Over the past three decades, genomic and epigenetic sciences have identified more than 70 genes involved in the molecular pathophysiology of Alzheimer’s disease (AD). DNA methylation, abnormal histone and chromatin regulation and the action of various miRNAs induce AD. The identification of mutated genes has paved the way for the development of diagnostic kits and the initiation of gene therapy trials. However, despite major advances in neuroscience research, there is yet no suitable treatment for AD. Therefore, the early diagnosis of this neurodegenerative disease raises several ethical questions, including the balance between the principle of non-maleficence and the principle of beneficence. The aims of this research were to present the genomic and ethical aspects of AD, and to highlight the ethical principles involved in its presymptomatic diagnosis and therapy. A systematic review of the literature in PubMed, Google Scholar and Science Direct was carried out to outline the genomic aspects and ethical principles relating not only to the presymptomatic diagnosis of AD, but also to its gene therapy. A total of 16 publications were selected. AD is a multifactorial disease that can be genetically classified into Sporadic Alzheimer’s Disease and Familial Alzheimer’s Disease based on family history. Gene therapy targeting specific disease-causing genes is a promising therapeutic strategy. Advancements in artificial intelligence applications may enable the prediction of AD onset several years in advance. While early diagnosis of AD may empower patients with full decision competence for early decision-making, it also carries implications for the patient’s family members, who are at risk of developing the disease, potentially becoming a source of confusion or anxiety. AD has a significant impact on the life of individuals at risk and their families. Given the absence of disease modifying therapy, genetic screening and early diagnosis for this condition raise ethical issues that must be carefully considered in the context of fundamental bioethical principles, including autonomy, beneficence, non-maleficence, and justice.
References
[1]
Matilla-Dueñas, A., Corral-Juan, M., Rodríguez-Palmero Seuma, A., Vilas, D., Ispierto, L., Morais, S., Sequeiros, J., Alonso, I., Volpini, V., Serrano-Munuera, C., Pintos-Morell, G., álvarez, R. and Sánchez, I. (2017) Rare Neurodegenerative Diseases: Clinical and Genetic Update. Advances in Experimental Medicine and Biology, 1031, 443-496. https://www.doi.org/10.1007/978-3-319-67144-4_25
[2]
Hanafy, A.S., Schoch, S. and Lamprecht, A. (2020) CRISPR/Cas9 Delivery Potentials in Alzheimer’s Disease Management: A Mini Review. Pharmaceutics, 12, Article No. 801. https://www.doi.org/10.3390/pharmaceutics12090801
[3]
Hall, K., Gureje, O., Gao, S., Ogunniyi, A., Hui, S.L., Baiyewu, O., Unverzagt, F.W., Oluwole, S. and Hendrie, H.C. (1998) Risk Factors and Alzheimer’s Disease: A Comparative Study of Two Communities. Australian & New Zealand Journal of Psychiatry, 32, 698-706. https://www.doi.org/10.3109/00048679809113126
[4]
Rudnicka, E., Napierała, P., Podfigurna, A., Męczekalski, B., Smolarczyk, R. and Grymowicz, M. (2020) The World Health Organization (WHO) Approach to Healthy Ageing. Maturitas, 139, 6-11. https://www.doi.org/10.1016/j.maturitas.2020.05.018
[5]
United Nations (2001) World Population Ageing: 1950-2050. https://www.un.org/development/desa/pd/sites/www.un.org.development.desa.pd/files/files/documents/2021/Nov/undesa_pd_2002_wpa_1950-2050_web.pdf
[6]
Lekoubou, A., Echouffo-Tcheugui, J.B. and Kengne, A.P. (2014) Epidemiology of Neurodegenerative Diseases in Sub-Saharan Africa: A Systematic Review. BMC Public Health, 14, Article No. 653. https://www.doi.org/10.1186/1471-2458-14-653
[7]
Sauzéat, L., Bernard, E., Perret-Liaudet, A., Quadrio, I., Broussolle, E., Leblanc, P. and Balter, V. (2019) Ageing & Neurodegenerative Diseases: New Constraints from the Metallomic. Integrative Human Evolution Symposium (IHES), Zurich, 2018.
