Chu‑Ting Wua,b, Liang‑Hsuan Huc, Hui‑Ying Wengd, Yen‑Ming Liue, Yung‑Feng Line, Shih‑Feng Tsaie, Raymond Y. Lof,g,h*, Yung‑Hao Chingc*
aDepartment of Medicine, Tzu Chi University, Hualien, Taiwan, bDepartment of Family Medicine, Puli Christian Hospital, Nantou, Taiwan, cDepartment of Molecular Biology and Human Genetics, Tzu Chi University, Hualien, Taiwan, dBiomedical Industry Ph.D. Program, National Yang Ming Chiao Tung University, Taipei, Taiwan, eInstitute of Molecular and Genomic Medicine, National Health Research Institute, Miaoli, Taiwan, fDepartment of Neurology, Taitung St. Mary’s Hospital, Taitung, Taiwan, gDepartment of Neurology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan, hDepartment of Biochemistry and Molecular Medicine, National Dong Hwa University, Hualien, Taiwan
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Open Access funded by Buddhist Compassion Relief Tzu Chi Foundation
Abstract
Objectives: We aimed to identify the early‑onset Alzheimer’s disease (EOAD)‑causing variants in the Eastern Taiwanese population. Materials and Methods: Twenty‑one patients diagnosed with EOAD in the memory clinic at Hualien Tzu Chi Hospital were enrolled during 2014–2018. We conducted whole‑exome sequencing to identify the disease‑causing variations and validated by Sanger sequencing. SIFT, PolyPhen‑2, and AlphaFold were applied to predict the functional impact of the identified variants. Results: Two unrelated normolipidemic EOAD patients were carrying a rare heterozygous APOE variant (rs373985746, NC_000019.10:g. 44905879G>A, NM_001302688.2:c. 11G>A, and NP_001289617.1:p.Gly4Glu) with the allele frequency as 0.000206. Sanger sequencing uncovered the ε haplotypes in which the c.11G>A variation resided. SIFT predicted that the variant severely impacts protein structure and, maybe thus, function. AlphaFold predicted a dysfunctional conformation of the mutant APOE precursor a protein (p.Gly4Glu). Conclusion: Our data strongly suggest that the rare p.Gly4Glu variant is associated with EOAD but does not cause dyslipidemia.
Keywords: Allele frequency, Apolipoproteins E, Early‑onset Alzheimer disease, Exome sequencing, High‑throughput nucleotide sequencing
