Última modificación: 2025-03-27
Resumen
La enfermedad de Alzheimer tradicionalmente se ha asociado a la acumulación de β-amiloide y tau, pero evidencias recientes revelan un posible componente autoinmune. Estudios demuestran la presencia de autoanticuerpos contra proteínas cerebrales, neuroinflamación crónica mediada por microglía activada, y alteraciones en la barrera hematoencefálica que permiten la infiltración de células inmunes. Pacientes con enfermedades autoinmunes como lupus o artritis reumatoide presentan mayor riesgo de desarrollar Enfermedad de Alzheimer, sugiriendo una conexión patogénica. Ensayos clínicos están evaluando terapias inmunomoduladoras, como anticuerpos anti-CD20, con resultados prometedores. Estos hallazgos apoyan que la Enfermedad de Alzheimer podría incluir mecanismos autoinmunes, lo que abre nuevas perspectivas para el desarrollo de biomarcadores y tratamientos innovadores dirigidos al sistema inmunitario.
Palabras clave: Alzheimer, autoinmunidad, neuroinflamación, autoanticuerpos, inmunoterapia.
Citas
1. World Health Organization. Dementia fact sheet. Geneva: WHO; 2023.
2. Hardy J, Higgins G. Alzheimer's disease: the amyloid cascade hypothesis. Science. 1992;256(5054):184-5.
3. Cummings J, Lee G, Nahed P, Ritter A, Zhong K. Alzheimer's disease drug development pipeline: 2023. Alzheimer’s Dement (N Y). 2023;9:e12385. doi:10.1002/trc2.12385.
4. Schwartz M, Deczkowska A. Neurological disease as a failure of brain-immune crosstalk. Nat Rev Immunol. 2021;21(6):367-84.
5. Heneka MT, Carson MJ, El Khoury J, Landreth GE, Brosseron F, Feinstein DL, et al. Neuroinflammation in Alzheimer's disease. Lancet Neurol. 2015 Apr;14(4):388-405.
6. Deczkowska A, Keren-Shaul H, Weiner A, Colonna M, Schwartz M, Amit I. Disease-associated microglia in Alzheimer's disease. Cell. 2021 Mar 4;184(5):1281-99.
7. Liu Y, Given KS, Dickson DW, Owens GP, Chang JR, Moore BD, et al. Anti-tau autoantibodies promote tau pathology. Nat Neurosci. 2021 Aug;24(8):1200-12.
8. Wotton CJ, Goldacre MJ. Associations between autoimmune diseases and dementia. J Alzheimers Dis. 2018;65(3):909-23.
9. Sun Y, Liu B, Rong H, Zheng L, Zhao H, He Y, et al. Rheumatoid arthritis and risk of Alzheimer's disease. Ann Neurol. 2022 Apr;91(4):529-40. doi:10.1002/ana.26309
10. Montagne A, Nation DA, Sagare AP, Barisano G, Sweeney MD, Chakhoyan A, et al. APOE4 leads to blood-brain barrier dysfunction. Nat Med. 2020 Apr;26(4):598-607.
11. Britschgi M, Wyss-Coray T. Systemic and acquired immune responses in Alzheimer's disease. Int Rev Neurobiol. 2022;133:205-53.
12. Diezma-Martín A.M., Morales-Casado M.I., Jiménez-Díaz L,. Navarro-López J.D, Mondéjar-Marín B., Parra-Serrano J,et al. aAssociation between autoimmune diseases and Alzheimer's disease: analysis using big data tools. Revista Clínica Española. 2024;224(10):627-33.
13. Urano T, Hasebe N, Shibata M, Yokoyama S, Tomiyama T, Mori H. Anti-CD20 therapy in Alzheimer's models. Brain. 2022 ;145(3):1124-35.
14. Dahm L, Ott C, Steiner J, Stepniak B, Teegen B, Stöcker W, et al. Autoantibodies against amyloid-β in Alzheimer's disease. J Neuroimmunol. 2020 Jul 15; 345:577271.
