A Protective Genetic Mutation against Alzheimer's Disease: APOE Christchurch Variant; a Potential Advancement in Alzheimer's through Gene Therapy.
DOI:
https://doi.org/10.58445/rars.4091Keywords:
Alzheimer's Disease, Gene therapy, APOE, ChristchurchAbstract
Alzheimer's disease (AD) is a progressive neurodegenerative disease with genetic, biological and environmental factors playing a role in its development. The accumulation of amyloid-beta (Aβ), for a long time considered one of the most important aspects of AD, has been associated with several other pathways that are presented in individuals with the rare variant of APOE3 Christchurch, such as tau pathology and neuroinflammation. This paper looks at the Christchurch variant and how it may give some resistance to cognitive decline in people with high genetic indices to AD and its possible application in gene therapy. A study of families in Colombia with PSEN1 E280A mutation found that a person, who had two copies of Christchurch, remained cognitively preserved for decades after significant accumulation of amyloid. Additional analysis indicates that Christchurch likely regulates the binding of apolipoprotein E to heparan sulfate proteoglycans and thus restricts the cellular uptake and distribution of tau. Recent experimental studies have explored gene delivery strategies that recapitulate the protective properties of Christchurch such as liver-directed AAV and astrocyte-based protein expression. This has been proven successful for the reduction of amyloid pathology, neuroinflammation and neurodegeneration in animal models. But studies within humans are currently ongoing as clinical trials recently started. In conclusion, the Christchurch variant offers a valuable model to explore genetic protection against AD and may be incorporated in future AD therapies that aim to change rather than simply treating AD symptoms.
References
Arboleda-Velasquez, J. F., Lopera, F., O’Hare, M., Delgado-Tirado, S., Marino, C., Chmielewska, N., Saez-Torres, K. L., Amarnani, D., Schultz, A. P., Sperling, R. A., Leyton-Cifuentes, D., Chen, K., Baena, A., Aguillon, D., Rios-Romenets, S., Giraldo, M., Guzmán-Vélez, E., Norton, D. J., Pardilla-Delgado, E., … Quiroz, Y. T. (2019). Resistance to autosomal dominant Alzheimer’s disease in an APOE3 Christchurch homozygote: A case report. Nature Medicine, 25(11), 1680–1683. https://doi.org/10.1038/s41591-019-0611-3
Chen, Y., & Holtzman, D. M. (2024). New insights into innate immunity in Alzheimer’s disease: From APOE protective variants to therapies. Trends in Immunology, 45(10), 768–782. https://doi.org/10.1016/j.it.2024.08.001
Cruddas, J., Pang, J. C., & Fornito, A. (2026). Cortical traveling waves in time and space: Physics, physiology, and psychology. Neuron, 114(6), 985–1005. https://doi.org/10.1016/j.neuron.2025.12.019
Halim, D. O., Di Biase, E., Rajon, A., Luc, J., Hallett, P. J., & Isacson, O. (2026). APOE3 astrocytes can rescue lipid abnormalities and dystrophic neurites of APOE4 human neurons. PNAS Nexus, 5(3). https://doi.org/10.1093/pnasnexus/pgag053
Jack, C. R., Jr., Andrews, J. S., Beach, T. G., Buracchio, T., Dunn, B., Graf, C., Hansson, O., Ho, C., Ikonomovic, M. D., Kantarci, K., Kukull, W., Montine, T. J., Salloway, S., Sperling, R., Carrillo, M. C., & the Alzheimer’s Association Workgroup. (2024). Revised criteria for diagnosis and staging of Alzheimer’s disease: Alzheimer’s Association Workgroup. Alzheimer’s & Dementia, 20(8), 5143–5169. https://doi.org/10.1002/alz.13859
