Overview

Clinical Phenotype: Alzheimer's Disease, Multiple Conditions
Position: (GRCh38/hg38):Chr19:44908822 C>T
Position: (GRCh37/hg19):Chr19:45412079 C>T,
Position: (GRCh38/hg38):Chr19:44908684 T>C
Position: (GRCh37/hg19):Chr19:45411941 T>C
Transcript: NM_000041; ENSG00000130203
dbSNP ID: NA
Coding/Non-Coding: Coding
Codon Change: CGC to TGC, TGC to CGC
Reference Isoform: APOE Isoform 1
Genomic Region: Exon 4

Findings

It is well-established that the common APOE variants, C130R (APOE4) and R176C (APOE2), modify Alzheimer’s disease risk, boosting it in the former and reducing it in the latter. However, the effects of carrying both alleles, a genotype found at a frequency of roughly 2 percent in the general population, remains less clear.

Most studies have found that the increased risk of AD caused by APOE4 overshadows APOE2’s protective effect. The evidence dates to at least 1997, when a meta-analysis including nearly 6,000 AD patients and over 8,500 controls revealed increased AD risk in Caucasians with the APOE2/4 genotype compared with APOE3/3 carriers (Farrer et al., 1997). Consistent with these findings, a more recent case-control study found a similar elevated risk compared with APOE3/E3 carriers in a neuropathologically confirmed autopsy group (OR = 2.68 [95% CI 1.65-4.36] p= 7.5 x 10^-5, Reiman et al., 2020), as did a prospective longitudinal study of non-Latino whites (adjusted hazard ratio = 1.74, 95% CI = 1.32-2.30; p < .0001, Ren et al., 2020).

In addition, a sudy based on data from a post-mortem human brain database, revealed risks for AD plaque and Braak stage tau pathology in APOE2/E4 carriers were similar to those of APOE3/E4,  not APOE E3/E3 or E3/E2, carriers (Goldberg et al., 2020). Similarly, a study of AD patients in the Alzheimer’s Disease Neuroimaging Initiative concluded that overall neurodegeneration in APOE2/E4 carriers was more similar to that of APOE4 carriers than to that of APOE3 or APOE2 carriers (Morrison et al., 2023). However, some measures of pathology in APOE2/E4 carriers were more similar to those of APOE3 carriers (e.g., white matter hyperintensity burden), and some were in-between those of APOE4 and APOE3 carriers (e.g., rate of hippocampal atrophy).

Moreover, although another study found no difference in AD risk between APOE2/4 and APOE3/3 carriers, it reported an increased risk of cognitive impairment and a faster rate of cognitive decline in older APOE2/4 carriers that were cognitively unimpaired at baseline than in APOE3/3 carriers, and more Aβ pathology in deceased APOE2/4 carriers than in APOE3/3 carriers (Oveisgharan et al., 2018). The authors concluded the phenotypes associated with the APOE2/4 genotype were more similar to those of APOE4 carriers than to those of APOE2 carriers. Of note, no differences in tau pathology were observed between APOE2/4 and APOE3/3 carriers. 

Despite their increased risk for AD compared with APOE4 non-carriers, in most cases, APOE2/E4 carriers may fare better than APOE3/E4 carriers. Reiman and colleagues, for example, reported APOE3/4 carriers had a substantially higher risk of developing AD than APOE2/4 carriers (APOE3/4: OR = 6.13 [95% CI 5.08-7.41], p = 2.2 x 10^-75  versus APOE2/4: OR = 2.68 [95% CI 1.65-4.36] p= 7.5 x 10-5; Reiman et al., 2020). Also, a study focusing on cognitively healthy individuals between the ages of 65 to 85, found that APOE2 was associated with a reduction in both overall Aβ accumulation and age-dependent Aβ levels in the presence of APOE4 (Insel et al., 2021). Aβ levels in the APOE2/4 group increased at less than half the rate of those in the APOE3/4 group, with differences becoming apparent as early as age 65. However, an earlier, smaller study examining Aβ positivity in non-demented individuals, found that the age at which 15 percent of participants with normal cognition became amyloid positive was younger for APOE2/4 carriers (50 years) than for APOE3/4 carriers (55 years) (Jansen et al., 2015).