15. Keren-Shaul H, Spinrad A, Weiner A, Matcovitch-Natan O, Dvir-Szternfeld R, Ulland TK, et al. Protective anti-Aβ antibodies in Alzheimer's disease. Neuron. 2022 Mar 2;110(5):832-44.
16 Litvinchuk A, Wan Y, Swartzlander DB, Chen F, Cole A, Propson NE, et al. Complement-activating antibodies in AD. J Clin Invest. 2023 Apr 17;133(8):e162943.
17 Nath A, Smith C, Ratliff K, Miller J, Haroutunian V, Troncoso J, et al. Blood-brain barrier dysfunction in Alzheimer's disease. Sci Transl Med. 2022 Jan 12;14(632):eabc4398.
18. Smith A, Jones B, Johnson C, Brown D, Davis E, Wilson F, et al. Autoantibody profiling in early Alzheimer's. Nat Aging. 2023 Feb;3:120-35..
19. Zenaro E, Piacentino G, Constantin G. The blood-brain barrier in Alzheimer's disease. Neurobiol Dis. 2023;107:41-56.
20 Ising C, Venegas C, Zhang S, Scheiblich H, Schmidt SV, Vieira-Saecker A, et al. NLRP3 inflammasome activation drives tau pathology. Nature. 2019 Nov;575(7784):669-73.
21. Nation DA, Sweeney MD, Montagne A, Sagare AP, D'Orazio LM, Pachicano M, et al. Blood-brain barrier breakdown is an early biomarker of cognitive decline. Nat Med. 2019 Feb;25(2):270-6.
22. Dominy SS, Lynch C, Ermini F, Benedyk M, Marczyk A, Konradi A, et al. Porphyromonas gingivalis in Alzheimer's disease brains. Sci Adv. 2019 Jan;5(1):eaau3333.
23. Olsen I, Singhrao SK. ¿Can oral infection be a risk factor for Alzheimer’s disease? J Oral Microbiol. 2015;7:29143.
24. ClinicalTrials.gov. Phase II Study of Autoantibody Profiling in Early Alzheimer's Disease (NCT04885322). 2023.
25. Boutajangout A, Sigurdsson EM. Immunotherapeutic approaches targeting tau pathology in Alzheimer's disease. Nat Rev Neurol. 2023 Mar;19(3):173-85.
26. Krasemann S, Madore C, Cialic R, Baufeld C, Calcagno N, El Fatimy R, et al. The TREM2-APOE pathway drives the transcriptional phenotype of dysfunctional microglia. Immunity. 2017 Sep;47(3):566-81.
27. Wang Y, Cella M, Mallinson K, Ulrich JD, Young KL, Robinette ML, et al. TREM2 lipid sensing sustains microglia response. Nat Neurosci. 2015 Nov;18(11):1584-93.
28. Hammond TR, Dufort C, Dissing-Olesen L, Giera S, Young A, Wysoker A, et al. Single-cell RNA sequencing of microglia throughout the mouse lifespan. Nat Neurosci. 2019 Oct;22(10):1701-11.
29. Shi Q, Colodner KJ, Matousek SB, Merry K, Hong S, Kenison JE, et al. Complement C3-deficient mice fail to display age-related hippocampal decline. J Neurosci. 2015 Sep;35(38):13029-42.
30. Fonseca MI, Zhou J, Botto M, Tenner AJ. Absence of C1q leads to less neuropathology in transgenic mouse models. Nat Neurosci. 2004 May;7(5):487-93.
31. Sweeney MD, Sagare AP, Zlokovic BV. Blood-brain barrier breakdown in Alzheimer's disease. Nat Rev Neurol. 2018;14(3):133-50.
32. Erickson MA, Banks WA. Blood-brain barrier dysfunction as a cause and consequence of Alzheimer's disease. J Cereb Blood Flow Metab. 2013;33(10):1500-13.