[8]
Alpinar-Sencan, Z., Schicktanz, S., Ulitsa, N., Shefet, D. and Werner, P. (2022) Moral Motivation Regarding Dementia Risk Testing among Affected Persons in Germany and Israel. Journal of Medical Ethics, 48, 861-867. https://www.doi.org/10.1136/medethics-2020-106990
[9]
Fan, Y., Goh, E.L.K. and Chan, J.K.Y. (2023) Neural Cells for Neurodegenerative Diseases in Clinical Trials. Stem Cells Translational Medicine, 12, 510-526. https://www.doi.org/10.1093/stcltm/szad041
[10]
Mormone, E. and Iorio, E.L. (2023) Editorial: Regenerative Medicine in Neurodegenerative Diseases and Aging: Challenging the Redox Homeostasis. Frontiers in Neuroscience, 17, Article ID: 1238781. https://www.doi.org/10.3389/fnins.2023.1238781
[11]
Quan, M., Cao, S., Wang, Q., Wang, S. and Jia, J. (2023) Genetic Phenotypes of Alzheimer’s Disease: Mechanisms and Potential Therapy. Phenomics, 3, 333-349. https://www.doi.org/10.1007/s43657-023-00098-x
[12]
Godrich, D., Martin, E.R., Schellenberg, G., Pericak-Vance, M.A., Cuccaro, M., Scott, W.K., Kukull, W., Montine, T. and Beecham, G.W. (2022) Neuropathological Lesions and Their Contribution to Dementia and Cognitive Impairment in a Heterogeneous Clinical Population. Alzheimer’s & Dementia, 18, 2403-2412. https://www.doi.org/10.1002/alz.12516
[13]
Jia, L., Fu, Y., Shen, L., Zhang, H., Zhu, M., Qiu, Q., Wang, Q., Yan, X., Kong, C., Hao, J., Wei, C., Tang, Y., Qin, W., Li, Y., Wang, F., Guo, D., Zhou, A., Zuo, X., Yu, Y., Li, D., Zhao, L., Jin, H. and Jia, J. (2020) PSEN1, PSEN2, and APP Mutations in 404 Chinese Pedigrees with Familial Alzheimer’s Disease. Alzheimer’s & Dementia, 16, 178-191. https://www.doi.org/10.1002/alz.12005
[14]
Reitz, C., Pericak-Vance, M.A., Foroud, T. and Mayeux, R. (2023) A Global View of the Genetic Basis of Alzheimer Disease. Nature Reviews Neurology, 19, 261-277. https://www.doi.org/10.1038/s41582-023-00789-z
[15]
Shi, H., Belbin, O., Medway, C., Brown, K., Kalsheker, N., Carrasquillo, M., Proitsi, P., Powell, J., Lovestone, S., Goate, A., Younkin, S., Passmore, P. and Morgan, K. (2012) Genetic Variants Influencing Human Aging from Late-Onset Alzheimer’s Disease (LOAD) genome-Wide Association Studies (GWAS). Neurobiology of Aging, 33, 1849.e5-18. https://www.doi.org/10.1016/j.neurobiolaging.2012.02.014
[16]
Lee, J. and Ryu, H. (2010) Epigenetic Modification Is Linked to Alzheimer’s Disease: Is It a Maker or a Marker? BMB Reports, 43, 649-655. https://www.doi.org/10.5483/BMBRep.2010.43.10.649
[17]
Qureshi, I.A. and Mehler, M.F. (2011) Advances in Epigenetics and Epigenomics for Neurodegenerative Diseases. Current Neurology and Neuroscience Reports, 11, 464-473. https://www.doi.org/10.1007/s11910-011-0210-2
[18]
Tremblay, G., Rousseau, J., Mbakam, C.H. and Tremblay, J.P. (2022) Insertion of the Icelandic Mutation (A673T) by Prime Editing: A Potential Preventive Treatment for Familial and Sporadic Alzheimer’s Disease. The CRISPR Journal, 5, 109-122. https://www.doi.org/10.1089/crispr.2021.0085
[19]
Erickson, M.A., Niehoff, M.L., Farr, S.A., Morley, J.E., Dillman, L.A., Lynch, K.M. and Banks, W.A. (2012) Peripheral Administration of Antisense Oligonucleotides Targeting the Amyloid-β Protein Precursor Reverses AβPP and LRP-1 Overexpression in the Aged SAMP8 Mouse Brain. Journal of Alzheimer’s Disease, 28, 951-960. https://www.doi.org/10.3233/jad-2011-111517
[20]
Hinrich, A.J., Jodelka, F.M., Chang, J.L., Brutman, D., Bruno, A.M., Briggs, C.A., James, B.D., Stutzmann, G.E., Bennett, D.A., Miller, S.A., Rigo, F., Marr, R.A. and Hastings, M.L. (2016) Therapeutic Correction of ApoER2 Splicing in Alzheimer’s Disease Mice Using Antisense Oligonucleotides. EMBO Molecular Medicine, 8, 328-345. https://www.doi.org/10.15252/emmm.201505846
[21]
Katsouri, L., Lim, Y.M., Blondrath, K., Eleftheriadou, I., Lombardero, L., Birch, A.M., Mirzaei, N., Irvine, E.E., Mazarakis, N.D. and Sastre, M. (2016) PPARγ-Coactivator-1α Gene Transfer Reduces Neuronal Loss and Amyloid-β Generation by Reducing β-Secretase in an Alzheimer’s Disease Model. Proceedings of the National Academy of Sciences of the United States of America, 113, 12292-12297. https://www.doi.org/10.1073/pnas.1606171113
[22]
Offen, D., Rabinowitz, R., Michaelson, D. and Ben-Zur, T. (2018) Towards Gene-Editing Treatment for Alzheimer’s Disease: ApoE4 Allele-Specific Knockout Using a CRISPR cas9 Variant. Cytotherapy, 20, S18.
