APOE targeting strategy in Alzheimer’s disease: lessons learned from protective variants
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Several rare and protective APOE variants (R154S Christchurch, V236E Jacksonville, and R251G) have been identified recently.
“Beyond the known effects of APOE ε2 and APOE ε4, several rare and protective APOE variants (R154S Christchurch (APOECh), V236E Jacksonville, and R251G) have been identified recently [3, 4].”
From Characterization of APOE Christchurch carriers in 455,306 UK Biobank participants (2023) · cites this paper as [3]
The main text identifies Christchurch, Jacksonville (V236E), and R251G as rare protective APOE variants. It labels the Christchurch mutation R136S, however, rather than the claimed R154S; our copy does not explain the difference in numbering. (LLM, conf=0.84)
Experimental — accuracy not yet measuredThe combination of rare variants and sufficiently large studies to determine their disease impact have potential to develop new avenues of drug development that target APOE.
“The combination of rare variants and sufficiently large studies to determine their disease impact have potential to develop new avenues of drug development that target APOE [23].”
From Discovery of a Missense Mutation (Q222K) of the <i>APOE</i> Gene from the Australian Imaging, Biomarker and Lifestyle Study (2023) · cites this paper as [23]
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Cites
<i>APOE3</i> -Jacksonville (V236E) variant reduces self-aggregation and risk of dementia
Liu, C.-C., Murray, M. E., Li, X., Zhao, N., Wang, N., Heckman, M. G., Shue, F., Martens, Y., Li, Y., Raulin, A.-C., et al. (2021) · Science Translational Medicine · doi:10.1126/scitranslmed.abc9375 · Cited by 108 · see citing works
Self-citationAssociation of Rare <i>APOE</i> Missense Variants V236E and R251G With Risk of Alzheimer Disease
Le Guen, Y., Belloy, M. E., Grenier-Boley, B., de Rojas, I., Castillo-Morales, A., Jansen, I., Nicolas, A., Bellenguez, C., Dalmasso, C., Küçükali, F., et al. (2022) · JAMA Neurology · doi:10.1001/jamaneurol.2022.1166 · Cited by 93 · see citing works
ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease
Li, Y., Macyczko, J. R., Liu, C.-C., & Bu, G. (2022) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2022.03.011 · Cited by 61 · see citing works
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Flagged first, then by citations
Research works printed but not linked: 12
- [1]Yamazaki Y Zhao N Caulfield TR Liu CC Bu G Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies Nat Rev Neurol 2019 15 9 501 518 10.1038/s41582-019-0228-7 31367008 PMC7055192 · DOI · Paper page
- [2]Li Z Shue F Zhao N Shinohara M Bu G APOE2: protective mechanism and therapeutic implications for Alzheimer's disease Mol Neurodegener 2020 15 1 63 10.1186/s13024-020-00413-4 33148290 PMC7640652 · DOI · Paper page
- [3]Guo T Zhang D Zeng Y Huang TY Xu H Zhao Y Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer's disease Mol Neurodegener 2020 15 1 40 10.1186/s13024-020-00391-7 32677986 PMC7364557 · DOI · Paper page
- [4]Martens YA Zhao N Liu CC Kanekiyo T Yang AJ Goate AM Holtzman DM Bu G ApoE Cascade hypothesis in the pathogenesis of Alzheimer's disease and related dementias Neuron 2022 110 8 1304 1317 10.1016/j.neuron.2022.03.004 35298921 PMC9035117 · DOI · Paper page
- [6]Shinohara M, Kanekiyo T, Yang L, Linthicum D, Fu Y, Price L, Frisch-Daiello JL, Han X, Fryer JD, Bu G. APOE2 eases cognitive decline during Aging: Clinical and preclinical evaluations. Ann Neurol. 2016;79(5):758-74. 10.1002/ana.24628. Epub 2016 Mar 29. PMC5010530 26933942 · DOI · Paper page
- [7]Shinohara M, Kanekiyo T, Tachibana M, Kurti A, Shinohara M, Fu Y, Zhao J, Han X, Sullivan PM, Rebeck GW, et al. APOE2 is associated with longevity independent of Alzheimer's disease. Elife. 2020;9:e62199. 10.7554/eLife.62199. PMC7588231 33074098 · DOI · Paper page