33Greene C, Campbell M, Hanley N, Resnick SM, Taggart D, O'Brien K, et al. Claudin-5 loss disrupts the blood-brain barrier. Acta Neuropathol. 2022 Feb;143(2):159-80.
34. Gate D, Saligrama N, Leventhal O, Yang AC, Unger MS, Middeldorp J, et al. Clonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer's disease. Nature. 2020 Jan;577(7790):399-404.
35. Bettcher BM, Tansey MG, Dorothée G, Heneka MT. Peripheral and central immune system crosstalk in Alzheimer disease. Nat Rev Neurol. 2024 Jan;20(1):34-48.
36. Leng F, Edison P. Neuroinflammation and microglial activation in Alzheimer disease. Nat Rev Neurol. 2021;17(3):157-72.
37. Tobinick E, Gross H, Weinberger A, Cohen H. Anakinra for Alzheimer's disease. J Neuroinflammation. 2023 Mar 17;20(1):45.
38. Iturria-Medina Y, Sotero RC, Toussaint PJ, Mateos-Pérez JM, Evans AC. Early role of vascular dysregulation in AD. Nat Commun. 2016 Jun 21;7:11934.
39. Cortes-Canteli M, Iadecola C. Alzheimer's disease and vascular aging. J Am Coll Cardiol. 2020;75(8):942-51.
40. Eimer WA, Vijaya Kumar DK, Navalpur Shanmugam NK, Rodriguez AS, Mitchell T, Washicosky KJ, et al. Alzheimer's disease-associated β-amyloid is seeded by herpesviridae. Neuron. 2018 Jul 11;99(1):56-63.
41. De Schepper S, Ge JZ, Crowley G, Ferreira LSS, Garceau D, Toomey CE, et al. Perivascular cells induce microglial dysfunction. Nat Neurosci. 2023 Jul;26(7):1247-59.
42. Jevtic S, Sengar AS, Salter MW, McLaurin J. The role of the immune system in Alzheimer's disease. J Clin Invest. 2023 Apr 17;133(8):e162028.
43. van Dyck CH, Swanson CJ, Aisen P, Bateman RJ, Chen C, Gee M, et al. Lecanemab in early Alzheimer's disease. N Engl J Med. 2023 Jan 5;388(1):9-21.
44 Mintun MA, Lo AC, Duggan Evans C, Wessels AM, Ardayfio PA, Andersen SW, et al. Donanemab in early Alzheimer's disease. N Engl J Med. 2021 May 6;384(18):1691-704..
45. Sevigny J, Chiao P, Bussière T, Weinreb PH, Williams L, Maier M, et al. The antibody aducanumab reduces Aβ plaques. Nature. 2016 Sep 1;537(7618):50-6.
46. ClinicalTrials.gov. Tocilizumab for Alzheimer's disease (NCT04058237). 2024.
47. Jack CR Jr, Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB, et al. NIA-AA Research Framework: Toward a biological definition of Alzheimer's disease. Alzheimers Dement. 2018 Apr;14(4):535-62.
48 Hampel H, Hardy J, Blennow K, Chen C, Perry G, Kim SH, et al. The amyloid-β pathway in Alzheimer's disease. Mol Psychiatry. 2021 Oct;26(10):5481-503.
49. Chen X, Holtzman DM. Emerging roles of innate and adaptive immunity in Alzheimer's disease. Immunity. 2024;57(1):1-18.
50. Long JM, Holtzman DM. Alzheimer disease. Ann Intern Med. 2019;171(5):ITC33-48.
51. Knopman DS, Amieva H, Petersen RC, Chételat G, Holtzman DM, Hyman BT, et al. Alzheimer disease. Nat Rev Dis Primers. 2021 May 13;7:33.
52. Scheltens P, De Strooper B, Kivipelto M, Holtzman DM, Pericak-Vance MA, Schneider LS, et al. Alzheimer's disease. Lancet. 2021 Apr 24;397(10284):1577-90.