Genetic Variants, Prevention, and Gene Therapies: An Analysis of Genetic Predisposition to Dementia
DOI:
https://doi.org/10.47611/jsrhs.v13i3.7167Keywords:
dementia, genetic predisposition, genetic risk, Alzheimer's disease, frontotemporal dementia, amytrophic lateral sclerosis, Parkinson's disease, dementia with Lewy bodies, cardiovascular health, depression, dementia preventionAbstract
This review aimed to understand how genetic factors play a role in a predisposition to dementia, which is a range of diseases that cause cognitive decline. Dementia rates are increasing globally due to a prolonged lifespan and it is becoming a more critical subject in the medical world. Through a secondary literature review, the focus of this article is to understand the various aspects of genetic risk in dementia. Other prominent causes for dementia such as cardiovascular disease, depression, and lifestyle choices are also outlined in the review. Genes such as chromosome 9 open reading frame 72 (C9orf72), APP, PSEN1, PSEN2, TREM2, and the apolipoprotein E (APOE) ε4 allele are associated with an increased risk of dementia. The genetic factors for Alzheimer’s disease, frontotemporal dementia, amyotrophic lateral sclerosis, and Parkinson’s disease are analyzed as well. Genetic testing and counseling can identify the source of a person’s genetic predisposition. Studies are being conducted to elucidate the exact mechanisms of gene variants and to test new gene therapies, which are important for treating dementia. Lifestyle modifications and other actions may also be imperative in dementia prevention.
Downloads
References or Bibliography
Ailiya, X., Bao, L., Xijiri, X., Kakuta, S., & Eerdunfu, E. (2023). Role of adenosine A2A receptor in the olfactory system & implications in Alzheimer’s disease pathology. Society of Neuroscience. https://www.sfn.org/meetings/neuroscience-2023/call-for-abstracts/neuroscience-2023-abstracts
Blauwendraat, C., Reed, X., Krohn, L., Heilbron, K., Bandrés‐Ciga, S., Tan, M., Gibbs, J. R., Hernandez, D. G., Kumaran, R. I., Langston, R. G., Cookson, M., Alcalay, R. N., Hassin‐Baer, S., Greenbaum, L., Iwaki, H., Leonard, H., Grenn, F. P., Ruskey, J. A., Sabir, M. S., . . . Singleton, A. (2019). Genetic modifiers of risk and age at onset in GBA associated Parkinson’s disease and Lewy body dementia. Brain, 143(1), 234–248. https://doi.org/10.1093/brain/awz350
Braggin, J. E., Bucks, S. A., Course, M. M., Smith, C. L., Sopher, B., Osnis, L., Shuey, K. D., Domoto-Reilly, K., Caso, C., Kinoshita, C., Scherpelz, K. P., Cross, C., Grabowski, T., Nik, S. H. M., Newman, M., Garden, G. A., Leverenz, J. B., Tsuang, D., Latimer, C., Gonzalez-Cuyar, L. F., … Jayadev, S. (2019). Alternative splicing in a presenilin 2 variant associated with Alzheimer disease. Annals of clinical and translational neurology, 6(4), 762–777. https://doi.org/10.1002/acn3.755
Cappella, M., Pradat, P., Querin, G., & Biferi, M. G. (2021). Beyond the traditional clinical trials for amyotrophic lateral sclerosis and the future impact of gene therapy. Journal of Neuromuscular Diseases, 8(1), 25–38. https://doi.org/10.3233/jnd-200531
Combi, R., Salsone, M., Clara, V., & Ferini‐Strambi, L. (2021). Genetic Architecture and Molecular, Imaging and Prodromic Markers in Dementia with Lewy Bodies: State of the Art, Opportunities and Challenges. International Journal of Molecular Sciences, 22(8), 3960. https://doi.org/10.3390/ijms22083960
Crook, A., Jacobs, C., Newton‐John, T., & McEwen, A. (2022). Genetic counseling and diagnostic genetic testing for familial amyotrophic lateral sclerosis and/or frontotemporal dementia: A qualitative study of client experiences. Journal of Genetic Counseling, 31(5), 1206–1218. https://doi.org/10.1002/jgc4.1591
Dominguez, L., Veronese, N., Vernuccio, L., Giuseppina, C., Inzerillo, F., Salemi, G., & Barbagallo, M. (2021). Nutrition, Physical Activity, and Other Lifestyle Factors in the Prevention of Cognitive Decline and Dementia, 13(11), 4080. https://doi.org/10.3390/nu13114080
