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Apolipoprotein E
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<h2 id="evolution">Evolution</h2> <p>Apolipoproteins are not unique to mammals. Many terrestrial and marine <a href="/facts/Vertebrate/tT54FSTT">vertebrates</a> have versions of them.<a class="footnote-ref" id="fnref:8" href="#fn:8"><sup>8</sup></a> It is believed that <i>APOE</i> arose via gene duplications of <i><a href="/facts/APOC1/Qquo67tC">APOC1</a></i> before the fish–<a href="/facts/Tetrapoda/vWpAxzAW">tetrapod</a> split ca. 400 million years ago. Proteins similar in function have been found in <a href="/facts/Choanoflagellate/S2xjEI9J">choanoflagellates</a>, suggesting that they are a very old class of proteins predating the dawn of all living animals.<a class="footnote-ref" id="fnref:9" href="#fn:9"><sup>9</sup></a> </p><p>The three major human <a href="/facts/Allele/8FxCS9KA">alleles</a> (<i>E4</i>, <i>E3</i>, <i>E2</i>) arose after the primate–human split around 7.5 million years ago. These alleles are the by-product of non-synonymous mutations which led to changes in functionality. The first allele to emerge was E4. After the primate–human split, there were four amino acid changes in the human lineage, three of which had no effect on protein function (V174L, A18T, A135V). The fourth substitution (T61R) traded a threonine for an arginine altering the protein's functionality. This substitution occurred somewhere in the 6 million year gap between the primate–human split and the <a href="/facts/Denisovan/ysNIvyS0">Denisovan</a>–human split, since exactly the same substitutions were found in Denisovan <i>APOE</i>.<a class="footnote-ref" id="fnref:10" href="#fn:10"><sup>10</sup></a> </p><p>About 220,000 years ago, a cysteine to arginine substitution took place at amino acid 112 (Cys112Arg) of the <i>APOE4</i> gene, and this resulted in the <i>E3</i> allele. Finally, 80,000 years ago, another arginine to cysteine substitution at amino acid 158 (Arg158Cys) of the <i>APOE3</i> gene created the <i>E2</i> allele.<a class="footnote-ref" id="fnref:11" href="#fn:11"><sup>11</sup></a><a class="footnote-ref" id="fnref:12" href="#fn:12"><sup>12</sup></a> </p> <h2 id="structure">Structure</h2> <h3>Gene</h3> <p>The gene, <i>APOE</i>, is mapped to <a href="/facts/Chromosome_19_(human)/jcngrCTc">chromosome 19</a> in a <a href="/facts/Gene_cluster/0Goyb8eB">cluster</a> with the <a href="/facts/Apolipoprotein_C1/Qquo67tC">apolipoprotein C1</a> (<i>APOC1</i>) gene and the <a href="/facts/Apolipoprotein_C2/0t1gh6jC">apolipoprotein C2</a> (<i>APOC2</i>) gene. The <i>APOE</i> gene consists of four <a href="/facts/Exons/8KWJtLuN">exons</a> and three <a href="/facts/Introns/LS6YdBEK">introns</a>, totaling 3597 <a href="/facts/Base_pair/xmPpPQ9W">base pairs</a>. <i>APOE</i> is transcriptionally activated by the <a href="/facts/Liver_X_receptor/A8Sct6kz">liver X receptor</a> (an important regulator of <a href="/facts/Cholesterol/TnfPlYc1">cholesterol</a>, <a href="/facts/Fatty_acid/JGg3erIu">fatty acid</a>, and <a href="/facts/Glucose/oUSkoLCD">glucose</a> <a href="/facts/Homeostasis/rloTGAHa">homeostasis</a>) and <a href="/facts/Peroxisome_proliferator-activated_receptor/GSYTtaDv">peroxisome proliferator-activated receptor</a> γ, <a href="/facts/Nuclear_receptor/9aYqKxnM">nuclear receptors</a> that form <a href="/facts/Heterodimer/c8LwFJPG">heterodimers</a> with <a href="/facts/Retinoid_X_receptor/VhHIuyLy">retinoid X receptors</a>.<a class="footnote-ref" id="fnref:13" href="#fn:13"><sup>13</sup></a> In <a href="/facts/Melanocyte/z8KowoXP">melanocytic cells</a> <i>APOE</i> gene expression may be regulated by <a href="/facts/Microphthalmia-associated_transcription_factor/loE6X4HQ">MITF</a>.