[23]
Sun, J., Carlson-Stevermer, J., Das, U., Shen, M., Delenclos, M., Snead, A.M., Koo, S.Y., Wang, L., Qiao, D., Loi, J., Petersen, A.J., Stockton, M., Bhattacharyya, A., Jones, M.V., Zhao, X., McLean, P.J., Sproul, A.A., Saha, K. and Roy, S. (2019) CRISPR/Cas9 Editing of APP C-Terminus Attenuates β-Cleavage and Promotes α-Cleavage. Nature Communications, 10, Article No. 53. https://www.doi.org/10.1038/s41467-018-07971-8
[24]
Burlot, M.A., Braudeau, J., Michaelsen-Preusse, K., Potier, B., Ayciriex, S., Varin, J., Gautier, B., Djelti, F., Audrain, M., Dauphinot, L., Fernandez-Gomez, F.J., Caillierez, R., Laprévote, O., Bièche, I., Auzeil, N., Potier, M.C., Dutar, P., Korte, M., Buée, L., Blum, D. and Cartier, N. (2015) Cholesterol 24-Hydroxylase Defect Is Implicated in Memory Impairments Associated with Alzheimer-Like Tau Pathology. Human Molecular Genetics, 24, 5965-5976. https://www.doi.org/10.1093/hmg/ddv268
[25]
Krishnamurthy, K., Cantillana, V., Wang, H., Sullivan, P.M., Kolls, B.J., Ge, X., Lin, Y., Mace, B. and Laskowitz, D.T. (2020) ApoE Mimetic Improves Pathology and Memory in a Model of Alzheimer’s Disease. Brain Research, 1733, Article ID: 146685. https://www.doi.org/10.1016/j.brainres.2020.146685
[26]
Gupta, S., Singh, V., Ganesh, S., Singhal, N.K. and Sandhir, R. (2022) siRNA Mediated GSK3β Knockdown Targets Insulin Signaling Pathway and Rescues Alzheimer’s Disease Pathology: Evidence from in Vitro and in Vivo Studies. ACS Applied Materials & Interfaces, 14, 69-93. https://www.doi.org/10.1021/acsami.1c15305
[27]
Park, H., Oh, J., Shim, G., Cho, B., Chang, Y., Kim, S., Baek, S., Kim, H., Shin, J., Choi, H., Yoo, J., Kim, J., Jun, W., Lee, M., Lengner, C.J., Oh, Y.K. and Kim, J. (2019) In Vivo Neuronal Gene Editing via CRISPR-Cas9 Amphiphilic Nanocomplexes Alleviates Deficits in Mouse Models of Alzheimer’s Disease. Nature Neuroscience, 22, 524-528. https://www.doi.org/10.1038/s41593-019-0352-0
[28]
Mummery, C.J., Börjesson-Hanson, A., Blackburn, D.J., Vijverberg, E.G.B., De Deyn, P.P., Ducharme, S., Jonsson, M., Schneider, A., Rinne, J.O., Ludolph, A.C., Bodenschatz, R., Kordasiewicz, H., Swayze, E.E., Fitzsimmons, B., Mignon, L., Moore, K.M., Yun, C., Baumann, T., Li, D., Norris, D.A., Crean, R., Graham, D.L., Huang, E., Ratti, E., Bennett, C.F., Junge, C. and Lane, R.M. (2023) Tau-Targeting Antisense Oligonucleotide MAPT(Rx) in Mild Alzheimer’s Disease: A Phase 1b, Randomized, Placebo-Controlled Trial. Nature Medicine, 29, 1437-1447. https://www.doi.org/10.1038/s41591-023-02326-3
[29]
Fol, R., Braudeau, J., Ludewig, S., Abel, T., Weyer, S.W., Roederer, J.P., Brod, F., Audrain, M., Bemelmans, A.P., Buchholz, C.J., Korte, M., Cartier, N. and Müller, U.C. (2016) Viral Gene Transfer of APPsα Rescues Synaptic Failure in an Alzheimer’s Disease Mouse Model. Acta Neuropathologica, 131, 247-266. https://www.doi.org/10.1007/s00401-015-1498-9
[30]