Fan, J., Wan, T., Li, X., Li, H., Zhang, J., Wei, D., Chen, Y., & Zhang, Z. (2019). The contribution of genetic factors to cognitive impairment and dementia: apolipoprotein E gene, gene interactions, and polygenic risk. International Journal of Molecular Sciences, 20(5), 1177. https://doi.org/10.3390/ijms20051177
Ghasemi, M., Keyhanian, K., & Douthwright, C. (2021). Glial cell dysfunction in C9ORF72-Related amyotrophic lateral sclerosis and frontotemporal dementia. Cells, 10(2), 249. https://doi.org/10.3390/cells10020249
Goldman, J., & Van Deerlin, V. M. (2018). Alzheimer’s Disease and frontotemporal Dementia: The current state of genetics and genetic testing since the advent of Next-Generation sequencing. Molecular Diagnosis & Therapy, 22(5), 505–513. https://doi.org/10.1007/s40291-018-0347-7
Hall‐Roberts, H., Agarwal, D., Obst, J., Smith, T. B., Monzón‐Sandoval, J., Di Daniel, E., Webber, C., James, W., Mead, E., Davis, J. B., & Cowley, S. A. (2020). TREM2 Alzheimer’s variant R47H causes similar transcriptional dysregulation to knockout, yet only subtle functional phenotypes in human iPSC-derived macrophages. Alzheimer’s Research & Therapy, 12(1). https://doi.org/10.1186/s13195-020-00709-z
Jin, Y., Li, F., Li, Z., Ikezu, T. C., O’Leary, J., Zhu, Y., Martens, Y. A., Koga, S., Li, Y., Lu, W., You, Y., Lolo, K., Deture, M., Davis, M., McLean, P. J., Ross, O., Kanekiyo, T., Ikezu, Y., Wszolek, Z., . . . Zhao, N. (2023b). Modeling Synucleinopathies with SNCA Triplication iPSC-Derived Cortical Organoids and Identifying Therapeutic Drugs. Society of Neuroscience. https://www.sfn.org/meetings/neuroscience-2023/call-for-abstracts/neuroscience-2023-abstracts
Koga, S., Sekiya, H., Kondru, N., Ross, O. A., & Dickson, D. W. (2021). Neuropathology and molecular diagnosis of Synucleinopathies. Molecular Neurodegeneration, 16(1). https://doi.org/10.1186/s13024-021-00501-z
Kragh, C. L., Ubhi, K., Wyss-Coray, T., & Masliah, E. (2012). Autophagy in dementias. Brain pathology (Zurich, Switzerland), 22(1), 99–109.https://doi.org/10.1111/j.1750-3639.2011.00545.x
Lai, D., Alipanahi, B., Fontanillas, P., Schwantes‐An, T., Aasly, J., Alcalay, R. N., Beecham, G. W., Berg, D., Bressman, S., Brice, A., Brockman, K., Clark, L. N., Cookson, M., S, D., Van Deerlin, V. M., Follett, J., Farrer, M. J., Trinh, J., Gasser, T., . . . Foroud, T. (2021). Genomewide association studies of LRRK2 modifiers of Parkinson’s Disease. Annals of Neurology, 90(1), 76–88. https://doi.org/10.1002/ana.26094
Limia, C. G., Baird, M., Schwartz, M., Saxena, S., Meyer, K., & Wein, N. (2022). Emerging perspectives on gene therapy delivery for neurodegenerative and neuromuscular disorders. Journal of Personalized Medicine, 12(12), 1979. https://doi.org/10.3390/jpm12121979
Livingston, G., Huntley, J., Sommerlad, A., Ames, D., Ballard, C., Banerjee, S., Brayne, C., Burns, A., Cohen‐Mansfield, J., Cooper, C., Costafreda, S. G., Dias, A., Fox, N. C., Gitlin, L. N., Howard, R., Kales, H. C., Kivimäki, M., Larson, E. B., Ogunniyi, A., . . . Mukadam, N. (2020). Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. The Lancet, 396(10248), 413–446. https://doi.org/10.1016/s0140-6736(20)30367-6
Loy, C. T., Schofield, P. R., Turner, A., & Kwok, J. B. (2014). Genetics of dementia. Lancet (British Edition), 383(9919), 828–840. https://doi.org/10.1016/s0140-6736(13)60630-3
Mamalaki, E., Charisis, S., Anastasiou, C. A., Ntanasi, E., Georgiadi, K., Balomenos, V., Kosmidis, M. H., Dardiotis, E., Hadjigeorgiou, G. M., Sakka, P., Scarmeas, N., & Yannakoulia, M. (2022). The Longitudinal Association of Lifestyle with Cognitive Health and Dementia Risk: Findings from the HELIAD Study. Nutrients, 14(14), 2818. https://doi.org/10.3390/nu14142818