<a class="footnote-ref" id="fnref:14" href="#fn:14"><sup>14</sup></a> </p> <h3>Protein</h3> <p>Apoe-E is 299 <a href="/facts/Amino_acid/WDxYwBny">amino acids</a> long and contains multiple <a href="/facts/Amphipathic/FkmYh9JI">amphipathic</a> <a href="/facts/%CE%91-helices/7CESPIYJ">α-helices</a>. According to crystallography studies, a hinge region connects the N- and C-terminal regions of the protein. The N-terminal region (<a href="/facts/Residue_(chemistry)/xE6sUTDa">residues</a> 1–167) forms an anti-parallel four-helix bundle such that the non-polar sides face inside the protein. Meanwhile, the C-terminal domain (residues 206–299) contains three α-helices which form a large exposed <a href="/facts/Hydrophobic/Ifya0CXQ">hydrophobic</a> surface and interact with those in the N-terminal helix bundle domain through <a href="/facts/Hydrogen_bond/85V86IIg">hydrogen bonds</a> and salt-bridges. The C-terminal region also contains a <a href="/facts/Low_density_lipoprotein_receptor/zsSjTYyb">low density lipoprotein receptor</a> (LDLR)-binding site.<a class="footnote-ref" id="fnref:15" href="#fn:15"><sup>15</sup></a> </p> <h3>Polymorphisms</h3> <p><i>APOE</i> is <a href="/facts/Gene_polymorphism/6U9NzHwH">polymorphic</a>,<a class="footnote-ref" id="fnref:16" href="#fn:16"><sup>16</sup></a><a class="footnote-ref" id="fnref:17" href="#fn:17"><sup>17</sup></a> with three major <a href="/facts/Allele/8FxCS9KA">alleles</a> (epsilon 2, epsilon 3, and epsilon 4): <i>APOE-ε2</i> (cys112, cys158), <i>APOE-ε3</i> (cys112, arg158), and <i>APOE-ε4</i> (arg112, arg158).<a class="footnote-ref" id="fnref:18" href="#fn:18"><sup>18</sup></a><a class="footnote-ref" id="fnref:19" href="#fn:19"><sup>19</sup></a><a class="footnote-ref" id="fnref:20" href="#fn:20"><sup>20</sup></a> Although these allelic forms differ from each other by only one or two amino acids at positions 112 and 158,<a class="footnote-ref" id="fnref:21" href="#fn:21"><sup>21</sup></a><a class="footnote-ref" id="fnref:22" href="#fn:22"><sup>22</sup></a><a class="footnote-ref" id="fnref:23" href="#fn:23"><sup>23</sup></a> these differences alter APOE structure and function. </p><p>There are several low-frequency polymorphisms of APOE. APOE5 comes in two subtypes E5f and E5s, based on migration rates. APOE5 E5f and APOE7 combined were found in 2.8% of Japanese males.<a class="footnote-ref" id="fnref:24" href="#fn:24"><sup>24</sup></a>[<i>unreliable medical source</i>] APOE7 is a mutation of APOE3 with two lysine residues replacing glutamic acid residues at positions 244 and 245.<a class="footnote-ref" id="fnref:25" href="#fn:25"><sup>25</sup></a> </p> <table><tbody><tr><th>Polymorphism</th><th>Worldwide allele frequency</th><th>Disease relevance</th></tr><tr><td>ε2 (rs7412-T, rs429358-T)</td><td>8.4%<a class="footnote-ref" id="fnref:26" href="#fn:26"><sup>26</sup></a></td><td>This variant of the apoprotein binds poorly to cell surface receptors while E3 and E4 bind well.<a class="footnote-ref" id="fnref:27" href="#fn:27"><sup>27</sup></a> E2 is associated with both increased and decreased risk for <a href="/facts/Atherosclerosis/WIS8QQ6v">atherosclerosis</a>. Individuals with an E2/E2 combination may clear dietary fat slowly and be at greater risk for early vascular disease and the <a href="/facts/Genetic_disorder/hFqt2NLn">genetic disorder</a> <a href="/facts/Type_III_hyperlipoproteinemia/dNgWszEr">type III hyperlipoproteinemia</a>—94.4% of people with such disease are E2/E2 but only ~2% of E2/E2 develop it, so other environmental and genetic factors are likely to be involved (such as cholesterol in the diet and age).<a class="footnote-ref" id="fnref:28" href="#fn:28"><sup>28</sup></a><a class="footnote-ref" id="fnref:29" href="#fn:29"><sup>29</sup></a><a class="footnote-ref" id="fnref:30" href="#fn:30"><sup>30</sup></a> E2 has also been implicated in <a href="/facts/Parkinson%27s_disease/xpekKj6x">Parkinson's disease</a>,<a class="footnote-ref" id="fnref:31" href="#fn:31"><sup>31</sup></a> but this finding was not replicated in a larger population association study.<a class="footnote-ref" id="fnref:32" href="#fn:32"><sup>32</sup></a></td></tr><tr><td>ε3 (rs7412-C, rs429358-T)</td><td>77.9%<a class="footnote-ref" id="fnref:33" href="#fn:33"><sup>33</sup></a></td><td>This variant is considered the "neutral" <i>APOE</i> genotype.