Novel Treatments Could Turn the Tide for Alzheimer Disease


Anti-amyloid antibody administration decreased plaque volume in clinical trials of patients with early AD, indicating that passive immunotherapies could be a promising treatment for the disease.

Alzheimer disease (AD) is an age-related neurodegenerative condition that is multifaceted, intricate, irreversible and advances over time. In individuals older than 60 years, the incidence of AD doubles every 10 years.1 Progressive memory loss and functional impairment are typical features of AD. Patients with AD experience behavioral and psychological dementia symptoms, such as delusions, misinterpretations, mood swings, and behavioral abnormalities.2

The most common cause of dementia, AD, is identified by the co-occurrence of tau and amyloid.3 β-amyloid (Aβ) and tau are 2 misfolded proteins that are considered the pathological hallmarks of AD. Tau accumulation is linked with Aβ deposition,4 whereas neurodegeneration, brain atrophy, and glucose hypometabolism are linked with tau accumulation.5,6

Image of a brain missing a puzzle piece, dementia, Alzheimer disease concept

Image credit: © Orawan |

Current therapies are unable to stop the progression of AD or produce adequate therapeutic results, despite the significant and long-lasting symptoms. Acetylcholinesterase inhibitors (AChEIs) and NMDA-receptor antagonists (NMDAR) are part of the existing approved therapy, but their combination only offers momentary symptom relief. The FDA-approved medications to treat AD are galantamine (Razadyne; Janssen), donepezil (Aricept; Eisai Inc. and Pfizer), rivastigmine (Exelon; Novartis), and memantine (Namenda; AbbVie). AChEIs comprise the first 4 medications, whereas NMDAR antagonists make up the final medication.

AChEIs are recommended as the first-line medication for mild to moderate AD in American and European guidelines. AChEIs, however, only exhibit non-significant efficacy on functional ability and only modest effects on cognitive deficits in mild to moderate AD.7 Without any functional improvement, memantine's effectiveness in treating cognitive symptoms is quite limited.8 According to the amyloid hypothesis, one of the main causes of AD pathogenesis is Aβ formation and one of AD's current therapy goals is to reduce the buildup of Aβ. Immunotherapy directed against amyloids is a therapeutic strategy examined by the relevant authorities to combat AD.9

Aducanumab (Aduhelm; Biogen), an anti-amyloid immunotherapy for AD, was controversially given fast track FDA approval in June 2021 after showing a decrease in Aβ; still, it is unknown if it will stop cognitive deterioration in patients with early AD, and adverse effects are frequent.10,11 As a result of aducanumab's ambiguous clinical benefits, the US Centers for Medicare and Medicaid Services declared that any future anti-amyloid antibodies that the FDA approved would need to undergo more research and said the agency would only pay for aducanumab treatment for patients enrolled in clinical trials.12

Research on numerous novel anti-amyloid treatments is still ongoing.13 According to data from a recent 18-month clinical trial, lecanemab (Leqembi; Eisai) demonstrated less cognitive and functional deterioration when compared to a placebo.14 Lecanemab was recently given full approval by the FDA15 and is thought to target the most toxic pathologic amyloid species. It exhibited high selectivity for soluble aggregated species of Aβ when compared with monomeric amyloid and moderate selectivity for fibrillar amyloid.16-20 The mean amyloid level of 22.99 centiloids in the lecanemab group, following 18 months of treatment in the amyloid sub-study, was below the threshold for amyloid positivity of about 30 centiloids, above which participants are considered to have elevated brain amyloid levels.21 Except for neurofilament light chain, which is less sensitive to neurodegeneration than the other markers and changes more slowly than the others, lecanemab significantly decreased markers of amyloid, tau, neurodegeneration, and neuroinflammation in the cerebrospinal fluid sub-study, and plasma analyses involving the entire population. According to van Dyck et al., infusion-related responses accounted for the majority of adverse events (affecting over 10% of participants) in the lecanemab group (26.4% with lecanemab and 7.4% with placebo).14

The need for novel AD treatments has reached a critical point. Researchers from all around the world are working hard to find new targets and create innovative therapeutic molecules to treat AD. Anti-amyloid antibody administration decreased plaque volume in clinical trials of patients with early AD, indicating that passive immunotherapies could be a promising treatment for the disease.