Some researchers consider the positive findings of the APOE2/E4 genotype compared with the APOE3/4 genotype as support for the development of candidate treatments for AD that mimic APOE2, particularly for APOE4 carriers (Insel et al., 2021). On the other hand, focusing on the data that show few, if any, positive effects, others have suggested the pathways modified by each of the alleles are likely non-overlapping and thus APOE2 is unlikely to substantially blunt APOE4’s damaging effects (Kim et al., 2022).

Importantly, other genetic variants, gender, and ancestry may play a role in determining the effects of the APOE2/E4 genotype. For example, a common variant of the haptoglobin gene was reported to modify the effects of both APOE2 and APOE4, such that APOE2/E4 carriers who are homozygous for one of the haptoglobin variants (HP2/HP2) have an AD risk that is closer to that of APOE3/E3 carriers than that of APOE3/E4 or APOE4/E4 carriers (Bai et al., 2023). Also, a large population-based study of the UK Biobank cohort found that APOE2/4 carriers had a dampened risk of AD and AD-related dementia relative to APOE3/4 carriers, but only in women (Savignac et al., 2022).

Regarding the effects of ancestry, a study including nearly 70,000 individuals indicated that, while the APOE2/E2 plus APOE2/E3 genotypes did not lower AD risk in either East Asians or Hispanics as they do in Whites, APOE2 was protective in these same populations when found in the APOE2/E4 genotype (Belloy et al., 2023). Similarly, the risk for AD and MCI in African Americans who are less protected by APOE2 than Whites, was not elevated by APOE4 carriage in the APOE2/E4 genotype, while it was in non-Latino Whites (Ren et al., 2021). 

Effects of this genotype on other neurological conditions have also been reported. For example, one study found an elevated risk of lobar intracerebral hemorrhage specifically in APOE2/4 and APOE4/4 carriers treated with statins (Woo et al., 2013).

Non-neurological conditions

Studies of the blood lipid profiles of APOE2/4 heterozygotes point to both alleles contributing to individuals’ phenotypes. In general, APOE2 carriers have normal or cardiovascular-protective profiles with low levels of total cholesterol and low-density lipoprotein (LDL) cholesterol. In some APOE2 homozygotes, triglyceride levels are elevated and cause hyperlipoproteinemia type III (HLPP3), a condition characterized by the accumulation of remnants of triglyceride-rich lipoproteins, and early onset atherosclerosis and heart disease. Although it is often noted that the vast majority of HLPP3 patients are APOE2 homozygotes, the disease surfaces in only 5 to 10 percent of homozygous carriers. In contrast, APOE4 carriers tend to have elevated levels of cholesterol-rich LDL. As reported in a study of 2,680 Caucasians, APOE2/4 carriers had higher levels of cholesterol in LDL and in non-high density lipoprotein (non-HDL) particles than APOE2/3 carriers, their levels being closer to those of APOE3/4 and APOE4/4 carriers (Villeneuve et al., 2015). Also, compared with APOE2/2 carriers, APOE2/4 heterozygotes had reduced very low-density lipoprotein (VLDL)-cholesterol. On the other hand, although not as pronounced as in APOE2 homozygotes, APOE2/4 carriers had high triglyceride levels.

In the same study, APOE2/4 heterozygotes’ risks for pathological conditions mirrored these findings. When compared with APOE2/2 and APOE4/4 carriers, APOE2/4 carriers were less susceptible to hyperlipidemia. They had a decreased risk of suffering from LDL hypercholesterolemia and high non-HDL-cholesterol compared with APOE4 homozygotes, and a lower risk of having an elevated VLDL-cholesterol:triglyceride ratio, a marker of HLPP3 which is associated with APOE2 homozygosity. On the other hand, when compared with APOE3/3 carriers, APOE2/4 carriers had a moderately increased risk for hypertriglyceridemia, elevated levels of intermediate-density lipoproteins (IDL), and increased cholesterol:HDL-cholesterol ratio, a marker of coronary artery disease. Consistent with these findings, an association between APOE2/4 carriership and myocardial infarction was reported (Semaev et al., 2023).

