Overview

Clinical Phenotype: Alzheimer's Disease, Blood Lipids/Lipoproteins, Hyperlipoproteinemia Type IIa
Position: (GRCh38/hg38):Chr19:44907784 C>T
Position: (GRCh37/hg19):Chr19:45411041 C>T
Transcript: NM_000041; ENSG00000130203
dbSNP ID: rs776242156
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GCG to GTG
Reference Isoform: APOE Isoform 1
Genomic Region: Exon 3

Findings

This variant was examined in a study of dementia, including Alzheimer’s disease (AD), but an association with disease remains uncertain (Rasmussen et al., 2020). In two cohorts totaling more than 100,000 individuals from Copenhagen, Denmark, the variant was found in 9 individuals, six who were 60 years or older, and one of whom had AD (1.8 percent of non-carriers in this age group had AD).

In the 9 carriers, several lipid species, including cholesterol in low-density lipoprotein particles (LDL-C), cholesterol in high-density lipoprotein particles (HDL-C), and triglycerides, were within normal levels (Rasmussen et al., 2020). Plasma ApoE levels were reduced. A subsequent study including eight of the nine carriers, also reported a mean reduction in ApoE levels (13 percent), but the p-value was high (0.14) (Rasmussen et al., 2023). This latter study also identified reductions in remnant cholesterol (33 percent, p=0.07) and triglycerides (29 percent, p=0.05), and an increase in HDL-C (18 percent, p=0.07). All carriers were APOE3/APOE3 homozygotes, except for one in the original paper who was an APOE3/APOE4 homozygote. 

The variant was also identified in a French patient in a cohort of nearly 6,000 unrelated individuals with primary dyslipidemia (Abou Khalil et al., 2022). The carrier had elevated LDL-C and was diagnosed with autosomal dominant hypercholesterolemia, also known as hyperlipoproteinemia type IIa (HLPP2a), with cardiovascular disease. They did not carry mutations in the genes most commonly associated with HLPP2a, LDLR, PCSK9, APOB, but they had a strong probability of their condition being due to variants in multiple genes (weighted polygenic risk scores in decile IX). Their APOE genotype was APOE3/E4.

The frequency of A23V in the gnomAD variant database (0. 002425; v2.1.1, Apr 2022) was much lower than that reported in the Danish study (Copenhagen City Heart Study = 0.01 and the Copenhagen General Population Study = 0.04; Rasmussen et al., 2020). Of note, all six carriers reported in gnomAD were heterozygotes of European ancestry.

Biological Effect

The biological effect of this variant is unknown. Multiple computational algorithms predicted it is benign and its PHRED-scaled CADD score, which integrates diverse information in silico, was only 0.001, substantially less than 20, a commonly used threshold to predict deleteriousness (CADD v.1.6, Apr 2022, Abou Khalil et al., 2022).

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References

Paper Citations

1. Rasmussen KL, Tybjaerg-Hansen A, Nordestgaard BG, Frikke-Schmidt R. APOE and dementia - resequencing and genotyping in 105,597 individuals. Alzheimers Dement. 2020 Dec;16(12):1624-1637. Epub 2020 Aug 18 PubMed.
2. Rasmussen KL, Luo J, Nordestgaard BG, Tybjærg-Hansen A, Frikke-Schmidt R. APOE and vascular disease: Sequencing and genotyping in general population cohorts. Atherosclerosis. 2023 Nov;385:117218. Epub 2023 Aug 9 PubMed.
3. Abou Khalil Y, Marmontel O, Ferrières J, Paillard F, Yelnik C, Carreau V, Charrière S, Bruckert E, Gallo A, Giral P, Philippi A, Bluteau O, Boileau C, Abifadel M, Di-Filippo M, Carrié A, Rabès JP, Varret M. APOE Molecular Spectrum in a French Cohort with Primary Dyslipidemia. Int J Mol Sci. 2022 May 21;23(10) PubMed.

Further Reading

No Available Further Reading