</td></tr><tr><td>ε4 (rs7412-C, rs429358-C)</td><td>13.7%<a class="footnote-ref" id="fnref:34" href="#fn:34"><sup>34</sup></a></td><td><p>E4 has been implicated in <a href="/facts/Atherosclerosis/WIS8QQ6v">atherosclerosis</a>,<a class="footnote-ref" id="fnref:35" href="#fn:35"><sup>35</sup></a><a class="footnote-ref" id="fnref:36" href="#fn:36"><sup>36</sup></a> <a href="/facts/Alzheimer%27s_disease/w7Ad6tdg">Alzheimer's disease</a>,<a class="footnote-ref" id="fnref:37" href="#fn:37"><sup>37</sup></a><a class="footnote-ref" id="fnref:38" href="#fn:38"><sup>38</sup></a> impaired <a href="/facts/Cognitive_function/8L95q3bX">cognitive function</a>,<a class="footnote-ref" id="fnref:39" href="#fn:39"><sup>39</sup></a><a class="footnote-ref" id="fnref:40" href="#fn:40"><sup>40</sup></a> reduced <a href="/facts/Hippocampal/X7CqbP8X">hippocampal</a> volume,<a class="footnote-ref" id="fnref:41" href="#fn:41"><sup>41</sup></a> <a href="/facts/HIV/ulY2rgzu">HIV</a>,<a class="footnote-ref" id="fnref:42" href="#fn:42"><sup>42</sup></a> faster disease progression in <a href="/facts/Multiple_sclerosis/vghXl0IQ">multiple sclerosis</a>,<a class="footnote-ref" id="fnref:43" href="#fn:43"><sup>43</sup></a><a class="footnote-ref" id="fnref:44" href="#fn:44"><sup>44</sup></a> unfavorable outcome after <a href="/facts/Traumatic_brain_injury/DTq110vw">traumatic brain injury</a>,<a class="footnote-ref" id="fnref:45" href="#fn:45"><sup>45</sup></a> ischemic <a href="/facts/Cerebrovascular_disease/Y11DmQk4">cerebrovascular disease</a>,<a class="footnote-ref" id="fnref:46" href="#fn:46"><sup>46</sup></a> <a href="/facts/Sleep_apnea/mstY43ok">sleep apnea</a>,<a class="footnote-ref" id="fnref:47" href="#fn:47"><sup>47</sup></a><a class="footnote-ref" id="fnref:48" href="#fn:48"><sup>48</sup></a> both the extension and shortening of <a href="/facts/Telomere/RQ4Gp9LT">telomeres</a>,<a class="footnote-ref" id="fnref:49" href="#fn:49"><sup>49</sup></a><a class="footnote-ref" id="fnref:50" href="#fn:50"><sup>50</sup></a><a class="footnote-ref" id="fnref:51" href="#fn:51"><sup>51</sup></a><a class="footnote-ref" id="fnref:52" href="#fn:52"><sup>52</sup></a> reduced <a href="/facts/Neurite/A1dzfEKy">neurite</a> outgrowth,<a class="footnote-ref" id="fnref:53" href="#fn:53"><sup>53</sup></a> and <a href="/facts/COVID-19/YsUgvsaX">COVID-19</a>.<a class="footnote-ref" id="fnref:54" href="#fn:54"><sup>54</sup></a> However, E4 has also been associated with enhanced <a href="/facts/Vitamin_D/No0zQB2W">vitamin D</a> and <a href="/facts/Calcium/hf252CC0">calcium</a> status,<a class="footnote-ref" id="fnref:55" href="#fn:55"><sup>55</sup></a> higher <a href="/facts/Fecundity/e0oMColj">fecundity</a>,<a class="footnote-ref" id="fnref:56" href="#fn:56"><sup>56</sup></a> protection against early childhood <a href="/facts/Infection/182XrncP">infection</a> and <a href="/facts/Malnutrition/KasQy5MR">malnutrition</a>,<a class="footnote-ref" id="fnref:57" href="#fn:57"><sup>57</sup></a> and decreased <a href="/facts/Fetal/evocHd0Y">fetal</a>, <a href="/facts/Perinatal/VpV3S4lu">perinatal</a>, and <a href="/facts/Infant/gaEL1QL4">infant</a> mortality.<a class="footnote-ref" id="fnref:58" href="#fn:58"><sup>58</sup></a></p></td></tr></tbody></table> <p>Much remains to be learned about the APOE isoforms, including the interaction of other protective genes.<a class="footnote-ref" id="fnref:59" href="#fn:59"><sup>59</sup></a> Indeed, the apolipoprotein ε4 isoform is more protective against cognitive decline than other isoforms in some cases,<a class="footnote-ref" id="fnref:60" href="#fn:60"><sup>60</sup></a> so caution is advised before making determinant statements about the influence of APOE polymorphisms on cognition, development of Alzheimer's disease, cardiovascular disease, telomere shortening, etc. Many of the studies cited that purport these adverse outcomes are from single studies that have not been replicated and the research is based on unchecked assumptions about this isoform. As of 2007, there was no evidence that APOE polymorphisms influence cognition in younger age groups (other than possible increased episodic memory ability and neural efficiency in younger APOE4 age groups), nor that the APOE4 isoform places individuals at increased risk for any infectious disease.<a class="footnote-ref" id="fnref:61" href="#fn:61"><sup>61</sup></a> </p><p>However, the association between the APOE4 allele and Alzheimer's disease has been shown to be weaker in minority groups differently compared to their Caucasian counterparts.<a class="footnote-ref" id="fnref:62" href="#fn:62"><sup>62</sup></a> <a href="/facts/Alzheimer%27s_disease_in_the_Hispanic/Latino_population/kWJxbzQ6">Hispanics/Latinos</a> and <a href="/facts/Alzheimer%27s_disease_in_African_Americans/8IBvdpSu">African Americans</a> who were homozygous for the APOE4 allele had 2.2 and 5.7 times the odds, respectively of developing Alzheimer's disease.<a class="footnote-ref" id="fnref:63" href="#fn:63"><sup>63</sup></a><a class="footnote-ref" id="fnref:64" href="#fn:64"><sup>64</sup></a> The APOE4 allele has an even stronger effect in <a href="/facts/Alzheimer%27s_Disease_in_the_East_Asian_Population/9drqPaT0">East Asian populations</a>, with Japanese populations have 33 times the odds compared to other populations.<a class="footnote-ref" id="fnref:65" href="#fn:65"><sup>65</sup></a> Caucasians who were homozygous for the allele had 12.5 times the odds.<a class="footnote-ref" id="fnref:66" href="#fn:66"><sup>66</sup></a><a class="footnote-ref" id="fnref:67" href="#fn:67"><sup>67</sup></a> </p> <h2 id="function">Function</h2> <p>As a component of the lipoprotein lipid transport system, APOE facilitates the transport of <a href="/facts/Lipid/TdQR87HX">lipids</a>, fat-soluble <a href="/facts/Vitamins/SnW0LYBL">vitamins</a>, and <a href="/facts/Cholesterol/TnfPlYc1">cholesterol</a> via the blood. It interacts with the LDL receptor to facilitate endocytosis of VLDL remnants. It is synthesized principally in the <a href="/facts/Liver/Rtp4Fk2b">liver</a>, but has also been found in other tissues such as the <a href="/facts/Brain/EKla9NkJ">brain</a>, <a href="/facts/Kidney/HBspPrv9">kidneys</a>, and <a href="/facts/Spleen/6NKn9d8s">spleen</a>.<a class="footnote-ref" id="fnref:68" href="#fn:68"><sup>68</sup></a> APOE synthesized in the liver associates with <a href="/facts/High-density_lipoprotein/x7cs1ys9">HDL</a> which can then distribute it to newly formed <a href="/facts/VLDL/uoQTgwX4">VLDL</a> or <a href="/facts/Chylomicron/YPkGLpI6">chylomicron</a> particles to facilitate their eventual uptake by the liver. </p><p>In the nervous system, non-neuronal cell types, most notably <a href="/facts/Astrocyte/PBUuHKzS">astroglia</a> and <a href="/facts/Microglia/fU9dhL72">microglia</a>, are the primary producers of APOE, while neurons preferentially express the receptors for APOE.<a class="footnote-ref" id="fnref:69" href="#fn:69"><sup>69</sup></a> There are seven currently identified mammalian <a href="/facts/Receptor_(biochemistry)/tjTAC76a">receptors</a> for APOE which belong to the evolutionarily conserved LDLR family.<a class="footnote-ref" id="fnref:70" href="#fn:70"><sup>70</sup></a> </p><p>APOE was initially recognized for its importance in lipoprotein <a href="/facts/Metabolism/WxDrm8k5">metabolism</a> and <a href="/facts/Cardiovascular_disease/HD420nMv">cardiovascular disease</a>. Defects in APOE result in <a href="/facts/Familial_dysbetalipoproteinemia/dNgWszEr">familial dysbetalipoproteinemia</a> aka type III <a href="/facts/Hyperlipoproteinemia/3QNcXN9l">hyperlipoproteinemia</a> (HLP III), in which increased plasma <a href="/facts/Cholesterol/TnfPlYc1">cholesterol</a> and triglycerides are the consequence of impaired clearance of <a href="/facts/Chylomicron/YPkGLpI6">chylomicron</a>, <a href="/facts/VLDL/uoQTgwX4">VLDL</a> and <a href="/facts/LDL/R5VLPxAg">LDL</a>.<a class="footnote-ref" id="fnref:71" href="#fn:71"><sup>71</sup></a><a class="footnote-ref" id="fnref:72" href="#fn:72"><sup>72</sup></a> More recently, it has been studied for its role in several biological processes not directly related to lipoprotein transport, including Alzheimer's disease (AD), <a href="/facts/Immune_system/HRCTf1pb">immunoregulation</a>, and <a href="/facts/Cognition/ga0tSBul">cognition</a>.<a class="footnote-ref" id="fnref:73" href="#fn:73"><sup>73</sup></a> Though the exact mechanisms remain to be elucidated, isoform 4 of APOE, encoded by an APOE allele, has been associated with increased calcium ion levels and apoptosis following mechanical injury.<a class="footnote-ref" id="fnref:74" href="#fn:74"><sup>74</sup></a> </p><p>In the field of immune regulation, a growing number of studies point to APOE's interaction with many immunological processes, including suppressing <a href="/facts/T_cell/5z6PQ9UN">T cell</a> proliferation, <a href="/facts/Macrophage/z7hkQu3o">macrophage</a> functioning regulation, lipid antigen presentation facilitation (by <a href="/facts/CD1/azbcKmxT">CD1</a>)<a class="footnote-ref" id="fnref:75" href="#fn:75"><sup>75</sup></a> to <a href="/facts/Natural_Killer_T_cell/fokQzmL3">natural killer T cell</a> as well as modulation of <a href="/facts/Inflammation/Ura86MIy">inflammation</a> and <a href="/facts/Oxidation/Pyd5RVcj">oxidation</a>.<a class="footnote-ref" id="fnref:76" href="#fn:76"><sup>76</sup></a> APOE is produced by macrophages and APOE secretion has been shown to be restricted to classical monocytes in PBMC, and the secretion of APOE by monocytes is down regulated by inflammatory cytokines and upregulated by TGF-beta.<a class="footnote-ref" id="fnref:77" href="#fn:77"><sup>77</sup></a> </p> <h2 id="clinical-significance">Clinical significance</h2> <h3>Alzheimer's disease</h3> <p>As of 2012, the E4 variant was the largest known genetic risk factor for late-onset sporadic <a href="/facts/Alzheimer%27s_disease/w7Ad6tdg">Alzheimer's disease</a> (AD) in a variety of ethnic groups.<a class="footnote-ref" id="fnref:78" href="#fn:78"><sup>78</sup></a> However, the E4 variant does not correlate with risk in every population. Nigerian people have the highest observed frequency of the <i>APOE4</i> allele in world populations,<a class="footnote-ref" id="fnref:79" href="#fn:79"><sup>79</sup></a> but AD is rare among them.<a class="footnote-ref" id="fnref:80" href="#fn:80"><sup>80</sup></a><a class="footnote-ref" id="fnref:81" href="#fn:81"><sup>81</sup></a> This may be due to their low cholesterol levels.<a class="footnote-ref" id="fnref:82" href="#fn:82"><sup>82</sup></a><a class="footnote-ref" id="fnref:83" href="#fn:83"><sup>83</sup></a><a class="footnote-ref" id="fnref:84" href="#fn:84"><sup>84</sup></a><a class="footnote-ref" id="fnref:85" href="#fn:85"><sup>85</sup></a> Caucasian and Japanese carriers of two E4 alleles have between 10 and 30 times the risk of developing AD by 75 years of age, as compared to those not carrying any E4 alleles. This may be caused by an interaction with <a href="/facts/Amyloid/IjBcvNvV">amyloid</a>.<a class="footnote-ref" id="fnref:86" href="#fn:86"><sup>86</sup></a> Alzheimer's disease is characterized by build-ups of aggregates of the <a href="/facts/Peptide/C4ltc7UG">peptide</a> <a href="/facts/Beta-amyloid/QkXy91f9">beta-amyloid</a>. Apolipoprotein E enhances <a href="/facts/Proteolytic/GtQdv6J7">proteolytic</a> break-down of this peptide, both within and between cells. The <a href="/facts/Isoform/oWmzfg4l">isoform</a> APOE-ε4 is not as effective as the others at promoting these reactions, resulting in increased vulnerability to AD in individuals with that gene variation.<a class="footnote-ref" id="fnref:87" href="#fn:87"><sup>87</sup></a> </p><p>Recently, the amyloid hypothesis of Alzheimer's disease has been questioned, and an article in <i><a href="/facts/Science_(journal)/uTyzjkwD">Science</a></i> claimed that "Just as removing smoke does not extinguish a fire, reducing amyloid plaques may not affect the course of Alzheimer's disease."