McKean, N. E., McMurray, C., Handley, R. R., McLaughlan, C., Rudiger, S. R., Kelly, J., Zetterberg, H., Pearson, J., Reid, S., Verma, P., Gusella, J. F., Owen, M. J., Hardy, J. A., Waldvogel, H. J., Faull, R. L., Bawden, S., & Snell, R. G. (2023). Sheep models of Alzheimer’s Disease. Society of Neuroscience. https://www.sfn.org/meetings/neuroscience-2023/call-for-abstracts/neuroscience-2023-abstracts
Ng, J., Barral, S., Waddington, S. N., & Kurian, M. A. (2023). Gene therapy for dopamine dyshomeostasis: From Parkinson’s to primary neurotransmitter diseases. Movement Disorders, 38(6), 924–936. https://doi.org/10.1002/mds.29416
Pal, G., Cook, L., Schulze, J., Verbrugge, J., Alcalay, R. N., Merello, M., Sue, C. M., Bardien, S., Bonifati, V., Chung, S. J., Foroud, T., Gatto, E., Hall, A., Hattori, N., Lynch, T., Marder, K., Mascalzoni, D., Novaković, I., Thaler, A., . . . Klein, C. (2023). Genetic testing in Parkinson’s disease. Movement Disorders, 38(8), 1384–1396. https://doi.org/10.1002/mds.29500
Peloso, G. M., Beiser, A. S., Satizabal, C. L., Xanthakis, V., Vasan, R. S., Pase, M. P., DeStefano, A. L., & Seshadri, S. (2020). Cardiovascular health, genetic risk, and risk of dementia in the Framingham Heart Study. Neurology, 95(10). https://doi.org/10.1212/wnl.0000000000010306
Peters, R., Booth, A., Rockwood, K., Peters, J., D’Este, C., & Anstey, K. J. (2019). Combining modifiable risk factors and risk of dementia: a systematic review and meta-analysis. BMJ Open, 9(1), e022846. https://doi.org/10.1136/bmjopen-2018-022846
Prince, M., Ali, G., Guerchet, M., Prina, M., Albanese, E., & Wu, Y. (2016). Recent global trends in the prevalence and incidence of dementia, and survival with dementia. Alzheimer’s Research & Therapy, 8(1). https://doi.org/10.1186/s13195-016-0188-8
Raz, L., Knoefel, J. E., & Bhaskar, K. (2015). The neuropathology and cerebrovascular mechanisms of dementia. Journal of Cerebral Blood Flow and Metabolism, 36(1), 172–186. https://doi.org/10.1038/jcbfm.2015.164
Reitz, C., Pericak‐Vance, M. A., Foroud, T., & Mayeux, R. (2023). A global view of the genetic basis of Alzheimer disease. Nature Reviews Neurology, 19(5), 261–277. https://doi.org/10.1038/s41582-023-00789-z
Schofield, P. R., Weiner, M., Xiong, C., Beckett, L. A., Coble, D. W., Saito, N., Aisen, P. S., Allegri, R., Benzinger, T. L., Berman, S., Cairns, N. J., Carrillo, M. C., Chui, H. C., Chhatwal, J. P., Cruchaga, C., Fagan, A. M., Farlow, M. R., Fox, N. C., Ghetti, B., . . . Buckles, V. (2022). Autosomal dominant and sporadic late onset Alzheimer’s disease share a commonin vivopathophysiology. Brain, 145(10), 3594–3607. https://doi.org/10.1093/brain/awac181
Smeyers, J., Banchi, E. G., & Latouche, M. (2021). C9ORF72: What It Is, What It Does, and Why It Matters. Frontiers in cellular neuroscience, 15, 661447. https://doi.org/10.3389/fncel.2021.661447
Tai, X. Y., Veldsman, M., Lyall, D. M., Littlejohns, T. J., Langa, K. M., Husain, M., Ranson, J. M., & Llewellyn, D. J. (2022). Cardiometabolic multimorbidity, genetic risk, and dementia: a prospective cohort study. The Lancet Healthy Longevity, 3(6), e428–e436. https://doi.org/10.1016/s2666-7568(22)00117-9
Van Nostrand, W. E. (2016). The influence of the amyloid ß-protein and its precursor in modulating cerebral hemostasis. Biochimica Et Biophysica Acta (BBA) - Molecular Basis of Disease, 1862(5), 1018–1026. https://doi.org/10.1016/j.bbadis.2015.10.020
Wang, S., Han, K., Kim, N., Um, Y. H., Kang, D. W., Na, H., Lee, C., & Lim, H. K. (2021). Late-life depression, subjective cognitive decline, and their additive risk in incidence of dementia: A nationwide longitudinal study. PLOS ONE, 16(7), e0254639. https://doi.org/10.1371/journal.pone.0254639
Published
How to Cite
Issue
Section
Copyright (c) 2024 Sarayu Chittireddy; Coach Jo, Prahlad Parajuli
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
Copyright holder(s) granted JSR a perpetual, non-exclusive license to distriute & display this article.