Revilla, S., Ursulet, S., álvarez-López, M.J., Castro-Freire, M., Perpiñá, U., García-Mesa, Y., Bortolozzi, A., Giménez-Llort, L., Kaliman, P., Cristòfol, R., Sarkis, C. and Sanfeliu, C. (2014) Lenti-GDNF Gene Therapy Protects against Alzheimer’s Disease-Like Neuropathology in 3xTg-AD Mice and MC65 Cells. CNS Neuroscience & Therapeutics, 20, 961-972. https://www.doi.org/10.1111/cns.12312
[31]
Rafii, M.S., Baumann, T.L., Bakay, R.A., Ostrove, J.M., Siffert, J., Fleisher, A.S., Herzog, C.D., Barba, D., Pay, M., Salmon, D.P., Chu, Y., Kordower, J.H., Bishop, K., Keator, D., Potkin, S. and Bartus, R.T. (2014) A Phase 1 Study of Stereotactic Gene Delivery of AAV2-NGF for Alzheimer’s Disease. Alzheimer’s & Dementia, 10, 571-581. https://www.doi.org/10.1016/j.jalz.2013.09.004
[32]
Zhou, Y., Zhu, F., Liu, Y., Zheng, M., Wang, Y., Zhang, D., Anraku, Y., Zou, Y., Li, J., Wu, H., Pang, X., Tao, W., Shimoni, O., Bush, A.I., Xue, X. and Shi, B. (2020) Blood-Brain Barrier-Penetrating siRNA Nanomedicine for Alzheimer’s Disease Therapy. Science Advances, 6, eabc7031. https://www.doi.org/10.1126/sciadv.abc7031
[33]
Rafii, M.S., Tuszynski, M.H., Thomas, R.G., Barba, D., Brewer, J.B., Rissman, R.A., Siffert, J. and Aisen, P.S. (2018) Adeno-Associated Viral Vector (Serotype 2)-Nerve Growth Factor for Patients with Alzheimer Disease: A Randomized Clinical Trial. JAMA Neurology, 75, 834-841. https://www.doi.org/10.1001/jamaneurol.2018.0233
[34]
Li, S., Lei, Z. and Sun, T. (2023) The Role of microRNAs in Neurodegenerative Diseases: A Review. Cell Biology and Toxicology, 39, 53-83. https://www.doi.org/10.1007/s10565-022-09761-x
[35]
Hébert, S.S., Horré, K., Nicolaï, L., Papadopoulou, A.S., Mandemakers, W., Silahtaroglu, A.N., Kauppinen, S., Delacourte, A. and De Strooper, B. (2008) Loss of microRNA Cluster miR-29a/b-1 in Sporadic Alzheimer’s Disease Correlates with Increased BACE1/beta-Secretase Expression. Proceedings of the National Academy of Sciences of the United States of America, 105, 6415-6420. https://www.doi.org/10.1073/pnas.0710263105
[36]
Lukiw, W.J. (2007) Micro-RNA Speciation in Fetal, Adult and Alzheimer’s Disease Hippocampus. Neuroreport, 18, 297-300. https://www.doi.org/10.1097/WNR.0b013e3280148e8b
[37]
Ouyang, Q., Liu, K., Zhu, Q., Deng, H., Le, Y., Ouyang, W., Yan, X., Zhou, W. and Tong, J. (2022) Brain-Penetration and Neuron-Targeting DNA Nanoflowers Co-Delivering miR-124 and Rutin for Synergistic Therapy of Alzheimer’s Disease. Small, 18, e2107534. https://www.doi.org/10.1002/smll.202107534
[38]
Filser, S., Ovsepian, S.V., Masana, M., Blazquez-Llorca, L., Brandt Elvang, A., Volbracht, C., Müller, M.B., Jung, C.K. and Herms, J. (2015) Pharmacological Inhibition of BACE1 Impairs Synaptic Plasticity and Cognitive Functions. Biological Psychiatry, 77, 729-739. https://www.doi.org/10.1016/j.biopsych.2014.10.013
[39]
Cui, J.G., Li, Y.Y., Zhao, Y., Bhattacharjee, S. and Lukiw, W.J. (2010) Differential Regulation of Interleukin-1 Receptor-Associated Kinase-1 (IRAK-1) and IRAK-2 by microRNA-146a and NF-kappaB in Stressed Human Astroglial Cells and in Alzheimer Disease. Journal of Biological Chemistry, 285, 38951-38960. https://www.doi.org/10.1074/jbc.M110.178848
[40]
