Overview

Clinical Phenotype: Alzheimer's Disease, Blood Lipids/Lipoproteins
Position: (GRCh38/hg38):Chr19:44909057 T>A
Position: (GRCh37/hg19):Chr19:45412314 T>A
Transcript: NM_000041; ENSG00000130203
dbSNP ID: rs199768005
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GTG to GAG
Reference Isoform: APOE Isoform 1
Genomic Region: Exon 4

Findings

This variant, sometimes referred to as Jacksonville, reduces the risk of late-onset AD (LOAD). The initial study reporting this effect focused on coding variants found in genetic loci previously identified by genome-wide association studies of LOAD, using a case control series including 4,128 LOAD patients and 4,986 non-demented controls (Medway et al., 2014). Two V254E heterozygotes were identified in the AD group and 23 in the control group. Analysis by a Fisher’s exact test showed significant association of V254E with reduced LOAD risk. Consistent with this result, one of the two carriers in the AD group, who harbored the mutation on a homozygous APOE3 background, developed dementia very late in life, at age 98, and the other, diagnosed at 68, was an APOE3/APOE4 heterozygote. The authors noted that the presence of APOE4 could have countered the protection provided by V254E. They also pointed out the protective effect was similar, or even greater, than that of the well-known AD protective variant R176C (APOE2).

A large association study, including more than 500,000 individuals of European and admixed European ancestry, subsequently revealed a 3-fold decrease in AD risk in carriers of the variant (odds ratio, 0.37; 95% CI, 0.25-0.56; P = 1.9 × 10^-6; June 2022 news, Le Guen et al., 2022). Stratifying by APOE2/3/4 genotype, APOE3 homozygotes carrying the V236E variant had a similar AD risk as APOE2/3 non-carriers. The study also showed that the variant delayed age at onset by 10.5 years, and the population incidence in carriers grew more slowly with age than in non-carriers.

Of note, V254E is usually inherited with the APOE3 allele, forming a unique haplotype (Medway et al., 2014). Indeed, except for one APOE4 homozygote, all 241 carriers studied in two large Danish cohorts carried the APOE3 allele, with 79 percent being APOE3 homozygotes (Rasmussen et al., 2020). 

V254E was first described in a Dutch man with severe hyperlipoproteinemia, including high triglyceride and cholesterol levels (van den Maagdenberg et al., 1993). However, examination of 12 family members, including five mutation carriers, failed to demonstrate co-segregation with this condition. In the same study, the mutation was also found in an unrelated Dutch man with moderate hypertriglyceridemia who, in addition, carried the R269G mutation (coincidentally also associated with decreased AD risk), and the APOE4 allele. A subsequent study of this man and seven of his family members, spanning three generations, revealed that members who carried only the V254E variant, an APOE3 homozygote and an APOE3/APOE4 heterozygote, had normal plasma lipid levels (Zhao et al., 1994).  No additional members were found to carry both the R269G and V254E mutations. V254E was also identified in an APOE3/E4 heterozygote carrying another rare APOE variant, L46P (Rasmussen et al., 2023).

Consistent with V254E not affecting plasma lipid levels substantially, the 241 carriers studied by Rasmussen and colleagues had levels of plasma ApoE, high-density lipoprotein (HDL) cholesterol, and triglycerides that were very similar to those of non-carriers, although levels of low-density lipoprotein (LDL) cholesterol were moderately reduced (Rasmussen et al., 2020, Rasmussen et al., 2023). Also, in a group of 623 non-Hispanic whites, V254E was associated with reduced levels of both LDL cholesterol (β = −35.36; p = 0.043; FDR = 0.139) and triglycerides (β = -0.40; p = 0.028; FDR = 0.074), after adjusting for the presence of the common APOE2 and APOE4 alleles (Radwan et al., 2014).

Worldwide, the frequency of V254E has been reported as 0.00045 (gnomAD v2.1.1, June 2022), but it appears to be higher in European populations, with 78 of 89 heterozygote carriers in the gnomAD variant database being of non-Finnish European ancestry, and eight being of African ancestry. Moreover, in one population of European Americans, the variant was present at a 0.0012 frequency (Medway et al., 2014). Also of note, the variant was present at a frequency of 0.0004 in a repository of genetic variants from nearly 500 people age 60 or older who had no neurodegenerative pathology at time of death (HEX database, March 2020).