<a class="footnote-ref" id="fnref:88" href="#fn:88"><sup>88</sup></a> The role that the E4 variant carries can still be fully explained even in the absence of a valid amyloid hypothesis given the fact that <a href="/facts/Reelin/PzkFDjn2">reelin</a> signaling emerges to be one of the key processes involved in Alzheimer's disease<a class="footnote-ref" id="fnref:89" href="#fn:89"><sup>89</sup></a> and the E4 variant is shown to interact with <a href="/facts/ApoER2/xmCkNnHw">ApoER2</a>, one of the neuronal reelin receptors, thereby obstructing reelin signaling.<a class="footnote-ref" id="fnref:90" href="#fn:90"><sup>90</sup></a> </p><p>Although 40–65% of AD patients have at least one copy of the ε4 allele, <i>APOE4</i> is not a determinant of the disease. At least one-third of patients with AD are <i>APOE4</i> negative and some <i>APOE4</i> homozygotes never develop the disease. Yet those with two ε4 alleles have up to 20 times the risk of developing AD.<a class="footnote-ref" id="fnref:91" href="#fn:91"><sup>91</sup></a> There is also evidence that the <i>APOE2</i> allele may serve a protective role in AD.<a class="footnote-ref" id="fnref:92" href="#fn:92"><sup>92</sup></a> Thus, the genotype most at risk for Alzheimer's disease and at an earlier age is APOE4,4. Using genotype APOE3,3 as a benchmark (with the persons who have this genotype regarded as having a risk level of 1.0) and for white populations only, individuals with genotype APOE4,4 have an <a href="/facts/Odds_ratio/7WcmubfN">odds ratio</a> of 14.9 of developing Alzheimer's disease. Individuals with the APOE3,4 genotype face an odds ratio of 3.2, and people with a copy of the 2 allele and the 4 allele (APOE2,4), have an odds ratio of 2.6. Persons with one copy each of the 2 allele and the 3 allele (APOE2,3) have an odds ratio of 0.6. Persons with two copies of the 2 allele (APOE2,2) also have an odds ratio of 0.6.<a class="footnote-ref" id="fnref:93" href="#fn:93"><sup>93</sup></a> </p> <table><tbody><tr><td colspan="5">Estimated worldwide human allele frequencies of APOE in Caucasian population<a class="footnote-ref" id="fnref:94" href="#fn:94"><sup>94</sup></a></td></tr><tr><th>Allele</th><th>ε2</th><th>ε3</th><th>ε4</th></tr><tr><td>General frequency</td><td>8.4%</td><td>77.9%</td><td>13.7%</td></tr><tr><td>AD frequency</td><td>3.9%</td><td>59.4%</td><td>36.7%</td></tr></tbody></table> <p>While ApoE4 has been found to greatly increase the odds that an individual will develop Alzheimer's, a 2002 study concluded, that in persons with any combination of APOE alleles, high serum total cholesterol and high blood pressure in mid-life are independent risk factors which together can nearly triple the risk that the individual will later develop AD.<a class="footnote-ref" id="fnref:95" href="#fn:95"><sup>95</sup></a> Projecting from their data, some researchers have suggested that lowering serum cholesterol levels may reduce a person's risk for Alzheimer's disease, even if they have two ApoE4 alleles, thus reducing the risk from nine or ten times the odds of getting AD down to just two times the odds.<a class="footnote-ref" id="fnref:96" href="#fn:96"><sup>96</sup></a> </p><p>Women are more likely to develop AD than men across most ages and APOE genotypes. Premorbid women with the ε4 allele have significantly more neurological dysfunction than men.<a class="footnote-ref" id="fnref:97" href="#fn:97"><sup>97</sup></a> </p><p><i>APOE-ε4</i> increases the risk not only for AD but also for dementia in pure alpha-synucleinopathies.<a class="footnote-ref" id="fnref:98" href="#fn:98"><sup>98</sup></a> The influence of <i>APOE</i>-ε4 on hippocampal atrophy was suggested to be more predominant early in the course of AD at milder stages prior to more widespread neurodegeneration.<a class="footnote-ref" id="fnref:99" href="#fn:99"><sup>99</sup></a> </p><p>With the approval of the first disease-modifying therapies for Alzheimer's disease based on monoclonal antibodies against amyloid-beta, which delay disease progression, APOE genotyping has also become important in assessing a patient’s risk of side effects under therapy. In November 2024, the <a href="/facts/Committee_for_Medicinal_Products_for_Human_Use/yCkJTISe">Committee for Medicinal Products for Human Use</a> of the <a href="/facts/European_Medicines_Agency/h9FTtCYc">European Medicines Agency</a> following a re-examination procedure, adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Leqembi, intended for the treatment of early Alzheimer's disease in apolipoprotein E ε4 (ApoE ε4) non-carriers or heterozygotes.