Jackson, R. J., Keiser, M. S., Meltzer, J. C., Fykstra, D. P., Dierksmeier, S. E., Soroush Hajizadeh, Kreuzer, J., Morris, R., Melloni, A., Nakajima, T., Tecedor, L., Ranum, P. T., Carrell, E., Chen, Y., Nishtar, M. A., Holtzman, D. M., Haas, W., Davidson, B. L., & Hyman, B. T. (2024). APOE2 gene therapy reduces amyloid deposition and improves markers of neuroinflammation and neurodegeneration in a mouse model of Alzheimer disease. Molecular Therapy. https://doi.org/10.1016/j.ymthe.2024.03.024
Raulin, A.-C., Alnobani, A., Rodriguez-Martinez, P., Lee, E., Linares, C., Yslas, A. R., Li, M., Ren, Y., Doss, S. V., Roy, B., Kuchenbecker, L. A., Martens, Y. A., Liu, C.-C., Bu, G., & Kanekiyo, T. (2026). Astrocytic APOE3-Christchurch expression ameliorates brain amyloid-β
pathology in 5xFAD mice. Translational Psychiatry, 16(1). https://doi.org/10.1038/s41398-026-04002-9
Rellin, L., Heeren, J., & Beisiegel, U. (2008). Recycling of apolipoprotein E is not associated with cholesterol efflux in neuronal cells. Biochimica et Biophysica Acta, 1781(5), 232–238. https://doi.org/10.1016/j.bbalip.2008.02.001
Sepulveda-Falla, D., Sanchez, J. S., Almeida, M. C., Boassa, D., Acosta-Uribe, J., Vila-Castelar, C., Ramirez-Gomez, L., Baena, A., Aguillon, D., Villalba-Moreno, N. D., Littau, J. L., Villegas, A., Beach, T. G., White, C. L., Ellisman, M., Krasemann, S., Glatzel, M., Johnson, K. A., Sperling, R. A., Reiman, E. M., Arboleda-Velasquez, J. F., Kosik, K. S., Lopera, F., & Quiroz, Y. T. (2022). Distinct tau neuropathology and cellular profiles of an APOE3 Christchurch homozygote protected against autosomal dominant Alzheimer’s dementia. Acta Neuropathologica, 144(3), 589–601. https://doi.org/10.1007/s00401-022-02467-8
Tang, J.-Y., Tan, Q., Yu, Z.-Y., Yuan, Z.-Y., Zeng, R., Liu, X.-Y., Zhu, X.-Y., Zhao, Y., Li, J.-H., Bai, Y.-D., Zeng, G.-H., Wang, C., & Wang, Y.-J. (2026). Hepatic expression of APOE3 Christchurch mitigates APOE4-related Alzheimer’s disease pathologies in mice. Neuron. https://doi.org/10.1016/j.neuron.2026.04.027
Teter, B., Campagna, J., Spilman, P., & John, V. (2025). APOE gene editing as a therapeutic target toward precision medicine in AD. In Precision medicine approaches to Alzheimer’s disease (pp. 1–26). https://doi.org/10.1007/978-3-031-52641-1_73
van Dyck, C. H., Swanson, C. J., Aisen, P., Bateman, R. J., Chen, C., Gee, M., Kanekiyo, M., Li, D., Reyderman, L., Cohen, S., Froelich, L., Katayama, S., Sabbagh, M., Vellas, B., Watson, D., Dhadda, S., Irizarry, M., Kramer, L. D., & Iwatsubo, T. (2023). Lecanemab in early Alzheimer’s disease. New England Journal of Medicine, 388(1), 9–21. https://doi.org/10.1056/NEJMoa2212948
Wang, K., & Bu, G. (2026). Alzheimer disease protection from the periphery. Nature Reviews Neurology, 22(6), 335–336. https://doi.org/10.1038/s41582-026-01211-0
Williams, D. M., Heikkinen, S., Hiltunen, M., FinnGen, Davies, N. M., & Anderson, E. L. (2026). The proportion of Alzheimer’s disease attributable to apolipoprotein E. NPJ Dementia, 2(1), 1. https://doi.org/10.1038/s44400-025-00045-9
Winter, J. (2026). Weill Cornell Medicine awarded grant for Alzheimer’s gene therapy research. Weill Cornell Medicine.
Wu, L., & Zhao, L. (2016). ApoE2 and Alzheimer’s disease: Time to take a closer look. Neural Regeneration Research, 11(3), 412–413. https://doi.org/10.4103/1673-5374.179044
Zhang, J., Zhang, Y., Wang, J., Xia, Y., Zhang, J., & Chen, L. (2024). Recent advances in Alzheimer’s disease: Mechanisms, clinical trials and new drug development strategies. Signal Transduction and Targeted Therapy, 9(1). https://doi.org/10.1038/s41392-024-01911-3
Zvěřová, M. (2019). Clinical aspects of Alzheimer’s disease. Clinical Biochemistry, 72, 3–6. https://doi.org/10.1016/j.clinbiochem.2019.04.015
Downloads
Posted
Categories
License
Copyright (c) 2026 Research Archive of Rising Scholars
This work is licensed under a Creative Commons Attribution 4.0 International License.