1. Eratne D, Loi SM, Farrand S, Kelso W, Velakoulis D, Looi JCI. Alzheimer’s disease: Clinical update on epidemiology, pathophysiology and diagnosis. Australas Psychiatry. 2018;26(4):347–357. doi:10.1177/1039856218762308
2. Lin CH, Lane HY. The Role of N-Methyl-D-Aspartate Receptor Neurotransmission and Precision Medicine in Behavioral and Psychological Symptoms of Dementia. Front. Pharmacol. 2019(10)540. doi:10.3389/fphar.2019.00540
3. Scheltens P, Blennow K, Breteler MMB, et al. Alzheimer’s disease. Lancet. 2016;388(10043):505-517. doi:10.1016/S0140-6736(15)01124-1
4. Leal SL, Lockhart SN, Maass A, Bell RK, Jagust WJ. Subthreshold amyloid predicts tau deposition in aging. J. Neurosci. 2018;38(19):4482-4489. doi:10.1523/JNEUROSCI.0485-18.2018
5. Adams JN, Lockhart SN, Li L, Jagust WJ. Relationships between tau and glucose metabolism reflect Alzheimer’s disease pathology in cognitively normal older adults. Cereb Cortex. 2019;29(5):1997-2009. doi:10.1093/cercor/bhy078
6. Wang L, Benzinger TL, Su Y, et al. Evaluation of tau imaging in staging Alzheimer disease and revealing interactions between β-amyloid and tauopathy. JAMA Neurol. 2016;73(9):1070-1077. doi:10.1001/jamaneurol.2016.2078
7. Blanco-Silvente L, Castells X, Saez M, et al. Discontinuation, efficacy, and safety of cholinesterase inhibitors for Alzheimer’s disease: a meta-analysis and meta-regression of 43 randomized clinical trials enrolling 16,106 Patients. Int J Neuropsychopharmacol. 2017;20(7):519-528. doi:10.1093/ijnp/pyx012
8. Blanco-Silvente L, Capellà D, Garre-Olmo J, Vilalta-Franch J, Castells X. Predictors of discontinuation, efficacy, and safety of memantine treatment for Alzheimer’s disease: Meta-analysis and meta-regression of 18 randomized clinical trials involving 5004 patients. BMC Geriatr. 2018;18(1):168. doi:10.1186/s12877-018-0857-5
9. Golde TE. The Aβ hypothesis: leading us to rationally designed therapeutic strategies for the treatment or prevention of Alzheimer disease. Brain Pathol. 2005;15(1):84-87. doi:10.1111/j.1750-3639.2005.rb00104.x
10. Budd Haeberlein S, Aisen PS, Barkhof F, et al. Two randomized phase 3 studies of aducanumab in early Alzheimer’s disease. J Prev Alzheimers Dis. 2022;9(2):197–210. doi:10.14283/jpad.2022.30
11. FDA grants accelerated approval for Alzheimer’s drug. News release. FDA. July 6, 2021. Accessed June 10, 2024.
12. Monoclonal antibodies directed against amyloid for the treatment of Alzheimer’s disease. Centers for Medicare & Medicaid Services. April 7, 2022. Accessed June 10, 2024.
13. Cummings J, Lee G, Ritter A, Sabbagh M, Zhong K. Alzheimer’s disease drug development pipeline: 2020. Alzheimers Dement. 2020;6(1):e12050. doi:10.1002/trc2.12050
14. Van Dyck CH, Swanson CJ, Aisen P, et al. Lecanemab in early Alzheimer’s disease. N Engl J Med. 2023;388(1):9-21. doi:10.1056/NEJMoa2212948
15. FDA Grants Accelerated Approval for Alzheimer’s Disease Treatment. News release. FDA. January 6, 2023. Accessed June 10, 2024.
16. Tucker S, Möller C, Tegerstedt K, et al. The murine version of BAN2401 (mAb158) selectively reduces amyloid-β protofibrils in brain and cerebrospinal fluid of tg-ArcSwe mice. J Alzheimers Dis. 2015;43(2):575-88. doi:10.3233/JAD-140741
17. Magnusson K, Sehlin D, Syvänen S, et al. Specific uptake of an amyloid-β protofibril-binding antibody-tracer in AβPP transgenic mouse brain. J Alzheimers Dis. 2013;37(1):29-40. doi:10.3233/JAD-130029
18. Söderberg L, Johannesson M, Nygren P, et al. Lecanemab, aducanumab, and gantenerumab — binding profiles to different forms of amyloid-beta might explain efficacy and side effects in clinical trials for Alzheimer’s disease. Neurotherapeutics. 2023;20(1):195-206. doi:10.1007/s13311-022-01308-6
19. Lublin AL, Gandy S. Amyloid-β oligomers: possible roles as key neurotoxins in Alzheimer’s disease. Mt Sinai J Med. 2010;77(1):43-9. doi:10.1002/msj.20160
20. Haass C, Selkoe DJ. Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer’s amyloid beta-peptide. Nat Rev Mol Cell Biol. 2007;8(2):101-112. doi:10.1038/nrm2102
21. Fleisher AS, Chen K, Liu X, et al. Using positron emission tomography and florbetapir F18 to image cortical amyloid in patients with mild cognitive impairment or dementia due to Alzheimer disease. Arch Neurol. 2011;68:1404-1411. doi:10.1001/archneurol.2011.150

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