Aducanumab, a Novel Anti-Amyloid Monoclonal Antibody, for the Treatment of Alzheimer’s Disease: A Comprehensive Review
Alzheimer’s disease (AD) is the most common form of dementia affecting millions of individuals, including family members who often take on the role as caregiver. This debilitating disease reportedly consumes 8% of the total United States healthcare expenditure, with medical and nursing outlays accounting for an estimated $290 billion. Cholinesterase inhibitors and N-methyl-D-aspartate receptor antagonists have historically been the most widely used pharmacologic therapies for patients with AD, however, these drugs are not curative. This review discusses the epidemiology, pathophysiology, risk factors, presentation, and current treatment of AD followed by the role of the novel monoclonal antibody, aducanumab, in treatment of AD. Currently aducanumab is the only Food and Drug Administration (FDA) approved drug that acts to slow progression of this disease. Aducanumab is an anti-amyloid drug which functions by selectively binding amyloid aggregates in both the oligomeric and fibrillar states. Studies show aducanumab may help to restore neurological function in patients with AD by reducing beta-amyloid plaques and reestablishing neuronal calcium permeability. However, there is concern the magnitude of this drug’s benefit may only be statistically significant and not clinically significant. Despite this skepticism, aducanumab has proven to significantly decrease amyloid in all cortical brain regions examined. In summary, aducanumab has provided hope for those working toward the goal of providing patients a safe and viable treatment option in the management of AD.
1. Breijyeh Z, Karaman R. Comprehensive Review on Alzheimer's Disease: Causes and Treatment.
Molecules.2020;25(24):5789. doi:10.3390/molecules25245789
2. What is Alzheimer's? Alzheimer's Disease and Dementia. Accessed September 12,2021. https://alz.org/alzheimers-dementia/what-is-alzheimers
3. 2021 Alzheimer's disease facts and figures.Alzheimers Dement J Alzheimers Assoc.2021;17(3):327-406. doi:10.1002/alz.12328
4. Pudelewicz A, Talarska D, Baczyk G. Burden of caregivers of patients with Alzheimer's disease. Scand J Caring Sci.2019;33(2):336-341. doi:10.1111/scs.12626
5. Norins LC. Predicted economic damage from a quick, simple Alzheimer's disease cure. Med Hypotheses.2019;133:109398. doi:10.1016/j.mehy.2019.109398
6. DeTure MA, Dickson DW. The neuropathological diagnosis of Alzheimer's disease. Mol Neurodegener.2019;14(1):32. doi:10.1186/s13024-019-0333-5
7. Rajan KB, Weuve J, Barnes LL, McAninch EA, Wil- son RS, Evans DA. Population estimate of people with clinical Alzheimer's disease and mild cognitive impairment in the United States(2020-2060).
Alzheimers Dement J Alzheimers Assoc.2021;17(12):1966-1975. doi:10.1002/alz.12362
8. Centers for Disease Control and Prevention(CDC). Trends in aging--United States and worldwide.
MMWR Morb Mortal Wkly Rep.2003;52(6):101-104,106.
9. Hersi M, Irvine B, Gupta P, Gomes J, Birkett N, Krewski D. Risk factors associated with the onset and progression of Alzheimer's disease: A systematic review of the evidence. Neurotoxicology.
2017;61:143-187. doi:10.1016/j.neuro.2017.03.006
10. Armstrong RA. Risk factors for Alzheimer's disease. Folia Neuropathol.2019;57(2):87-105. doi:10.5114/fn.2019.85929
11. Silva MVF, Loures C de MG, Alves LCV, de Souza LC, Borges KBG, Carvalho M das G. Alzheimer's disease: risk factors and potentially protective measures. J Biomed Sci.2019;26(1):33. doi:10.1186/s12929-019-0524-y
12. Penney J, Ralvenius WT, Tsai LH. Modeling Alzheimer's disease with iPSC-derived brain cells. Mol Psychiatry.2020;25(1):148-167. doi:10.1038/s41380-019-0468-3
13. Serrano-Pozo A, Das S, Hyman BT. APOE and Alzheimer's disease: advances in genetics, pathophysiology, and therapeutic approaches. The Lancet Neurology.2021;20(1):68-80. doi:10.1016/s1474-4422(20)30412-9
14. Mayeux R, Stern Y. Epidemiology of Alzheimer Disease. Cold Spring Harb Perspect Med.2012;2(8):a006239. doi:10.1101/cshperspect.a006239
15. Livingston G, Huntley J, Sommerlad A, et al. Dementia prevention, intervention, and care:2020 report of the Lancet Commission. The Lancet.2020;396(10248):413-446. doi:10.1016/s0140-6736(20)30367-6
16. Lahiri DK, Maloney B. The “LEARn” (Latent Early-life Associated Regulation) model integrates environmental risk factors and the developmental basis of Alzheimer's disease, and proposes remedial steps. Exp Gerontol.2010;45(4):291-296. doi:10.1016/j.exger.2010.01.001
