Genetic profiles of familial late-onset Alzheimer's disease in China: The Shanghai FLOAD study

• Type of Material: Article
• Authors: Xin-Yi Xie, Shanghai Jiao Tong University; Qian-Hua Zhao, Fudan University; Qiang Huang, Shanghai Jiao Tong University; Eric Dammer, Emory University; Sheng-Di Chen, Shanghai Jiao Tong University; Ru-Jing Ren, Shanghai Jiao Tong University; Gang Wang, Shanghai Jiao Tong University
• Language: English
• Date: 2022-09-12
• Publisher: ELSEVIER
• Publication Version: Final Published Version
• Copyright Statement: © 2021 Chongqing Medical University. Production and hosting by Elsevier B.V.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.gendis.2021.05.001
• Title of Journal or Parent Work: GENES & DISEASES
• Volume: 9
• Issue: 6
• Start Page: 1639
• End Page: 1649
• Grant/Funding Information: Data collection and sharing for ADNI was funded by the Alzheimer's Disease Neuroimaging Initiative (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, the Alzheimer's Association; the Alzheimer's Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California.; This work was funded by the Natural Science Foundation of China (No. 81671043, 81971068, 82071200), the Natural Science Foundation of Shanghai (No. 219ZR1431500), the Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant (No. 20172001), the Shanghai Municipal Science and Technology Major Project (No. 2018SHZDZX01) and a Shanghai "Rising Stars of Medical Talent" Youth Development Program-Outstanding Youth Medical Talents Grant [2018].
• Keywords: Genetics & Heredity; MUTATIONS; ANGIOTENSIN-CONVERTING ENZYME; ACE; BETA; Alzheimer?s disease; TREM2; ASSOCIATION; Familial late-onset Alzheimer?s disease; Science & Technology; DEMENTIA; PSEN1; Life Sciences & Biomedicine; VARIANTS; Gene; RISK; METAANALYSIS; Mutation; Biochemistry & Molecular Biology
• Research Categories: Health Sciences, Medicine and Surgery

Abstract

Compared with early-onset familial AD (FAD), the heritability of most familial late-onset Alzheimer's disease (FLOAD) cases still remains unclear. However, there are few reported genetic profiles of FLOAD to date. In the present study, targeted sequencing of selected candidate genes was conducted for each of 90 probands with FLOAD and 101 unrelated matched normal controls among Chinese Han population. Results show a significantly lower rate of mutation in APP and PSENs, and APOE ε4 genetic risk is higher for FLOAD. Among the Chinese FLOAD population, the most frequent variant was CR1 rs116806486 [5.6%, 95% CI (1.8%, 12.5%)], followed by coding variants of TREM2 (4.4%, 95%CI (1.2%, 10.9%)) and novel mutations of ACE [3.3%, 95%CI (0.7%, 9.4%)]. Next, we found that novel pathogenic mutations in ACE including frame-shift and nonsense mutations were in association with FLOAD regardless of APOE ε4 status. Evidence from the Alzheimer's disease Neuroimaging Initiative (ADNI) database also supported this finding in different ethnicities. Results of in vitro analysis suggest that frame-shift and nonsense mutations in ACE may be involved in LOAD through decreased ACE protein levels without affecting direct processing of APP.