Overview

Clinical Phenotype: Alzheimer's Disease, Blood Lipids/Lipoproteins
Position: (GRCh38/hg38):Chr19:44908636 G>A
Position: (GRCh37/hg19):Chr19:45411893 G>A
Transcript: NM_000041; ENSG00000130203
dbSNP ID: rs1169728519
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GAG to AAG
Reference Isoform: APOE Isoform 1
Genomic Region: Exon 4

Findings

This variant has been associated with an increased risk of dementia and, in particular, Alzheimer’s disease (Rasmussen et al., 2020). In a study of more than 100,000 Danish individuals, 99 E144K carriers were identified, 52 of whom were at least 60 years old. Eight of these carriers had some form of dementia, including six with AD. The hazard ratio for dementia was 2.75 (95% C.I. 1.37-5.51, p=0.004) and when adjusted for the presence of the common APOE isoforms E2, E3, and E4, it was 3.30 (95% C.I. 1.65-6.61, p=0.001). The hazard ratio for AD was 3.64 (95% C.I. 1.63-8.13, p=0.002) and after APO E2/E3/E4 adjustment 4.66 (95% C.I. 2.09-10.40, p=0.0002).

Interestingly, plasma ApoE levels were substantially reduced, the average being in the 10th percentile. Based on their data from this variant and additional APOE variants associated with either increased or decreased plasma ApoE levels, the authors hypothesized that low ApoE in plasma increases AD risk beyond the effects of the common R176C (APOE2) and C130R (APOE4) isoforms. Also, in a subsequent paper, low ApoE levels in carriers of rare APOE variants were associated with an increased risk for ischemic cerebrovascular disease (Rasmussen et al., 2023).

The levels of several lipid species in the plasma of E114K carriers, including remnant cholesterol, cholesterol in high-density lipoprotein particles (HDL-C), and triglycerides, were within the normal range (Rasmussen et al., 2020, Rasmussen et al., 2023). Although the levels of low-density lipoprotein (LDL) cholesterol were initially reported to be within the normal range, the more recent study reported 14 percent lower LDL cholesterol levels in carriers compared with non-carriers. Also, compared with the overall population, carriers were less likely to be on a lipid-lowering therapy (three percent of carriers versus 11 percent of all individuals).

Although E114 is close to C130, the site of APOE4, the two variants appear to be inherited independently of each other, that is, they are not in linkage disequilibrium.

An APOE3/E4 heterozygote carrying E114K and another rare APOE variant, L46P, was identified, but no further information was provided (Rasmussen et al., 2023).

This variant was found at a very low frequency (0.000004391, 1 allele count) in the gnomAD database (gnomAD, Sept 2020). In the Danish study, however, the variant was present at a frequency of 0.05.

Biological Effect

At the molecular and cellular levels, the biological effects of this variant are unknown. However, its PHRED-scaled CADD score, which integrates diverse information in silico, was above 20, suggesting a deleterious effect (CADD v.1.6, Apr 2022).

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References

Mutations Citations

1. APOE R176C (ApoE2)
2. APOE C130R (ApoE4)
3. APOE L46P

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.

Further Reading

No Available Further Reading