17. Villain N, Dubois B. Alzheimer's Disease Including Focal Presentations. Semin Neurol.
2019;39(2):213-226. doi:10.1055/s-0039-1681041
18. Spires-Jones TL, Hyman BT. The intersection of amyloid beta and tau at synapses in Alzheimer's disease. Neuron.2014;82(4):756-771. doi:10.1016/j.neuron.2014.05.004
19. Serrano-Pozo A,Frosch MP,Masliah E,Hyman BT. Neuropathological Alterations in Alzheimer Disease. Cold Spring Harb Perspect Med.2011;1(1):a006189. doi:10.1101/cshperspect.a006189
20. Cras P,Kawai M,Lowery D,Gonzalez-DeWhitt P,Greenberg B, Perry G. Senile plaque neurites in Alzheimer disease accumulate amyloid precursor protein. Proc Natl Acad Sci US A.1991;88(17):7552-7556. doi:10.1073/pnas.88.17.7552
21. Eratne D, Loi SM, Farrand S, Kelso W, Velakoulis D, Looi JC. Alzheimer's disease: clinical update on epidemiology, pathophysiology and diagnosis.
Australas Psychiatry Bull R Aust NZ Coll Psychiatr.2018;26(4):347-357. doi:10.1177/1039856218762308
22. McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer's disease: Recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement J Alzheimers Assoc.2011;7(3):263-269. doi:10.1016/j.jalz.2011.03.005
23. Shea Y, Pan Y, Mak HKF, et al. A systematic review of atypical Alzheimer's disease including behavioural and psychological symptoms. Psychogeriatr Off IJpn Psychogeriatr Soc.2021;21(3):396-406. doi:10.1111/psy g.12665
24. Badcock JC, Laroi F, Kamp K, et al. Hallucinations in Older Adults: A Practical Review. Schizophr Bull.2020;46(6):1382-1395. doi:10.1093/schbul/sbaa073
25. Sáiz-Vazquez O, Gracia-Garcia P, Ubillos-Landa S, et al. Depression as a Risk Factor for Alzheimer's Disease: A Systematic Review of Longitudinal Meta-Analyses. J Clin Med.2021;10(9):1809. doi:10.3390/jcm10091809
26. Tsuno N, Homma A. What is the association between depression and Alzheimer's disease? Expert Rev Neurother.2009;9(11):1667-1676. doi:10.1586/ern.09.106
27. Mossello E, Ballini E. Management of patients with Alzheimer's disease: pharmacological treatment and quality of life. Ther Adv Chronic Dis.2012;3(4):183-193. doi:10.1177/2040622312452387
28. Grossberg GT, Manes F, Allegri RF, et al. The Safety, Tolerability, and Efficacy of Once-Daily Memantine(28 mg):A Multinational, Randomized, Double-Blind, Placebo-Controlled Trial in Patients with Moderate-to-Severe Alzheimer's Disease Taking Cholinesterase Inhibitors. CNS Drugs.2013;27(6):469-478. doi:10.1007/s40263-013-0077-7
29. Cumbo E, Ligori LD. Differential Effects of Current Specific Treatments on Behavioral and Psychological Symptoms in Patients with Alzheimer's Disease: A 12-Month, Randomized, Open-Label Trial. JAD.2014;39(3):477-485. doi:10.3233/JAD-131190
30. Bond M, Rogers G, Peters J, et al. The effectiveness and cost-effectiveness of donepezil, galantamine, rivastigmine and memantine for the treatment of Alzheimer's disease(review of Technology Appraisal No.111): a systematic review and economic model. Health Technol Assess.2012;16(21). doi:10.3310/hta16210
31. Grossberg GT,Tong G,Burke AD,Tariot PN. Present Algorithms and Future Treatments for Alzheimer's Disease. Fink A, ed. JAD.2019;67(4):1157-1171. doi:10.3233/JAD-180903
32. Briggs R, Kennelly SP, O'Neill D. Drug treatments in Alzheimer's disease. Clin Med. 2016;16(3):247-253. doi:10.7861/clinmedicine.16-3-247
33. Kabir MdT,Uddin MdS,Mamun AA,et al. Combination Drug Therapy for the Management of Alzheimer's Disease. IJMS.2020;21(9):3272. doi:10.3390/ijms21093272
34. Schneider L. A resurrection of aducanumab for Alzheimer's disease. The Lancet Neurology.2020;19(2):111-112. doi:10.1016/s1474-4422(19)30480-6
35. Sevigny J,Chiao P, Bussiere T,et al. The antibody aducanumab reduces Ap plaques in Alzheimer's disease. Nature.2016;537(7618):50-56. doi:10.1038/nature19323
