Early-onset Alzheimer’s Disease (EOAD): neuropathological characteristics and associated genetic variants.
DOI:
https://doi.org/10.20453/rnp.v84i2.3998Keywords:
Early-onset Alzheimer’s Disease, Amyloid beta-Peptides, Presenilin, Apolipoprotein E4, Tau protein, MutationAbstract
The most common neurodegenerative disease in the world is Alzheimer’s Disease (AD). Ten percent of Alzheimer patients experience symptoms before the age of 65, and almost all of them present genetic features of autosomal dominant inheritance nature, and penetrance of 92 to 100%. In the present review, we searched for genetic variants associated with early onset Alzheimer's disease (EOAD), emphasizing the most important characteristics and the main mutations. The genes most commonly related to the onset of EOAD are APP, PSEN1, PSEN2 and MAPT, whose mutations affect the metabolism and structure of these proteins. This process results in accumulations of Aβ peptide that leads to activation of the microglia and release of neurotoxic and pro-inflammatory factors that accelerate neurodegeneration. The PSEN1 gene is responsible for 70% of the known mutations in EOAD, while L166P is associated with below 30 years as the starting age of occurrence. APP mutations lead to protein aggregation in neurodegenerative plaques. All of the mutations described for MAPT are associated with an increase in neurofibrillary tangles. The E4 polymorphism of Apolipoprotein E (APOE) influences an increased risk of EOAD increasing up to three times the chances for heterozygous, and between eight and ten times for homozygotes carriers. Only 5% of the mutations associated with EOAD are known; new studies will show other candidate genes, as well as the importance of epigenetic factors changes in the etio-pathogenesis of this disease.
References
Falco A, Cukierman S, Hauser-Davis A, Rey A. Doença de Alzheimer: hipóteses etiológicas e perspectivas de tratamento.Química Nova. 2016, 39(1): 63-80.
Cacace R, Sleegers K, Broeckhoven CV. Molecular genetics of early-onset Alzheimer’s disease. Alzheimer’s & Dementia. 2016, 12: 733-748.
Carvajal C. Biología molecular de la enfermedad de Alzheimer. Medicina Legal de Costa Rica. Associación Costarricense de Medicina Legal y Disciplinas Afines. 2016;33(2).
Associação Brasileira de Alzheimer. Fatores de Risco. Brasilia: Associação Brasileira de Alzheimer; 2019. (Acesso em: Janeiro 2021). Disponível em: https://abraz.org.br/2020/sobre-alzheimer/fatores- de-risco-2/#:~:text=S%C3%A3o%20 considerados%20fatores%20de%20 risco,retardar%20o%20aparecimento%20da%20 doen%C3%A7a
Kumar A, Singh A, Ekavali. A review on Alzheimer’s disease pathophysiology and its management: an update. Pharmacological Reports. 2015 abr;67(2):195–203.
Ortiz GG, Pacheco-Moisés FP, González-Renovato E, Figuera L, Macías-Islas MA., Mireles-Ramírez, et al. Genetic, biochemical and histopathological aspects of familiar Alzheimer’s disease. Em: Alzheimer’s Disease-Challenges for the Future. IntechOpen; 2015. p.297-324.
Dai M-H, Zheng H, Zeng L-D, Zhang Y. The genes associated with early-onset Alzheimer’s disease. Oncotarget. 2018; 9(19):15132–43.
ALZFORUM. Networking for a cure. ALZFORUM; 2020. (Acesso em: Janeiro 2021). Disponível em: https://www.alzforum.org/mutations
Perl DP. Neuropathology of Alzheimer’s Disease. Mt Sinai J Med. 2010;77(1):32–42.
Pardi PC, Santos GAA, Silva Gois JC, Braz Jr RG, Olave E. Biomarcadores y Marcadores de Imagen de la Enfermedad de Alzheimer. Int J Morphol. 2017;35(3):864–9.