Biological Effect

V254E reduces ApoE aggregation in mammalian cells and when produced in bacteria (Liu et al., 2021, Oct 2021 news). Brain tissue samples from carriers had less insoluble ApoE, and increased ratios of soluble:insoluble ApoE than those of non-carriers. Also, carriers had fewer amyloid plaques and lower levels of insoluble Aβ peptides, Aβ40 and Aβ42, which co-deposit with ApoE in plaques. Moreover, in the 5xFAD (B6SJL) mouse model of AD, the variant reduced the number of plaques and dystrophic neurites.

Also of note, V254E appears to promote brain lipid metabolism, associating more efficiently with lipids and increasing cholesterol efflux, a process thought to require monomeric ApoE. This may reduce toxic intracellular accumulation of lipids associated with aging and AD, and promote repair. Compared with wildtype mice, transgenic mice expressing the variant only in astrocytes harbored more lipids involved in membrane homeostasis and synaptic function, such as phosphatidylserine, phosphatidylethanolamine, phosphatidic acid, sulfatide, and cerebroside, in their brains.

V254E may also promote endocytic trafficking of ApoE-interacting receptors such as ApoE receptor 2 (ApoER2/LRP8), glutamate receptors, insulin receptors, and the lipid-efflux transporter ABCA1 (Liu et al., 2021, Oct 2021 news, Bu, 2022). The increased acidity resulting from the substitution of a nonpolar, hydrophobic residue for a negatively charged, hydrophilic residue may help prevent vesicular stalling that can occur with the loss of solubility of basic proteins such as ApoE4 in endosomes (Vance et al., 2024). 

Moreover, the location of the substitution, in a region next to the lipid-binding region thought to be involved in ApoE oligomerization (Frieden and Garai, 2012), may help explain V254E’s tendency to reduce aggregation on either ApoE3 or ApoE4 backbones (Liu et al., 2021). On the other hand, V254E has been reported to facilitate dimerization (Le Guen et al., 2022), which may affect receptor binding.

V254E may also alter sialylation or glycosylation patterns, as suggested by the variant’s unexpected migration on an isoelectric focusing gel after cysteamine treatment (van den Maagdenberg et al., 1993).

This variant's PHRED-scaled CADD score, which integrates diverse information in silico, was above 20, predicting a functional effect (CADD v.1.6, June 2022).

Note on nomenclature

When it was originally discovered, this variant was named APOE*2(Val-236-->Glu) because its encoded protein migrates to the same isoelectric position as ApoE2. It has also been called APOE3-Jacksonville or APOE3-Jac because of its strong linkage to APOE3 and its identification as an AD protective variant by a research group in Jacksonville, Florida.

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References

Mutations Citations

1. APOE R176C (ApoE2)
2. APOE R269G
3. APOE L46P

News Citations

1. Two ApoE Mutations Decrease Risk for Alzheimer's Disease 10 Jun 2022
2. Protective APOE3 Variant Binds More Lipids, Self-Aggregates Less 1 Oct 2021

Research Models Citations

1. 5xFAD (B6SJL)