36. Fillit H, Green A. Aducanumab and the FDA-where are we now? Nat Rev Neurol.2021;17(3):129-130. doi:10.1038/s41582-020-00454-9
37. Decourt B, Boumelhem F, Pope ED, Shi J, Mari Z, Sabbagh MN. Critical Appraisal of Amyloid Lowering Agents in AD. Curr Neurol Neurosci Rep.2021;21(8):39. doi:10.1007/s11910-021-01125-y
38. Arndt JW, Qian F, Smith BA, et al. Structural and kinetic basis for the selectivity of aducanumab for aggregated forms of amyloid-β. Sci Rep.2018;8:6412. doi:10.1038/s41598-018-24501-0
39. Frost CV, Zacharias M. From monomer to fibril: Abeta-amyloid binding to Aducanumab antibody studied by molecular dynamics simulation. Proteins.2020;88(12):1592-1606. doi:10.1002/prot.25978
40. Linse S, Scheidt T, Bernfur K, et al. Kinetic fingerprints differentiate the mechanisms of action of anti-Aβ antibodies. Nat Struct Mol Biol.2020;27(12):1125-1133. doi:10.1038/s41594-020-0505-6
41. Tolar M, Abushakra S, Hey JA, Porsteinsson A, Sabbagh M. Aducanumab, gantenerumab, BAN2401, and ALZ-801-the first wave of amyloid-targeting drugs for Alzheimer's disease with potential for near term approval. Alzheimers Res Ther.2020;12:95. doi:10.1186/s13195-020-00663-w
42. Kastanenka KV, Bussiere T, Shakerdge N, et al. Immunotherapy with Aducanumab Restores Calcium Homeostasis in Tg2576 Mice. J Neurosci.2016;36(50):12549-12558. doi:10.1523/jneurosci.2080-16.2016
43. Gamage KK, Kumar S. Aducanumab Therapy Ameliorates Calcium Overload in a Mouse Model of Alzheimer's Disease. J Neurosci Off J Soc Neurosci.2017;37(17):4430-4432. doi:10.1523/jneurosci.0420-17.2017
44. Ferrero J, Williams L, Stella H, et al. First-in-human, double-blind, placebo-controlled, single-dose escalation study of aducanumab(BIIB037) in mild-to-moderate Alzheimer's disease. Alzheimers Dement Transl Res Clin Interv.2016;2(3):169-176. doi:10.1016/j.trci.2016.06.002
45. Mo JJ, Li JY, Yang Z, Liu Z, Feng JS. Efficacy and safety of anti-amyloid-β immunotherapy for Alzheimer's disease: a systematic review and network meta-analysis. Ann Clin Transl Neurol.2017;4(12):931-942. doi:10.1002/acn3.469
46. Tian Hui Kwan A, Arfaie S, Therriault J, Rosa-Neto P, Gauthier S. Lessons Learnt from the Second Generation of Anti-Amyloid Monoclonal Antibodies Clinical Trials. Dement Geriatr Cogn Disord.2020;49(4):334-348. doi:10.1159/000511506
47. Avgerinos KI, Ferrucci L, Kapogiannis D. Effects of monoclonal antibodies against amyloid-β on clinical and biomarker outcomes and adverse event risks: A systematic review and meta-analysis of phase III RCTs in Alzheimer's disease. Ageing Res Rev.2021;68:101339. doi:10.1016/j.arr.2021.101339
48. Howard R, Liu KY. Questions EMERGE as Biogen claims aducanumab turnaround. Nat Rev Neurol.2020;16(2):63-64. doi:10.1038/s41582-019-0295-9
49. Knopman DS, Jones DT, Greicius MD. Failure to demonstrate efficacy of aducanumab: An analysis of the EMERGE and ENGAGE trials as reported by Biogen, December 2019. Alzheimers Dement.2021;17(4):696-701. doi:10.1002/alz.12213
50. Cummings J, Aisen P, Lemere C, Atri A, Sabbagh M, Salloway S. Aducanumab produced a clinically meaningful benefit in association with amyloid lowering. Alzheimers Res Ther.2021;13:98. doi:10.1186/s13195-021-00838-z
51. Kuller LH, Lopez OL. ENGAGE and EMERGE: Truth and consequences? Alzheimers Dement.2021;17(4):692-695. doi:10.1002/alz.12286
52. Alexander GC, Emerson S, Kesselheim AS. Evaluation of Aducanumab for Alzheimer Disease: Scientific Evidence and Regulatory Review Involving Efficacy, Safety, and Futility. JAMA.2021;325(17):1717-1718. doi:10.1001/jama.2021.3854
53. Andrews JS, Desai U, Kirson NY, Zichlin ML, Ball DE, Matthews BR. Disease severity and minimal clinically important differences in clinical outcome assessments for Alzheimer's disease clinical trials. Alzheimers Dement N YN.2019;5:354-363. doi:10.1016/j.trci.2019.06.005