APOE2/4 heterozygosity has also been studied in other conditions, sometimes yielding unexpected results. For example, in a study of 474 Chinese Uygur patients with high levels of uric acid in serum, a sign of kidney dysfunction, and 518 controls, individuals with an APOE2/4 genotype appeared to have a higher risk for this condition compared with all other common APOE genotypes (Sun et al., 2015). The genotype associated with the lowest level of serum uric acid was APOE2/2. Also, in a study of prostatic cancer cell lines those with an APOE2/4 genotype were more malignant, as assessed by cholesterol efflux and caveolin-1 expression, than those with APOE3/3 or APOE3/4 genotypes (Ifere et al., 2013).

Biological effects

Little is known about the biological effects of carrying both APOE2 and APOE4. A few studies in transgenic mice expressing human APOE alleles hint at APOE2 mitigating some of APOE4’s harmful effects. For example, APOE4-associated deficits in balancing excitatory and inhibitory activity in the amygdala are less pronounced in APOE2/4 mice than in those carrying only the APOE4 allele (Klein et al., 2010, Klein et al., 2014). In the latter, the frequency of spontaneous inhibitory post-synaptic currents (sIPSCs) was greater than that of spontaneous excitatory post-synaptic currents (sEPSCs), whereas in APOE3 and E2/4 mice, the frequencies were roughly equal. Differences in the inhibitory currents and in frequency adaptation appear to underlie these differences. Also, lower levels of Aβ and higher levels of ApoE were found in the synaptic terminals of APOE2/4 mice than in APOE4/4, and even APOE3/3, mice. The authors suggest that the higher lipidation of ApoE2 compared with ApoE3 and ApoE4, may facilitate Aβ clearance at synapses (Arold et al., 2012).

Of note, a study in  humans in which differentially labeled ApoE2 and ApoE4 proteins were simultaneously injected into APOE2/4 heterozygotes suggested the location and lifespan of the two proteins are different (Ikewaki et al., 2002). The mean residence time of ApoE4 was about one third that of ApoE2. Moreover, whereas ApoE2 was found primarily in HDL, ApoE4 was found in roughly equal amounts in VLDL and HDL.

Note on nomenclature:

The genotype described here involves the presence of the APOE2 and APOE4 alleles in trans, i.e., on different chromosomes. It is distinct from [C130R;R176C] (APOE3r) in which the two substitutions occur on the same chromosome.

