Rare APOE p.Gly4Glu: A putative disease-causing variant for early-onset Alzheimer's disease identified by next-generation sequencing.

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.