- [8]Wang T, Huynh K, Giles C, Mellett NA, Duong T, Nguyen A, Lim WLF, Smith AA, Olshansky G, Cadby G, et al. APOE ε2 resilience for Alzheimer's disease is mediated by plasma lipid species: Analysis of three independent cohort studies. Alzheimers Dement. 2022. 10.1002/alz.12538. Online ahead of print PMC9787288 35077012 · DOI
- [9]Zhao N Ren Y Yamazaki Y Qiao W Li F Felton LM Mahmoudiandehkordi S Kueider-Paisley A Sonoustoun B Arnold M Alzheimer's risk factors age, APOE genotype, and sex drive distinct molecular pathways Neuron 2020 106 5 727 742.e726 10.1016/j.neuron.2020.02.034 32199103 PMC7388065 · DOI · Paper page
- [10]Arboleda-Velasquez JF Lopera F O'Hare M Delgado-Tirado S Marino C Chmielewska N Saez-Torres KL Amarnani D Schultz AP Sperling RA Resistance to autosomal dominant Alzheimer's disease in an APOE3 Christchurch homozygote: a case report Nat Med 2019 25 11 1680 1683 10.1038/s41591-019-0611-3 31686034 PMC6898984 · DOI · Paper page
- [11]Medway CW, Abdul-Hay S, Mims T, Ma L, Bisceglio G, Zou F, Pankratz S, Sando SB, Aasly JO, Barcikowska M, et al. ApoE variant p.V236E is associated with markedly reduced risk of Alzheimer's disease. Mol Neurodegener. 2014;9:11. 10.1186/1750-1326-9-11. PMC3995879 24607147 · DOI · Paper page
- [13]Raulin AC Martens YA Bu G Lipoproteins in the central nervous system: from biology to pathobiology Annu Rev Biochem 2022 91 731 759 10.1146/annurev-biochem-032620-104801 35303786 PMC9634960 · DOI · Paper page
- [15]Chen J Li Q Wang J Topology of human apolipoprotein E3 uniquely regulates its diverse biological functions Proc Natl Acad Sci U S A 2011 108 36 14813 14818 10.1073/pnas.1106420108 21873229 PMC3169138 · DOI · Paper page
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Blood–Brain Barrier Breakdown in Alzheimer’s Disease: Mechanisms and Targeted Strategies
Alkhalifa, A. E., Al-Ghraiybah, N. F., Odum, J., Shunnarah, J. G., Austin, N., & Kaddoumi, A. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms242216288 · Cited by 212 · see citing works
APOE effects on regional tau in preclinical Alzheimer’s disease
Young, C. B., Johns, E., Kennedy, G., Belloy, M. E., Insel, P. S., Greicius, M. D., Sperling, R. A., Johnson, K. A., Poston, K. L., Mormino, E. C., et al. (2023) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00590-4 · Cited by 80 · see citing works
Current insights into apolipoprotein E and the immune response in Alzheimer's disease
Lin, P. B., & Holtzman, D. M. (2024) · Immunological Reviews · doi:10.1111/imr.13414 · Cited by 19 · see citing works
Characterization of APOE Christchurch carriers in 455,306 UK Biobank participants
He, K. Y., Khramtsova, E. A., Cabrera-Socorro, A., Zhang, Y., Li, S., Sarver, B. A. J., Smets, B., Li, Q. S., De Muynck, L., Parrado, A. R., et al. (2023) · Molecular Neurodegeneration · doi:10.1186/s13024-023-00684-7 · Cited by 8 · see citing works
Roberts, B. R., Laffoon, S. B., Roberts, A. M., Porter, T., Fowler, C., Masters, C. L., Dratz, E. A., Laws, S. M., & for the AIBL research group (2023) · Journal of Alzheimer's Disease Reports · doi:10.3233/adr-220075 · Cited by 2 · see citing works
- Authors
- Bu, G.
- Corresponding author
- Bu, Guojun
- ORCID
- Bu, Guojun
- Venue
- Molecular Neurodegeneration
- Published
- 2022-08-03
- Volume
- 17
- Issue
- 1
- Pages
- 51-51
- ISSN
- 1750-1326 (ISSN-L)
- PMC
- PMC9351235
- OpenAlex
- W4289549902
- Cited by
- 37
- References
- 3
- Citations by year
- 2026: 7 · 2025: 9 · 2024: 8 · 2023: 12 · 2022: 1
- FWCI
- 4.53
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Molecular Neurodegeneration (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
- Keywords
- apolipoprotein E, Alzheimer's disease, APOE ε4, treatment options
- MeSH terms
- Alzheimer Disease, Apolipoproteins E, Genotype, Humans, Apolipoprotein E4
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