nature14892] [PMID: 26280335]
[29]
Sun L, Zhou R, Yang G, Shi Y. Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Aβ42 and Aβ40 peptides by γ-secretase. Proc Natl Acad Sci USA 2017; 114(4): E476-85.
[http://dx.doi.org/10.1073/pnas.1618657114] [PMID: 27930341]
[30]
Ancolio K, Dumanchin C, Barelli H, et al. Unusual phenotypic alteration of β amyloid precursor protein (βAPP) maturation by a new Val-715 → Met βAPP-770 mutation responsible for probable early-onset Alzheimer’s disease. Proc Natl Acad Sci USA 1999; 96(7): 4119-24.
[http://dx.doi.org/10.1073/pnas.96.7.4119] [PMID: 10097173]
[31]
Nan SJ, Han YQ, Fan J, Chen QH. Blepharospasm in familial AD secondary to an APP mutation (V715M). Acta Neurol Belg 2014; 114(4): 333-4.
[http://dx.doi.org/10.1007/s13760-014-0291-1] [PMID: 24677022]
[32]
Cacace R, Sleegers K, Van Broeckhoven C. Molecular genetics of early‐onset Alzheimer’s disease revisited. Alzheimers Dement 2016; 12(6): 733-48.
[http://dx.doi.org/10.1016/j.jalz.2016.01.012] [PMID: 27016693]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy