APOE Loss of Function Variants

Mutation Clinical
Phenotype Studied		 DNA Change Expected RNA | Protein Consequence Coding/Non-Coding Genomic Region Biological Effect Primary
Papers
APOE g.45408560_45410359del
(DEL 19:44905303-44907102)		 Alzheimer's Disease Deletion Deletion | Deletion Both Promoter, Exon 1, Exon 2

Predicted to eliminate APOE expression.

 Chemparathy et al., 2024
APOE W5Ter
(p.W5*, p.Thr5*)		 Alzheimer's Disease, Blood Lipids/Lipoproteins Substitution Substitution | Nonsense Coding Exon 2

Predicted to abrogate production of ApoE as it introduces a stop codon in the signal peptide. PHRED-scaled CADD = 35.

 Leren et al., 2016
APOE L8Ter
(p.L8*)		 Alzheimer's Disease Substitution Substitution | Nonsense Coding Exon 2

Predicted to eliminate functional ApoE expression. 

 Chemparathy et al., 2024
APOE E27fs (E9fs)
Blood Lipids/Lipoproteins, Kidney Disorder: Nephrotic Syndrome Deletion Deletion | Frame Shift Coding Exon 3

Unknown, predicted to be degraded by nonsense-mediated mRNA decay.
APOE Q39Ter (Q21Ter)
(p.Q39*)		 Alzheimer's Disease Substitution Substitution | Nonsense Coding Exon 3

Predicted to eliminate functional APOE expression.

 Chemparathy et al., 2024
APOE G49fs (G31fs)
Hyperlipoproteinemia Type III Deletion Deletion | Frame Shift Coding Exon 3

Eliminates protein, likely by nonsense-mediated decay of mRNA.

 Feussner et al., 1992
APOE c.237-1A>G
(3592 A>G)		 Blood Lipids/Lipoproteins, Hyperlipoproteinemia Type III Substitution Splicing Alteration | Non-Coding intron 3

Disrupted splicing resulting in near abrogation of ApoE expression.

 Ghiselli et al., 1981;
Cladaras et al., 1987
APOE E84Ter (E66Ter)
(p.E84*)		 Progressive Supranuclear Palsy Substitution Substitution | Nonsense Coding Exon 4

Predicted to abrogate ApoE full-length synthesis introducing an early stop codon.

 Chemparathy et al., 2024
APOE E98fs (E80fs)
(E97fs)		 Alzheimer's Disease, Cardiovascular Disease, Hyperlipoproteinemia Type III Deletion Deletion | Frame Shift Coding Exon 4

Eliminates expression of ApoE protein.

 Mak et al., 2014
APOE E114fs (E96fs)
(ApoE3 Groningen)		 Hyperlipoproteinemia Type III Insertion Insertion | Frame Shift Coding Exon 4

Predicted to result in a truncated ApoE species or in elimination of its production.

 Dijck-Brouwer et al., 2005
APOE R154fs (R136fs)
(ApoE Australia, ApoE0)		 Hyperlipoproteinemia Type III Deletion Deletion | Frame Shift Coding Exon 4

Absence of ApoE, at least in VLDL lipoprotein.

 Tate et al., 2001
APOE A227_E230del (A209_E212del)
Blood Lipids/Lipoproteins, Cardiovascular Disease, Hyperlipoproteinemia Type III Deletion Deletion | Frame Shift Coding Exon 4

Predicted to cause a frameshift introducing a stop codon at amino acid 247. In homozygous form, resulted in near elimination of ApoE protein.

 Feussner et al., 1996
APOE W228Ter (W210Ter)
(ApoE3 Washington)		 Alzheimer's Disease, Blood Lipids/Lipoproteins, Hyperlipoproteinemia Type III Substitution Substitution | Nonsense Coding Exon 4

Generated a truncated protein and, in homozygous form, nearly eliminated ApoE from plasma. In cells, decreased ApoE production and secretion by ~2/3. Lipoprotein and lipid profiles in blood indicated a reduction in hepatic removal of remnant lipoprotein particles.

 Lohse et al., 1992

APOE loss-of-function (LoF) variants are of particular interest to the Alzheimer’s disease field. They shed light on the effects of reducing ApoE levels, and provide insight into the mechanisms by which other APOE genetic variants, such as the major AD risk factor C103R (APOE4), mediate their effects (see e.g. Belloy et al., 2019). Indeed, LoF variants have lent support to the toxic gain-of-function hypothesis for APOE4, a finding critical for the development of AD therapeutic strategies targeting this harmful allele.

Under physiological conditions, ApoE is produced and secreted primarily by astrocytes and activated microglia, and expressed at low levels in neurons. It plays key roles in metabolizing and transporting lipids to neurons, and facilitates synaptogenesis, axonal regeneration, as well as neural stem cell maintenance and differentiation (for reviews see Koutsodendris et al., 2021; Raulin et al., 2022).

Despite these important functions, multiple studies suggest that partial loss of ApoE is tolerated (Vance et al., 2024). Of particular note, the cognitive health of several aged, heterozygous carriers of LoF variants indicated a 50 percent loss is benign and likely protective when in phase with APOE4 (Chemparathy et al., 2024; Aug 2023 news). Two carriers of the LoF variant W5Ter, for example, were individuals with APOE3/E4 genotypes who carried W5Ter in phase with the APOE4 allele and remained cognitively healthy with minimal neuropathology until old age, one until age 90. 

Biological Effects

In mice, multiple studies have found that reducing or eliminating ApoE in models of amyloid deposition reduces amyloid accumulation (e.g., Kim et al., 2011, Bien-Ly et al., 2012, Huynh et al., 2017, Fernandez et al., 2022). However, the effects of ApoE deficiency appear to vary across cell types. Selective reduction of astrocytic ApoE, for example, reduced Aβ accumulation and plaque-related pathology (Mahan et al., 2022), while microglial ApoE loss attenuated the microglial activation required for responding to amyloid and tau pathology (Ulrich et al., 2018, Shi et al., 2017). Indeed, ApoE appears to be critical for the emergence of disease-associated microglia (DAM) (June 2017 news; Sep 2017 news). Moreover, ApoE deficiency has been associated with alterations in mouse neuronal development, inhibiting axon growth stimulated by astroglial exosomes and reducing cortical spine density (Jin et al., 2023).

Knocking out APOE in endothelial cells, on the other hand, has been associated with neurovascular dysfunction (Marottoli et al., 2023) and a proteomic signature tied to accelerated aging (Todorov-Völgyi et al., 2024). Also, systemic ApoE deficiency was reported to aggravate blood-brain barrier disruption in a mouse model of ischemic stroke (Leng et al., 2024). 

Studies in human cells have also revealed different effects of ApoE loss across cell-types. Interestingly, in human microglia transplanted into a mouse model of amyloid pathology, knocking out ApoE had little impact on DAM, but interfered with the transition from DAM to a microglial phenotype likely related to antigen presentation in response to amyloid plaques—the human leukocyte antigen (HLA) state (Mancuso et al., 2024). In the same model system, ApoE knockout microglia showed similar epigenetic and gene expression changes as ApoE4 microglia, both downregulating the mitochondrial gene CHCHD2, as well as ostensibly protective genes that harbor genetic variants associated with AD risk (Murphy et al., 2024; Aug 2024 conference news).

Moreover, in cerebral organoids derived from human induced pluripotent stem cells (iPSCs), APOE deficiency resulted in altered neural differentiation and cholesterol biosynthesis (Zhao et al., 2023). Another study reported deletion of APOE in human mesenchymal progenitor cells conferred resistance to cellular senescence, possibly due to abrogating ApoE-mediated heterochromatin destabilization (Zhao et al., 2022). Although a study using iPSC-derived neurons showed ApoE-null cells had similar phenotypes as cells expressing ApoE3, including tau phosphorylation, Aβ production, and GABAergic neuron degeneration  (Wang et al., 2018), a study in which ApoE-null iPSC neurons were transplanted into hippocampi of APOE4 knockin mice found that the transplanted cells induced amyloid plaques with a more diffuse morphology than APOE-expressing neurons, suggestive of a more benign phenotype (Rao et al., 2024). 

The non-neurological effects of ApoE loss have been studied extensively in the context of atherosclerosis. Developed in 1992, APOE knockout mice are one of the most widely used preclinical models of this disease (see e.g., Getz et al., 2016; Oppi et al., 2019; Xiang et al., 2024).