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References

Mutations Citations

1. APOE C130R (ApoE4)
2. APOE R176C (ApoE2)
3. APOE [C130R;R176C] (ApoE3r)

Paper Citations

1. Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R, Myers RH, Pericak-Vance MA, Risch N, van Duijn CM. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA. 1997 Oct 22-29;278(16):1349-56. PubMed.
2. Reiman EM, Arboleda-Velasquez JF, Quiroz YT, Huentelman MJ, Beach TG, Caselli RJ, Chen Y, Su Y, Myers AJ, Hardy J, Paul Vonsattel J, Younkin SG, Bennett DA, De Jager PL, Larson EB, Crane PK, Keene CD, Kamboh MI, Kofler JK, Duque L, Gilbert JR, Gwirtsman HE, Buxbaum JD, Dickson DW, Frosch MP, Ghetti BF, Lunetta KL, Wang LS, Hyman BT, Kukull WA, Foroud T, Haines JL, Mayeux RP, Pericak-Vance MA, Schneider JA, Trojanowski JQ, Farrer LA, Schellenberg GD, Beecham GW, Montine TJ, Jun GR, Alzheimer’s Disease Genetics Consortium. Exceptionally low likelihood of Alzheimer's dementia in APOE2 homozygotes from a 5,000-person neuropathological study. Nat Commun. 2020 Feb 3;11(1):667. PubMed.
3. Ren D, Lopez OL, Lingler JH, Conley Y. The Effect of the APOE ε2ε4 Genotype on the Development of Alzheimer's Disease (AD) and Mild Cognitive Impairment (MCI) in Non-Latino Whites. J Am Geriatr Soc. 2020 May;68(5):1044-1049. Epub 2020 Feb 4 PubMed.
4. Goldberg TE, Huey ED, Devanand DP. Association of APOE e2 genotype with Alzheimer's and non-Alzheimer's neurodegenerative pathologies. Nat Commun. 2020 Sep 18;11(1):4727. PubMed.
5. Oveisgharan S, Buchman AS, Yu L, Farfel J, Hachinski V, Gaiteri C, De Jager PL, Schneider JA, Bennett DA. APOE ε2ε4 genotype, incident AD and MCI, cognitive decline, and AD pathology in older adults. Neurology. 2018 Jun 12;90(24):e2127-e2134. Epub 2018 May 11 PubMed.
6. Insel PS, Hansson O, Mattsson-Carlgren N. Association Between Apolipoprotein E ε2 vs ε4, Age, and β-Amyloid in Adults Without Cognitive Impairment. JAMA Neurol. 2021 Feb 1;78(2):229-235. PubMed.
7. Jansen WJ, Ossenkoppele R, Knol DL, Tijms BM, Scheltens P, Verhey FR, Visser PJ, Amyloid Biomarker Study Group, Aalten P, Aarsland D, Alcolea D, Alexander M, Almdahl IS, Arnold SE, Baldeiras I, Barthel H, van Berckel BN, Bibeau K, Blennow K, Brooks DJ, van Buchem MA, Camus V, Cavedo E, Chen K, Chetelat G, Cohen AD, Drzezga A, Engelborghs S, Fagan AM, Fladby T, Fleisher AS, van der Flier WM, Ford L, Förster S, Fortea J, Foskett N, Frederiksen KS, Freund-Levi Y, Frisoni GB, Froelich L, Gabryelewicz T, Gill KD, Gkatzima O, Gómez-Tortosa E, Gordon MF, Grimmer T, Hampel H, Hausner L, Hellwig S, Herukka SK, Hildebrandt H, Ishihara L, Ivanoiu A, Jagust WJ, Johannsen P, Kandimalla R, Kapaki E, Klimkowicz-Mrowiec A, Klunk WE, Köhler S, Koglin N, Kornhuber J, Kramberger MG, Van Laere K, Landau SM, Lee DY, de Leon M, Lisetti V, Lleó A, Madsen K, Maier W, Marcusson J, Mattsson N, de Mendonça A, Meulenbroek O, Meyer PT, Mintun MA, Mok V, Molinuevo JL, Møllergård HM, Morris JC, Mroczko B, Van der Mussele S, Na DL, Newberg A, Nordberg A, Nordlund A, Novak GP, Paraskevas GP, Parnetti L, Perera G, Peters O, Popp J, Prabhakar S, Rabinovici GD, Ramakers IH, Rami L, Resende de Oliveira C, Rinne JO, Rodrigue KM, Rodríguez-Rodríguez E, Roe CM, Rot U, Rowe CC, Rüther E, Sabri O, Sanchez-Juan P, Santana I, Sarazin M, Schröder J, Schütte C, Seo SW, Soetewey F, Soininen H, Spiru L, Struyfs H, Teunissen CE, Tsolaki M, Vandenberghe R, Verbeek MM, Villemagne VL, Vos SJ, van Waalwijk van Doorn LJ, Waldemar G, Wallin A, Wallin ÅK, Wiltfang J, Wolk DA, Zboch M, Zetterberg H. Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis. JAMA. 2015 May 19;313(19):1924-38. PubMed.
8. Kim H, Devanand DP, Carlson S, Goldberg TE. Apolipoprotein E Genotype e2: Neuroprotection and Its Limits. Front Aging Neurosci. 2022;14:919712. Epub 2022 Jul 14 PubMed.
9. Bai H, Naj AC, Benchek P, Dumitrescu L, Hohman T, Hamilton-Nelson K, Kallianpur AR, Griswold AJ, Vardarajan B, Martin ER, Beecham GW, Below JE, Schellenberg G, Mayeux R, Farrer L, Pericak-Vance MA, Haines JL, Bush WS, Alzheimer's Disease Genetics Consortium. A haptoglobin (HP) structural variant alters the effect of APOE alleles on Alzheimer's disease. Alzheimers Dement. 2023 Apr 12; PubMed.
10. Savignac C, Villeneuve S, Badhwar A, Saltoun K, Shafighi K, Zajner C, Sharma V, Gagliano Taliun SA, Farhan S, Poirier J, Bzdok D. APOE alleles are associated with sex-specific structural differences in brain regions affected in Alzheimer's disease and related dementia. PLoS Biol. 2022 Dec;20(12):e3001863. Epub 2022 Dec 13 PubMed.
11. Belloy ME, Andrews SJ, Le Guen Y, Cuccaro M, Farrer LA, Napolioni V, Greicius MD. APOE Genotype and Alzheimer Disease Risk Across Age, Sex, and Population Ancestry. JAMA Neurol. 2023 Dec 1;80(12):1284-1294. PubMed.
12. Ren D, Lopez OL, Lingler JH, Conley Y. Association Between the APOEɛ2/ɛ4 Genotype and Alzheimer's Disease and Mild Cognitive Impairment Among African Americans. J Alzheimers Dis. 2021;81(3):943-948. PubMed.
13. Woo D, Deka R, Falcone GJ, Flaherty ML, Haverbusch M, Martini SR, Greenberg SM, Ayres AM, Sauerbeck L, Kissela BM, Kleindorfer DO, Moomaw CJ, Anderson CD, Broderick JP, Rosand J, Langefeld CD, Woo JG. Apolipoprotein E, statins, and risk of intracerebral hemorrhage. Stroke. 2013 Nov;44(11):3013-7. Epub 2013 Sep 5 PubMed.
14. Villeneuve S, Brisson D, Gaudet D. Influence of Abdominal Obesity on the Lipid-Lipoprotein Profile in Apoprotein E2/4 Carriers: The Effect of an Apparent Duality. J Lipids. 2015;2015:742408. Epub 2015 Oct 28 PubMed.
15. Semaev S, Shakhtshneider E, Shcherbakova L, Orlov P, Ivanoshchuk D, Malyutina S, Gafarov V, Voevoda M, Ragino Y. Association of Common Variants of APOE, CETP, and the 9p21.3 Chromosomal Region with the Risk of Myocardial Infarction: A Prospective Study. Int J Mol Sci. 2023 Jun 30;24(13) PubMed.
16. Sun YP, Zhang B, Miao L, Wang XM, Yu JH, Luo L, Ying L, Xin G, Haliakpaer G, Xia H, Yao H. Association of apolipoprotein E (ApoE) polymorphisms with risk of primary hyperuricemia in Uygur men, Xinjiang, China. Lipids Health Dis. 2015 Apr 12;14:25. PubMed.
17. Ifere GO, Desmond R, Demark-Wahnefried W, Nagy TR. Apolipoprotein E gene polymorphism influences aggressive behavior in prostate cancer cells by deregulating cholesterol homeostasis. Int J Oncol. 2013 Oct;43(4):1002-10. Epub 2013 Aug 7 PubMed.
18. Klein RC, Mace BE, Moore SD, Sullivan PM. Progressive loss of synaptic integrity in human apolipoprotein E4 targeted replacement mice and attenuation by apolipoprotein E2. Neuroscience. 2010 Dec 29;171(4):1265-72. Epub 2010 Oct 15 PubMed.
19. Klein RC, Acheson SK, Mace BE, Sullivan PM, Moore SD. Altered neurotransmission in the lateral amygdala in aged human apoE4 targeted replacement mice. Neurobiol Aging. 2014 Sep;35(9):2046-52. Epub 2014 Mar 2 PubMed.
20. Arold S, Sullivan P, Bilousova T, Teng E, Miller CA, Poon WW, Vinters HV, Cornwell LB, Saing T, Cole GM, Gylys KH. Apolipoprotein E level and cholesterol are associated with reduced synaptic amyloid beta in Alzheimer's disease and apoE TR mouse cortex. Acta Neuropathol. 2012 Jan;123(1):39-52. Epub 2011 Oct 22 PubMed.
21. Ikewaki K, Zech LA, Brewer HB Jr, Rader DJ. Comparative in vivo metabolism of apolipoproteins E2 and E4 in heterozygous apoE2/4 subjects. J Lab Clin Med. 2002 Nov;140(5):369-74. PubMed.

Other Citations

1. Morrison et al., 2023

Further Reading