Mendez MF. Early-Onset Alzheimer Disease. Neurologic Clinics. 2017;35(2):263–81
Mendez MF. Early-onset Alzheimer Disease and Its Variants. CONTINUUM: Lifelong Learning in Neurology. 2019;25(1):34–51.
Militão AO, Barros A. Doença de Alzheimer: Genética e Novos Avanços. Temas em Saúde. 2017; 17(1): 262-280.
Guzen FP, Cavalcanti JR. Influência das Proteínas Beta Amiloide e Tau na Doença de Alzheimer. Revista de Ciências da Saúde Nova Esperança.2012; 10(1): 58-61.
Morelli L. La contribución de la hipótesis amiloide a la comprensión de la enfermedad de Alzheimer: una visión crítica. Química Viva. 2016; 15(1): 7-12.
Ballard C, Gauthier S, Corbett A, Brayne C, Aarsland D, Jones E. Alzheimer’s disease. The Lancet. 2011;377(9770):1019–31.
Tellechea P, Pujol N, Esteve-Belloch P, Echeveste B, García-Eulate MR, Arbizu J, et al. Enfermedad de Alzheimer de inicio precoz y de inicio tardío: ¿son la misma entidad? Neurología. 2018;33(4):244–5.
Campion D, Charbonnier C, Nicolas G. SORL1 genetic variants and Alzheimer disease risk: a literature review and meta-analysis of sequencing data. Acta Neuropathol. 2019;138(2):173–86.
Prado D, Cardoso IL. Apolipoproteína E e Doença de Alzheimer. Rev Neurocienc. 2013;21(1):118–25.
Karch CM, Cruchaga C, Goate AM. Alzheimer’s Disease Genetics: From the Bench to the Clinic. Neuron. 2014;83(1):11–26.
Huynh T-PV, Davis AA, Ulrich JD, Holtzman DM. Apolipoprotein E and Alzheimer’s disease: the influence of apolipoprotein E on amyloid-β and other amyloidogenic proteins. J Lipid Res. 2017;58(5):824– 36.
Cruts M, Theuns J, Van Broeckhoven C. Locus- specific mutation databases for neurodegenerative brain diseases. Hum Mutat. 2012;33(9):1340–4.
An SS, Park SA, Bagyinszky E, Bae SO, Kim Y-J, Im JY, et al. A genetic screen of the mutations in the Korean patients with early-onset Alzheimer’s disease. CIA. 2016; 11:1817–22.
van der Kant R, Goldstein LSB. Cellular functions of the amyloid precursor protein from development to dementia. Developmental Cell. 2015;32(4):502–15.
Ghani M, Reitz C, George-Hyslop PS, Rogaeva E. Genetic Complexity of Early-Onset Alzheimer’s Disease. Em: Galimberti D, Elio Scarpini E, editors Neurodegenerative Diseases. Springer International Publishing; 2018. p. 29–50.
Rosa MDO, Machado FDS, Frusciante MR, Gutierrez LLP, Funchal C. Efeito Protetor do Resveratrol na Doença de Alzheimer. RBM. 2017; 20(1):174.
Muratore CR, Rice HC, Srikanth P, Callahan DG, Shin T, Benjamin LNP, et al. The familial Alzheimer’s disease APPV717I mutation alters APP processing and Tau expression in iPSC-derived neurons. Human Molecular Genetics. 2014; 23(13):3523–36.
Chávez-Gutiérrez L, Szaruga M. Mechanisms of neurodegeneration — Insights from familial Alzheimer’s disease. Seminars in Cell & Developmental Biology. 2020;105:75–85.
Bi C, Bi S, Li B. Processing of Mutant β-Amyloid Precursor Protein and the Clinicopathological Features of Familial Alzheimer’s Disease. Aging and disease. 2019;10(2):383.
Jonsson T, Atwal JK, Steinberg S, Snaedal J, Jonsson PV, Bjornsson S, et al. A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline. Nature. 2012;488(7409):96–9.
Lardenoije R, Iatrou A, Kenis G, Kompotis K, Steinbusch HWM, Mastroeni D, et al. The epigenetics of aging and neurodegeneration. Progress in Neurobiology. 2015;131:21–64.
