A Primer on the Evolution of Aducanumab: The First Antibody Approved for Treatment of Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is the most common form of dementia with global burden projected to triple by 2050. It incurs significant biopsychosocial burden worldwide with limited treatment options. Aducanumab is the first monoclonal antibody recently approved by the US-FDA for mild AD through the accelerated approval pathway. It is the first molecule to be approved for AD since 2003 and carries with it a therapeutic promise for the future. As the definition of AD has evolved from a pathological entity to a clinic-biological construct over the years, the amyloid-β (Aβ) pathway has been increasingly implicated in its pathogenesis. The approval of Aducanumab is based on reduction of the Aβ load in the brain, which forms a surrogate marker for this pathway. The research populace has, however, been globally divided by skepticism and hope regarding this approval. Failure to meet clinical endpoints in the trials, alleged transparency issues, cost-effectiveness, potential adverse effects, need for regular monitoring, and critique of ‘amyloid cascade hypothesis’ itself are the main caveats concerning the antibody. With this controversy in background, this paper critically looks at antibody research in AD therapeutics, evidence, and evolution of Aducanumab as a drug and the potential clinical implications of its use in future. While the efficacy of this monoclonal antibody in AD stands as a test of time, based on the growing evidence it is vital to rethink and explore alternate pathways of pathogenesis (oxidate stress, neuroinflammation, cholesterol metabolism, vascular factors, etc.) as possible therapeutic targets that may help elucidate the enigma of this complex yet progressive and debilitating neurodegenerative disorder.

Unconjugated PLGA nanoparticles attenuate temperature-dependent β-amyloid aggregation and protect neurons against toxicity: implications for Alzheimer’s disease pathology

“…The cholinesterase inhibitors and the glutamate NMDA receptor antagonist memantine that have been approved for the treatment provide symptomatic relief for only a fraction of AD patients [ 9 , 82 , 83 ]. The beneficial effects of recently approved disease modifying Aβ monoclonal antibody Aducanumab on AD patients remain to be determined [ 84 , 85 ]. Some earlier studies have shown that PLGA nanoparticles functionalized with various drugs/agents such as donepezil, galantamine, quercetin, memantine and curcumin can exhibit beneficial effects on cellular and/or animal models of AD compared to cells/mice treated with drugs alone or vehicles used for dissolving drugs/PLGA nanoparticles [ 37 , 39 , 40 , 67 , 69 , 70 , 86 , 87 ].…”

Knowledge of the public about the role of lumbar puncture in the diagnosis of Alzheimer's disease in China

“…In 2019, the China Food and Drug Administration (CFDA) approved Sodium Oligomannate for the treatment of mild-moderate AD, which can effectively improve the cognitive function of AD patients and delay the progression of the disease [21][22][23]. In 2021, the U.S. FDA approved Aducanumab for the early treatment of AD, which can reduce Aβ deposition and tau phosphorylation and delay disease progression [24], all of which demonstrate that early diagnosis is important for AD patients. Therefore, we advise that physicians should put more effort into introducing the signi cance of early diagnosis and obtain patients' understanding.…”

Exploring the Efficacy of Anti-amyloid-β Therapeutics in Treating Alzheimer Disease

“…Aducanumab, gantenerumab, and BAN2401 all bind primarily to insoluble and soluble aggregates [28]. A major drawback in the current clinical trials of passive immunotherapy is the lack of specific targeting in most toxic Aβ oligomers, for example, aducanumab and gantenerumab bind to Aβ fibrillation or aggregates, while crenezumab can recognise different Aβ forms [90][91][92][93]. Through the 'peripheral sink' hypothesis, the antibody that targets soluble Aβ may play a role in the preclinical stages of AD.…”