Ge, X., Guo, M., Hu, T., Li, W., Huang, S., Yin, Z., Li, Y., Chen, F., Zhu, L., Kang, C., Jiang, R., Lei, P. and Zhang, J. (2020) Increased Microglial Exosomal miR-124-3p Alleviates Neurodegeneration and Improves Cognitive Outcome after rmTBI. Molecular Therapy, 28, 503-522. https://www.doi.org/10.1016/j.ymthe.2019.11.017
[41]
Miele, E., Spinelli, G.P., Miele, E., Di Fabrizio, E., Ferretti, E., Tomao, S. and Gulino, A. (2012) Nanoparticle-Based Delivery of Small Interfering RNA: Challenges for Cancer Therapy. International Journal of Nanomedicine, 7, 3637-3657. https://www.doi.org/10.2147/ijn.S23696
[42]
Uddin, F., Rudin, C.M. and Sen, T. (2020) CRISPR Gene Therapy: Applications, Limitations, and Implications for the Future. Frontiers in Oncology, 10, Article No. 1387. https://www.doi.org/10.3389/fonc.2020.01387
[43]
Moreno, C.L., Della Guardia, L., Shnyder, V., Ortiz-Virumbrales, M., Kruglikov, I., Zhang, B., Schadt, E.E., Tanzi, R.E., Noggle, S., Buettner, C. and Gandy, S. (2018) iPSC-Derived Familial Alzheimer’s PSEN2 (N141I) Cholinergic Neurons Exhibit Mutation-Dependent Molecular Pathology Corrected by Insulin Signaling. Molecular Neurodegeneration, 13, Article No. 33. https://www.doi.org/10.1186/s13024-018-0265-5
[44]
György, B., Lööv, C., Zaborowski, M.P., Takeda, S., Kleinstiver, B.P., Commins, C., Kastanenka, K., Mu, D., Volak, A., Giedraitis, V., Lannfelt, L., Maguire, C.A., Joung, J.K., Hyman, B.T., Breakefield, X.O. and Ingelsson, M. (2018) CRISPR/Cas9 Mediated Disruption of the Swedish APP Allele as a Therapeutic Approach for Early-Onset Alzheimer’s Disease. Molecular Therapy Nucleic Acids, 11, 429-440. https://www.doi.org/10.1016/j.omtn.2018.03.007
[45]
Weller, J. and Budson, A. (2018) Current Understanding of Alzheimer’s Disease Diagnosis and Treatment. F1000Research, 7, Article No. 1161. https://www.doi.org/10.12688/f1000research.14506.1
[46]
Lebert, F., Boitte, P., de Bouvet, A. and Pasquier, F. (2012) Alzheimer’s Disease and Related Disorders: Specificity of Young Onset Patients, Including Ethical Aspects. Gériatrie et Psychologie Neuropsychiatrie du Vieillissement, 10, 65-72. https://www.doi.org/10.1684/pnv.2012.0316
[47]
Goldman, J.S. (2015) Genetic Testing and Counseling in the Diagnosis and Management of Young-Onset Dementias. Psychiatric Clinics of North America, 38, 295-308. https://www.doi.org/10.1016/j.psc.2015.01.008
[48]
Viaña, J.N.M. (2021) Deep Brain Stimulation for Preclinical and Prodromal Alzheimer’s Disease: Integrating Beneficence, Non-Maleficence, and Autonomy Considerations through Responsible Innovation. AJOB Neuroscience, 12, 236-239. https://www.doi.org/10.1080/21507740.2021.1941406
[49]
Robillard, J.M., Wu, J.M., Feng, T.L. and Tam, M.T. (2019) Prioritizing Benefits: A Content Analysis of the Ethics in Dementia Technology Policies. Journal of Alzheimer’s Disease, 69, 897-904. https://www.doi.org/10.3233/jad-180938
[50]
Balls-Berry, J.J.E. and Babulal, G.M. (2022) Health Disparities in Dementia. Continuum (Minneap Minn), 28, 872-884. https://www.doi.org/10.1212/con.0000000000001088
