To Aducanumab or Not for Alzheimer’s Disease?

Aducanumab is a monoclonal antibody targeting amyloid beta protein plaque breakdown. These plaques are a cardinal feature in Alzheimer’s Disease.  Aducanumab has raised controversy over both its safety and efficacy.1 Safety is concerning for this monoclonal antibody as the drug can compromise the blood-brain-barrier with subsequent risk of asymptomatic intracranial hemorrhage or swelling in approximately 30-40% of patients, predominantly those patients positive for the APOE e4 allele with almost half of them discontinuing treatment .1,3

For efficacy issues, in the two incomplete Phase 3 studies (EMERGE and ENGAGE) submitted to the FDA, there was NO convincing evidence that aducanumab had effects on cognitive decline and both studies were stopped early due to Biogen (manufacturer) concluded the drug did not work.2 Both trials were of similar design of an 18-month trial comparing placebo to aducanumab.  The ENGAGE showed no benefit of drug over placebo even after reanalysis of the data.4 However, in the EMERGE trial, when Biogen reanalyzed the data, there was some benefit in the one arm of high dose drug.4 Moreover, the Advisory Committee of outside experts voted unanimously to not approve aducanumab due to the lack of evidence that the drug worked and the safety issues of brain swelling and bleeding.1,2  The approval was therefore based on the reduction of a secondary marker (amyloid) with very questionable benefit clinically. A key finding of these two trials was that family and clinicians detected no benefit in the treated patients.

While the F.D.A. approved this monoclonal antibody based solely on one trial the safety and efficacy remains debatable. Furthermore, the cost of the drug is estimated at around $60,000 annually plus the MRI scans needed for monitoring for intracranial hemorrhage and/or swelling. This includes the need for obtaining MRIs prior to the 7th and 12th infusions. If radiographic severe amyloid-related imaging abnormalities (ARIA) with microhemorrhages (ARIA-H) are observed, treatment may be continued with caution only after a clinical evaluation and a follow-up MRI demonstrates radiographic stabilization (i.e., no increase in size or number of ARIA-H). Caution and serious discussions with families and the patient should occur to keep the focus on patient-centered evidence-based best practices. From the literature there is scant credible evidence to support the use of this new agent and plenty of safety concerns. Perhaps Aducanumab is a stepping stone for future monoclonal antibodies that will show better efficacy and safety in Alzheimer’s disease? The jury is in recess. Unfortunately, Biogen has announced the required post-marketing testing the FDA mandated may take up to nine years – that is a long time to wait for such critical information. For example, the most common side-effect is edema of the brain manifest on MRI as signal abnormalities suggestive of vasogenic edema and sulcal effusions (ARIA-E). As mentioned above, these are much more common in APOE4 carriers. However, APOE genotyping is not referred to in the Prescribing Information. The two trials that have been performed to measure efficacy were limited to mild cognitive impairment and mild or early dementia in persons with amyloid deposition detected on PET scan. The Prescribing Information does not mention requiring evidence of amyloid on PET scanning and does not limit the use of this drug to the early stages as studied in the clinical trials – it can be given irrespective of the disease severity. We have no idea what the side-effect profile would be in such severely demented patients. Pre-clinical persons with amyloid, such as those with familial Alzheimer’s genes, are not included in the FDA approval although theoretically they would stand to benefit most. 

There is late-breaking news, though. Although the published package insert has not yet been revised, press releases from the manufacturer indicate the FDA has revised the indication: “Treatment with Aduhelm should be initiated in patients with mild cognitive impairment or mild dementia stage of disease, the population in which treatment was initiated in clinical trials. There are no safety or effectiveness data on initiating treatment at earlier or later stages of the disease than were studied." This revision certainly is more in line with the group that has been studied, and may help address some of the concerns about this "accelerated approval". 

Would you like to peek in as the world’s experts discuss this drug and the process that led to its approval in the US? I strongly recommend periodically checking Alzforum. 

The discussion about the FDA approval is here.


  1. Cummings J, Aisen P, Lemere C, Atri A, Sabbagh M, Salloway S. Aducanumab produced a clinically meaningful benefit in association with amyloid lowering. Alzheimer’s research & therapy. 2021;13(1):98. doi:10.1186/s13195-021-00838-z
  2. Kesselheim AS, Avorn J.“F.D.A. Has Reached a New Low” accessed June 15,2021 
  3. Schneider L, The Lancet. Neurology [Lancet Neurol], ISSN: 1474-4465, 2020 Feb; Vol. 19 (2), pp. 111-112; Publisher: Lancet Pub. Group; PMID: 31978357.
  4. Kuller LH, Lopez OL. ENGAGE and EMERGE: Truth and consequences? Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association. 2021;17(4):692-695. Accessed June 15, 2021. (Updated link 7/19/2021)
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