<a class="footnote-ref" id="fnref:100" href="#fn:100"><sup>100</sup></a><a class="footnote-ref" id="fnref:101" href="#fn:101"><sup>101</sup></a> The applicant for this medicinal product is Eisai GmbH.<a class="footnote-ref" id="fnref:102" href="#fn:102"><sup>102</sup></a> </p> <h3>Atherosclerosis</h3> <p><a href="/facts/Knockout_mouse/Aw50cobf">Knockout mice</a> that lack the apolipoprotein-E gene (APOE−/−) develop extreme <a href="/facts/Hypercholesterolemia/UlIDdQuT">hypercholesterolemia</a> when fed a high-fat diet.<a class="footnote-ref" id="fnref:103" href="#fn:103"><sup>103</sup></a> </p> <h3>Malaria</h3> <p>APOE−/− knockout mice show marked attenuation of cerebral <a href="/facts/Malaria/rN3g58CX">malaria</a> and increased survival, as well as decreased sequestration of parasites and T cells within the brain, likely due to protection of the <a href="/facts/Blood%E2%80%93brain_barrier/xYzvVwdu">blood–brain barrier</a>.<a class="footnote-ref" id="fnref:104" href="#fn:104"><sup>104</sup></a> Human studies have shown that the APOE2 polymorphism correlates with earlier infection, and APOE3/4 polymorphisms increase likelihood of severe malaria.<a class="footnote-ref" id="fnref:105" href="#fn:105"><sup>105</sup></a> </p> <h3>Lyme disease</h3> <p><i><a href="/facts/Borrelia_burgdorferi/sSvh5CyA">Borrelia burgdorferi</a></i>, the causative agent of <a href="/facts/Lyme_disease/820IycaC">Lyme disease</a>, is a host-adapted pathogen that acquires environmental cholesterol to form glycolipids for use in cell membrane maintenance. In one <a href="https://pubmed.ncbi.nlm.nih.gov/25870274/">experiment</a> in 2015, mice engineered with apoE deficiency were infected with <i>Borrelia</i> spirochetes. The knockout mice suffered from an increased spirochete burden in joints, as well as inflamed ankles, when compared with wild-type mice. This study suggests that apoE deficiency (and potentially other hyperlipidemias) may be a risk factor in the pathogenicity of Lyme disease. </p> <h2 id="interactions">Interactions</h2> <h3>Interactive pathway map</h3> <p><i>Click on genes, proteins and metabolites below to link to respective articles.</i> <a class="footnote-ref" id="fnref:106" href="#fn:106"><sup>106</sup></a> </p> <h2 id="further-reading">Further reading</h2> <ul><li>Ashford JW (2004). "APOE genotype effects on Alzheimer's disease onset and epidemiology". <i>Journal of Molecular Neuroscience</i>. 23 (3): 157–165. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1385%2FJMN%3A23%3A3%3A157">10.1385/JMN:23:3:157</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/15181244">15181244</a>. <a href="/facts/S2CID_(identifier)/ldJsHa2Y">S2CID</a> <a href="https://api.semanticscholar.org/CorpusID:14864342">14864342</a>.</li> <li>Beffert U, Danik M, Krzywkowski P, Ramassamy C, Berrada F, Poirier J (July 1998). "The neurobiology of apolipoproteins and their receptors in the CNS and Alzheimer's disease". <i>Brain Research. Brain Research Reviews</i>. 27 (2): 119–142. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1016%2FS0165-0173%2898%2900008-3">10.1016/S0165-0173(98)00008-3</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/9622609">9622609</a>. <a href="/facts/S2CID_(identifier)/ldJsHa2Y">S2CID</a> <a href="https://api.semanticscholar.org/CorpusID:28731779">28731779</a>.</li> <li>Bennet AM, Di Angelantonio E, Ye Z, Wensley F, Dahlin A, Ahlbom A, et al. (September 2007). "Association of apolipoprotein E genotypes with lipid levels and coronary risk". <i>JAMA</i>. 298 (11): 1300–1311. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1001%2Fjama.298.11.1300">10.1001/jama.298.11.1300</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/17878422">17878422</a>.