Last Updated: 06 Nov 2024

References

Mutations Citations

  1. APOE C130R (ApoE4)
  2. APOE W5Ter

News Citations

  1. Goodbye, APOE4. Hello, Healthy Brain?
  2. Hot DAM: Specific Microglia Engulf Plaques
  3. ApoE and Trem2 Flip a Microglial Switch in Neurodegenerative Disease
  4. Microglial Epigenetics Hints at How ApoE Toggles Alzheimer’s Risk

Paper Citations

  1. Belloy ME, Napolioni V, Greicius MD. A Quarter Century of APOE and Alzheimer's Disease: Progress to Date and the Path Forward. Neuron. 2019 Mar 6;101(5):820-838. PubMed.
  2. Koutsodendris N, Nelson MR, Rao A, Huang Y. Apolipoprotein E and Alzheimer's Disease: Findings, Hypotheses, and Potential Mechanisms. Annu Rev Pathol. 2022 Jan 24;17:73-99. Epub 2021 Aug 30 PubMed.
  3. Raulin AC, Martens YA, Bu G. Lipoproteins in the Central Nervous System: From Biology to Pathobiology. Annu Rev Biochem. 2022 Jun 21;91:731-759. Epub 2022 Mar 18 PubMed.
  4. 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.
  5. Chemparathy A, Le Guen Y, Chen S, Lee EG, Leong L, Gorzynski JE, Jensen TD, Ferrasse A, Xu G, Xiang H, Belloy ME, Kasireddy N, Peña-Tauber A, Williams K, Stewart I, Talozzi L, Wingo TS, Lah JJ, Jayadev S, Hales CM, Peskind E, Child DD, Roeber S, Keene CD, Cong L, Ashley EA, Yu CE, Greicius MD. APOE loss-of-function variants: Compatible with longevity and associated with resistance to Alzheimer's disease pathology. Neuron. 2024 Apr 3;112(7):1110-1116.e5. Epub 2024 Jan 31 PubMed.
  6. Kim J, Jiang H, Park S, Eltorai AE, Stewart FR, Yoon H, Basak JM, Finn MB, Holtzman DM. Haploinsufficiency of human APOE reduces amyloid deposition in a mouse model of amyloid-β amyloidosis. J Neurosci. 2011 Dec 7;31(49):18007-12. PubMed.
  7. Bien-Ly N, Gillespie AK, Walker D, Yoon SY, Huang Y. Reducing human apolipoprotein E levels attenuates age-dependent Aβ accumulation in mutant human amyloid precursor protein transgenic mice. J Neurosci. 2012 Apr 4;32(14):4803-11. PubMed.
  8. Huynh TV, Liao F, Francis CM, Robinson GO, Serrano JR, Jiang H, Roh J, Finn MB, Sullivan PM, Esparza TJ, Stewart FR, Mahan TE, Ulrich JD, Cole T, Holtzman DM. Age-Dependent Effects of apoE Reduction Using Antisense Oligonucleotides in a Model of β-amyloidosis. Neuron. 2017 Dec 6;96(5):1013-1023.e4. PubMed.
  9. Fernandez A, Gomez MT, Vidal R. Lack of ApoE inhibits ADan amyloidosis in a mouse model of familial Danish dementia. J Biol Chem. 2023 Jan;299(1):102751. Epub 2022 Nov 25 PubMed.
  10. Mahan TE, Wang C, Bao X, Choudhury A, Ulrich JD, Holtzman DM. Selective reduction of astrocyte apoE3 and apoE4 strongly reduces Aβ accumulation and plaque-related pathology in a mouse model of amyloidosis. Mol Neurodegener. 2022 Feb 2;17(1):13. PubMed.
  11. Ulrich JD, Ulland TK, Mahan TE, Nyström S, Nilsson KP, Song WM, Zhou Y, Reinartz M, Choi S, Jiang H, Stewart FR, Anderson E, Wang Y, Colonna M, Holtzman DM. ApoE facilitates the microglial response to amyloid plaque pathology. J Exp Med. 2018 Apr 2;215(4):1047-1058. Epub 2018 Feb 26 PubMed.
  12. Shi Y, Yamada K, Liddelow SA, Smith ST, Zhao L, Luo W, Tsai RM, Spina S, Grinberg LT, Rojas JC, Gallardo G, Wang K, Roh J, Robinson G, Finn MB, Jiang H, Sullivan PM, Baufeld C, Wood MW, Sutphen C, McCue L, Xiong C, Del-Aguila JL, Morris JC, Cruchaga C, Alzheimer’s Disease Neuroimaging Initiative, Fagan AM, Miller BL, Boxer AL, Seeley WW, Butovsky O, Barres BA, Paul SM, Holtzman DM. ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature. 2017 Sep 28;549(7673):523-527. Epub 2017 Sep 20 PubMed.
