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 ∑ 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.