Aducanumab is a IgG1 monoclonal antibody therapy that targets amyloid beta (Aβ), aiding in clearance of the Aβ plaques that are a defining molecular feature of Alzheimer’s Disease (AD). Controversy erupted in June 2021 when the FDA overruled their own advisory committee and approved aducanumab (Aduhelm, Biogen) for the treatment of AD. Three members of the Peripheral and Central Nervous System Drugs Advisory Committee resigned in protest and the U.S. House of Representatives and other groups are investigating the FDA’s decision, including the relationship between the FDA and Biogen, setting the stage for what may be landmark modifications to drug approval.

The Alzheimer’s Association estimates that over 6 million Americans are living with AD, and that number is projected to grow to 12.7 million people by the year 2050. The Alzheimer’s Association “enthusiastically” welcomed the approval, claiming it as “a victory for people living with AD and their families” ( Prior to this year, there were no pharmacologic treatments that slowed the progression of neuronal death caused by AD. Viewing AD in a person-centric manner, consider a 70-year-old patient who has seen relatives cognitively deteriorate and die of AD. This hypothetical patient is now experiencing their own cognitive decline and desires for their “golden years” to be lived in dignity without being a burden to their family. Add to the calculus that AD and other dementias will cost the U.S. $355 billion in 2021 alone, and we can all appreciate the unmet need to find an effective treatment for AD and the desperate search for a “penicillin”-like therapy.

“If aducanumab were widely prescribed and covered by Medicare, will Medicare programs or payment rates need to be cut for other services? Could this reverberate to other third-party payers? For these reasons alone, it is going to be important for the specialty to monitor utilization of aducanumab and other like medications in the pipeline.”

In this article, we will review the story behind aducanumab’s approval and explore the implications this may have on perioperative anesthesia and on the Medicare funding that quality health care for the nation is dependent on.

AD is characterized by a slow decline in cognitive function that seems to be correlated to a precursor period of Aβ plaque burden. Treatments have focused on the thought that “β-amyloid precursor protein mismetabolism and β-amyloid deposition are the primary events in the disease process” (Trends Pharmacol Sci 1991;12:383-8) since it was postulated 30 years ago. Aducanumab was shown to reduce Aβ plaque burden; convincing evidence can be found in its early-phase clinical trial (designed to evaluate dosages) and two subsequent Phase 3 studies with a combined 3,285 participants. However, the improvement in cognitive markers seen in one of the Phase 3 studies was not replicated in the other, and a preplanned pooled analysis led to the stoppage of both for futility. Meta-analysis of aducanumab with four other antibody drugs in Phase 3 trials showed large-effect sizes for biomarkers like Aβ-tracer uptake in brain imaging (reduced plaque burden), but small to no effect for the cognitive markers (Ageing Res Rev 2021;68:101339). So, when the advisory panel was asked, “is it reasonable to consider [the positive study] has primary evidence of effectiveness of aducanumab for the treatment of Alzheimer’s disease?” it is not surprising that there were 10 recommending against and one “uncertain” (

But the ultimate decision is determined by the FDA, not the advisory panel, and the agency granted approval through the “accelerated approval” process, where a drug need only meet these four requirements: “1) the drug must be for treatment of a serious disease with unmet medical needs; 2) the drug must be expected to provide meaningful clinical advantage over available therapy; 3) there must be a showing of an effect of the drug on a surrogate end point (typically, that reflects the underlying pathology of the disease); and 4) there must be a determination that it is reasonably likely that the effect on the surrogate end point predicts clinical benefit of the drug” (JAMA Intern Med 2021;181:1276-8). Although the initial approval was for anyone with AD, the FDA subsequently narrowed the indications to only those with mild AD or with mild cognitive impairment (MCI) due to AD. This was likely due, in part, to criticism of the cost – estimated to be $56,000 per year. If it was assumed that only 10% of the 6 million patients mentioned above went on aducanumab therapy, the cost for Medicare Part B drug spending would increase 88% (JAMA 2021;326:383-4). We can only imagine the effect this could have on Medicare funding for other critical elements of quality health care for Americans. If aducanumab were widely prescribed and covered by Medicare, will Medicare programs or payment rates need to be cut for other services? Could this reverberate to other third-party payers? For these reasons alone, it is going to be important for the specialty to monitor utilization of aducanumab and other like medications in the pipeline.

Yet to be discussed is what the practicing anesthesia provider needs to know about aducanumab (and the other anti-amyloid therapies). One of the most common side effects associated with these is Amyloid Related Imaging Abnormalities (ARIAs); these seem to occur in approximately 40% of aducanumab patients and may result from increased cerebrovascular permeability. ARIAs are imaging changes that signal vasogenic edema (ARIA-E) and intracerebral hemorrhage (ARIA-H). Most ARIAs are classified as mild and may present with symptoms that include headaches, dizziness, confusion, altered mental status, nausea, or vision changes. It has been theorized that the Aβ plaque mobilization that occurs with aducanumab leads to ARIAs, thus the more effective a treatment, the more likely ARIAs become (Ageing Res Rev 2021;68:101339). To monitor for ARIAs, patients receiving aducanumab need to undergo MRI within one year before starting treatment, before their seventh treatment, and again before their twelfth.

The perioperative care of patients with AD or MCI already presents unique challenges. The Perioperative Brain Health Expert Panel recently released their review of key actions to reduce the incidence of perioperative neurocognitive disorders, highlighting education, cognitive and delirium screening, non-pharmacologic interventions, pain control, and the avoidance of antipsychotics and benzodiazepines (Br J Anaesth 2021;126:423-32). Consensus recommendations on what drugs to give or to avoid in AD/MCI are lacking. Arguments can be made for regional-based approaches, EEG depth monitoring, and avoiding centrally active anticholinergic agents and neuromuscular blockade when possible (J Cardiothorac Vasc Anesth 2014;28:1609-23).

There is virtually no data available on perioperative concerns for a patient who is receiving aducanumab. But the following seem biologically plausible considerations. Whether or not anesthesia-related changes in cerebral blood flow or intracranial pressure could exacerbate the process that leads to ARIA is not known. It seems reasonable in a patient with symptomatic ARIA to treat the patient with goal-directed therapy that would limit exacerbation of vasogenic edema. At the time of this writing, there has been at least one death reported to the FDA’s Adverse Event Reporting System due to brain swelling in a patient taking aducanumab ( There may be some potential for an adverse reaction between monoclonal antibody therapy and anesthesia, or at least worsening of antibody-induced pathology. Herijgers et al. reported a case of acute transverse myelitis after spinal anesthesia in a patient taking obinutuzumab for follicular lymphoma (Reg Anesth Pain Med 2021;46:828-30). Careful questioning after the case reveled that an a priori underlying transverse myelitis was likely present; one could speculate that low-dose local anesthetic neurotoxicity could have led to the worsened clinical picture. They concluded with the recommendations that “the presented case warrants caution when performing neuraxial anesthesia in patients on monoclonal antibody therapies.”

In conclusion, the take-home messages:

  • We will be caring for patients on aducanumab in the perioperative period for which there is scant literature to base best practices.
  • At the very minimum, the pre-anesthesia evaluation for a patient taking aducanumab should focus on ARIA symptoms, and postponement of surgery (if possible) should be considered should any be present.
  • If surgery is necessary in a patient with ARIA symptomatology, goal-directed therapy based on a permeable blood-brain barrier should be considered.
  • There are hypothetical but unknown risks when performing neuraxial anesthesia for patients on antibody therapies.
  • Counseling of patients on the unknown interaction of aducanumab and anesthesia is also important, and it may be a factor in the overall risk-benefit discussion for surgery.