  13. Jin S, Chen X, Tian Y, Jarvis R, Promes V, Yang Y. Astroglial exosome HepaCAM signaling and ApoE antagonization coordinates early postnatal cortical pyramidal neuronal axon growth and dendritic spine formation. Nat Commun. 2023 Aug 24;14(1):5150. PubMed.
  14. Marottoli FM, Zhang H, Flores-Barrera E, de la Villarmois EA, Damen FC, Miguelez Fernández AM, Blesson HV, Chaudhary R, Nguyen AL, Nwokeji AE, Talati R, John AS, Madadakere K, Lutz SE, Cai K, Tseng KY, Tai LM. Endothelial Cell APOE3 Regulates Neurovascular, Neuronal, and Behavioral Function. Arterioscler Thromb Vasc Biol. 2023 Aug 31; PubMed.
  17. Mancuso R, Fattorelli N, Martinez-Muriana A, Davis E, Wolfs L, Van Den Daele J, Geric I, Premereur J, Polanco P, Bijnens B, Preman P, Serneels L, Poovathingal S, Balusu S, Verfaillie C, Fiers M, De Strooper B. Xenografted human microglia display diverse transcriptomic states in response to Alzheimer's disease-related amyloid-β pathology. Nat Neurosci. 2024 May;27(5):886-900. Epub 2024 Mar 27 PubMed.
  18. Murphy KB, Hu D, Wolfs L, Mancuso R, DeStrooper B, Marzi SJ. The APOE isoforms differentially shape the transcriptomic and epigenomic landscapes of human microglia in a xenotransplantation model of Alzheimer's disease. 2024 Jul 05 10.1101/2024.07.03.601874 (version 1) bioRxiv.
  19. Zhao J, Ikezu TC, Lu W, Macyczko JR, Li Y, Lewis-Tuffin LJ, Martens YA, Ren Y, Zhu Y, Asmann YW, Ertekin-Taner N, Kanekiyo T, Bu G. APOE deficiency impacts neural differentiation and cholesterol biosynthesis in human iPSC-derived cerebral organoids. Stem Cell Res Ther. 2023 Aug 21;14(1):214. PubMed.
  20. Zhao H, Ji Q, Wu Z, Wang S, Ren J, Yan K, Wang Z, Hu J, Chu Q, Hu H, Cai Y, Wang Q, Huang D, Ji Z, Li J, Belmonte JC, Song M, Zhang W, Qu J, Liu GH. Destabilizing heterochromatin by APOE mediates senescence. Nat Aging. 2022 Apr;2(4):303-316. Epub 2022 Mar 28 PubMed.
  21. Wang C, Najm R, Xu Q, Jeong DE, Walker D, Balestra ME, Yoon SY, Yuan H, Li G, Miller ZA, Miller BL, Malloy MJ, Huang Y. Gain of toxic apolipoprotein E4 effects in human iPSC-derived neurons is ameliorated by a small-molecule structure corrector. Nat Med. 2018 May;24(5):647-657. Epub 2018 Apr 9 PubMed.
  22. Rao A, Chen N, Kim MJ, Blumenfeld J, Yip O, Liang Z, Shostak D, Hao Y, Nelson MR, Koutsodendris N, Grone B, Ding L, Yoon SY, Arriola P, Zilberter M, Huang Y. Microglia depletion reduces human neuronal APOE4-related pathologies in a chimeric Alzheimer's disease model. Cell Stem Cell. 2024 Oct 30; Epub 2024 Oct 30 PubMed.
  23. Getz GS, Reardon CA. ApoE knockout and knockin mice: the history of their contribution to the understanding of atherogenesis. J Lipid Res. 2016 May;57(5):758-66. Epub 2016 Mar 25 PubMed.
  24. Oppi S, Lüscher TF, Stein S. Mouse Models for Atherosclerosis Research-Which Is My Line?. Front Cardiovasc Med. 2019;6:46. Epub 2019 Apr 12 PubMed.
  25. Xiang R, Wang Y, Shuey MM, Carvajal B, Wells QS, Beckman JA, Jaffe IZ. Development and Implementation of an Integrated Preclinical Atherosclerosis Database. Circ Genom Precis Med. 2024 Apr 2;:e004397. PubMed.

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