</li> <li>Bocksch L, Stephens T, Lucas A, Singh B (December 2001). "Apolipoprotein E: possible therapeutic target for atherosclerosis". <i>Current Drug Targets. Cardiovascular & Hematological Disorders</i>. 1 (2): 93–106. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.2174%2F1568006013337944">10.2174/1568006013337944</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/12769659">12769659</a>.</li> <li>de Knijff P, van den Maagdenberg AM, Frants RR, Havekes LM (1995). <a href="https://doi.org/10.1002%2Fhumu.1380040303">"Genetic heterogeneity of apolipoprotein E and its influence on plasma lipid and lipoprotein levels"</a>. <i>Human Mutation</i>. 4 (3): 178–194. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1002%2Fhumu.1380040303">10.1002/humu.1380040303</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/7833947">7833947</a>. <a href="/facts/S2CID_(identifier)/ldJsHa2Y">S2CID</a> <a href="https://api.semanticscholar.org/CorpusID:41959843">41959843</a>.</li> <li>Gunzburg MJ, Perugini MA, Howlett GJ (December 2007). <a href="https://doi.org/10.1074%2Fjbc.M706425200">"Structural basis for the recognition and cross-linking of amyloid fibrils by human apolipoprotein E"</a>. <i>The Journal of Biological Chemistry</i>. 282 (49): 35831–35841. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1074%2Fjbc.M706425200">10.1074/jbc.M706425200</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/17916554">17916554</a>.</li> <li>Huang Y, Weisgraber KH, Mucke L, Mahley RW (2004). "Apolipoprotein E: diversity of cellular origins, structural and biophysical properties, and effects in Alzheimer's disease". <i>Journal of Molecular Neuroscience</i>. 23 (3): 189–204. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1385%2FJMN%3A23%3A3%3A189">10.1385/JMN:23:3:189</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/15181247">15181247</a>. <a href="/facts/S2CID_(identifier)/ldJsHa2Y">S2CID</a> <a href="https://api.semanticscholar.org/CorpusID:40135107">40135107</a>.</li> <li>Itzhaki RF, Dobson CB, Shipley SJ, Wozniak MA (June 2004). "The role of viruses and of APOE in dementia". <i>Annals of the New York Academy of Sciences</i>. 1019 (1): 15–18. <a href="/facts/Bibcode_(identifier)/9HtdQSGB">Bibcode</a>:<a href="https://ui.adsabs.harvard.edu/abs/2004NYASA1019...15I">2004NYASA1019...15I</a>. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1196%2Fannals.1297.003">10.1196/annals.1297.003</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/15246985">15246985</a>. <a href="/facts/S2CID_(identifier)/ldJsHa2Y">S2CID</a> <a href="https://api.semanticscholar.org/CorpusID:28979273">28979273</a>.</li> <li>Kolbe D, da Silva NA, Dose J, Torres GG, Caliebe A, Krause-Kyora B, et al. (May 2023). <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10186601">"Current allele distribution of the human longevity gene APOE in Europe can mainly be explained by ancient admixture"</a>. <i>Aging Cell</i>. 22 (5). 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Reproduction is authorized provided the source is acknowledged. <a href="https://www.ema.europa.eu/en/news/leqembi-recommended-treatment-early-alzheimers-disease" target="_blank">https://www.ema.europa.eu/en/news/leqembi-recommended-treatment-early-alzheimers-disease</a> <a href="#fnref:102" class="footnote-back-ref">↩</a></p></li> <li id="fn:103"><p>McNeill E, Channon KM, Greaves DR (March 2010). "Inflammatory cell recruitment in cardiovascular disease: murine models and potential clinical applications". Clinical Science. 118 (11): 641–655. doi:10.1042/CS20090488. PMID 20210786. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:103" class="footnote-back-ref">↩</a></p></li> <li id="fn:104"><p>Kassa FA, Van Den Ham K, Rainone A, Fournier S, Boilard E, Olivier M (September 2016). "Absence of apolipoprotein E protects mice from cerebral malaria". Scientific Reports. 6: 33615. Bibcode:2016NatSR...633615K. doi:10.1038/srep33615. PMC 5028887. 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