Lord J, Cruchaga C. The epigenetic landscape of Alzheimer’s disease. Nat Neurosci. 2014;17(9):1138– 40.
Millan MJ. Linking deregulation of non-coding RNA to the core pathophysiology of Alzheimer’s disease: An integrative review. Progress in Neurobiology. 2017;156:1–68.
Sassi C, Guerreiro R, Gibbs R, Ding J, Lupton MK, Troakes C, et al. Exome sequencing identifies 2 novel presenilin 1 mutations (p.L166V and p.S230R) in British early-onset Alzheimer’s disease. Neurobiology of Aging. 2014;35(10):2422.
Gómez PY, Vilatela EA. Genética de las demencias. Arch Neurocien. 2016; 21:65-71.
Qiu Q, Jia L, Wang Q, Zhao L, Jin H, Li T, et al. Identification of a novel PSEN1 Gly111Val missense mutation in a Chinese pedigree with early- onset Alzheimer’s disease. Neurobiology of Aging. 2020;85:155.e1-155.
Muchnik C, Olivar N, Dalmasso MC, Azurmendi PJ, Liberczuk C, Morelli L, et al. Identification of PSEN2 mutation p.N141I in Argentine pedigrees with early- onset familial Alzheimer’s disease. Neurobiology of Aging. 2015 out;36(10):2674-2677.e1.
Marambaud P, Alves da Costa C, Ancolio K, Checler F. Alzheimer’s Disease-Linked Mutation of Presenilin 2 (N141I-PS2) Drastically Lowers APPα Secretion: Control by the Proteasome. Biochemical and Biophysical Research Communications. 1998;252(1):134–138.
Fernández MV, Cruchaga, C. Genética de la enfermedad de Alzheimer: presente y futuro. Revista Genética Médica News. 2016; 3(62):22-27.
Ikeuchi T, Imamura T, Kawase Y, Kitade Y, Tsuchiya M, Tokutake T, et al. Evidence for a Common Founder and Clinical Characteristics of Japanese Families with the MAPT R406W Mutation. Dement Geriatr Cogn Disord Extra. 2011;1(1):267–75.
Iqbal K, Liu F, Gong C-X, Grundke-Iqbal I. Tau in Alzheimer Disease and related tauopathies. CAR. 2010;7(8):656–64.
Cornejo-Olivas MR, Yu C-E, Mazzetti P, Mata IF, Meza M, Lindo-Samanamud S, et al. Clinical and molecular studies reveal a PSEN1 mutation (L153V) in a Peruvian family with early-onset Alzheimer’s disease. Neuroscience Letters. 2014;563:140–3. Doi: 10.1016/j.neulet.2014.01.016
Ramirez L, Acosta-Uribe J, Giraldo MM, Moreno S, Baena A, Alzate D, et al. Genetic origin of a large family with a novel PSEN1 mutation (Ile416Thr). Alzheimer’s & Dementia. 2019;15(5):709–19.
Itzcovich T, Chrem-Méndez P, Vázquez S, Barbieri- Kennedy M, Niikado M, Martinetto H, et al. A novel mutation in PSEN1 (p.T119I) in an Argentine family with early- and late-onset Alzheimer’s disease. Neurobiology of Aging. 2020;85:155-155.
Ramos C, Aguillon D, Cordano C, Lopera F. Genetics of dementia: insights from Latin America. Dement neuropsychol. 2020;14(3):223–36.
Bagyinszky E, Ch’ng G-S, Bae SO, An SS, Kim S. Identification of two novel mutations, PSEN1 E280K and PRNP G127S, in a Malaysian family. NDT. 2015; 2315.
Park JE, Kim HJ, Kim Y-E, Jang H, Cho SH, Kim SJ, et al. Analysis of dementia-related gene variants in APOE ε4 noncarrying Korean patients with early-onset Alzheimer’s disease. Neurobiology of Aging. 2020;85:155.e5-155.
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