Paper Citations

1. Medway CW, Abdul-Hay S, Mims T, Ma L, Bisceglio G, Zou F, Pankratz S, Sando SB, Aasly JO, Barcikowska M, Siuda J, Wszolek ZK, Ross OA, Carrasquillo M, Dickson DW, Graff-Radford N, Petersen RC, Ertekin-Taner N, Morgan K, Bu G, Younkin SG. ApoE variant p.V236E is associated with markedly reduced risk of Alzheimer's disease. Mol Neurodegener. 2014 Mar 10;9:11. PubMed.
2. Le Guen Y, Belloy ME, Grenier-Boley B, de Rojas I, Castillo-Morales A, Jansen I, Nicolas A, Bellenguez C, Dalmasso C, Küçükali F, Eger SJ, Rasmussen KL, Thomassen JQ, Deleuze JF, He Z, Napolioni V, Amouyel P, Jessen F, Kehoe PG, van Duijn C, Tsolaki M, Sánchez-Juan P, Sleegers K, Ingelsson M, Rossi G, Hiltunen M, Sims R, van der Flier WM, Ramirez A, Andreassen OA, Frikke-Schmidt R, Williams J, Ruiz A, Lambert JC, Greicius MD, Members of the EADB, GR@ACE, DEGESCO, DemGene, GERAD, and EADI Groups, Arosio B, Benussi L, Boland A, Borroni B, Caffarra P, Daian D, Daniele A, Debette S, Dufouil C, Düzel E, Galimberti D, Giedraitis V, Grimmer T, Graff C, Grünblatt E, Hanon O, Hausner L, Heilmann-Heimbach S, Holstege H, Hort J, Jürgen D, Kuulasmaa T, van der Lugt A, Masullo C, Mecocci P, Mehrabian S, de Mendonça A, Moebus S, Nacmias B, Nicolas G, Olaso R, Papenberg G, Parnetti L, Pasquier F, Peters O, Pijnenburg YA, Popp J, Rainero I, Ramakers I, Riedel-Heller S, Scarmeas N, Scheltens P, Scherbaum N, Schneider A, Seripa D, Soininen H, Solfrizzi V, Spalletta G, Squassina A, van Swieten J, Tegos TJ, Tremolizzo L, Verhey F, Vyhnalek M, Wiltfang J, Boada M, García-González P, Puerta R, Real LM, Álvarez V, Bullido MJ, Clarimon J, García-Alberca JM, Mir P, Moreno F, Pastor P, Piñol-Ripoll G, Molina-Porcel L, Pérez-Tur J, Rodríguez-Rodríguez E, Royo JL, Sánchez-Valle R, Dichgans M, Rujescu D. Association of Rare APOE Missense Variants V236E and R251G With Risk of Alzheimer Disease. JAMA Neurol. 2022 Jul 1;79(7):652-663. PubMed.
3. 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.
4. van den Maagdenberg AM, Weng W, de Bruijn IH, de Knijff P, Funke H, Smelt AH, Gevers Leuven JA, van't Hooft FM, Assmann G, Hofker MH. Characterization of five new mutants in the carboxyl-terminal domain of human apolipoprotein E: no cosegregation with severe hyperlipidemia. Am J Hum Genet. 1993 May;52(5):937-46. PubMed.
5. Zhao SP, Van den Maagdenberg AM, Vroom TF, Van 't Hooft FM, Gevers Leuvens JA, Havekes LM, Frants RR, Van der Laarse A, Smelt AH. Lipoprotein profiles in a family with two mutants of apolipoprotein E: possible association with hypertriglyceridaemia but not with dysbetalipoproteinaemia. Clin Sci (Lond). 1994 Mar;86(3):323-9. PubMed.
6. 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.
7. Radwan ZH, Wang X, Waqar F, Pirim D, Niemsiri V, Hokanson JE, Hamman RF, Bunker CH, Barmada MM, Demirci FY, Kamboh MI. Comprehensive evaluation of the association of APOE genetic variation with plasma lipoprotein traits in U.S. whites and African blacks. PLoS One. 2014;9(12):e114618. Epub 2014 Dec 12 PubMed.
8. Liu CC, Murray ME, Li X, Zhao N, Wang N, Heckman MG, Shue F, Martens Y, Li Y, Raulin AC, Rosenberg CL, Doss SV, Zhao J, Wren MC, Jia L, Ren Y, Ikezu TC, Lu W, Fu Y, Caulfield T, Trottier ZA, Knight J, Chen Y, Linares C, Wang X, Kurti A, Asmann YW, Wszolek ZK, Smith GE, Vemuri P, Kantarci K, Knopman DS, Lowe VJ, Jack CR Jr, Parisi JE, Ferman TJ, Boeve BF, Graff-Radford NR, Petersen RC, Younkin SG, Fryer JD, Wang H, Han X, Frieden C, Dickson DW, Ross OA, Bu G. APOE3-Jacksonville (V236E) variant reduces self-aggregation and risk of dementia. Sci Transl Med. 2021 Sep 29;13(613):eabc9375. PubMed.
9. Bu G. APOE targeting strategy in Alzheimer's disease: lessons learned from protective variants. Mol Neurodegener. 2022 Aug 3;17(1):51. PubMed.
10. Vance JM, Farrer LA, Huang Y, Cruchaga C, Hyman BT, Pericak-Vance MA, Goate AM, Greicius MD, Griswold AJ, Haines JL, Tcw J, Schellenberg GD, Tsai LH, Herz J, Holtzman DM. Report of the APOE4 National Institute on Aging/Alzheimer Disease Sequencing Project Consortium Working Group: Reducing APOE4 in Carriers is a Therapeutic Goal for Alzheimer's Disease. Ann Neurol. 2024 Apr;95(4):625-634. Epub 2024 Jan 5 PubMed.
11. Frieden C, Garai K. Structural differences between apoE3 and apoE4 may be useful in developing therapeutic agents for Alzheimer's disease. Proc Natl Acad Sci U S A. 2012 Jun 5;109(23):8913-8. Epub 2012 May 21 PubMed.

Other Citations

1. HEX database

Further Reading