AHFS Class:

• Monoclonal Antibodies 90:10.04

Generic Name(s):

• Aducanumab

• Aducanumab-avwa

Aducanumab is a recombinant human IgG₁ monoclonal antibody directed against amyloid beta plaques implicated in the pathogenesis of Alzheimer's disease.1

Alzheimer's Disease

Aducanumab-avwa is used for the treatment of Alzheimer's disease.1 Use of the drug should be limited to patients with mild cognitive impairment or mild dementia, which is reflective of the clinical trial population.1,3 There are no safety or effectiveness data on initiating treatment at earlier or later stages of the disease than were studied.1 The accelerated approval of aducanumab is based on the reduction in amyloid beta plaques observed in patients treated with the drug.1 Continued approval may be contingent upon verification of clinical benefit (e.g., long-term cognitive changes) in confirmatory studies.1

Clinical Experience

The approval of aducanumab for Alzheimer's disease is based principally on the results of two identically designed, phase 3, clinical studies (Studies 301 and 302) in patients with confirmed presence of amyloid pathology and mild cognitive impairment or mild dementia consistent with stage 3 and 4 Alzheimer's disease.1,2,3 Patients included in these studies had a Mini-Mental State Examination (MMSE) score of 24-30, a Repeatable Battery for Assessment of Neuropsychological Status (RBANS) delayed memory index score ≤85, and a Clinical Dementia Rating-Sum of Boxes (CDR-SB) global score of 0.5.1 Studies were stratified to include 80% of patients with stage 3 disease and 20% of patients with stage 4 disease.1 Both studies were double-blind and placebo-controlled; patients received low-dose aducanumab-avwa (3 or 6 mg/kg), high-dose aducanumab-avwa (10 mg/kg), or placebo by IV infusion every 4 weeks for 18 months, followed by an optional long-term extension period.1 Dosage was titrated over a period of up to 6 months to the maximum target dosage.1 The primary efficacy end point in both studies was change in the CDR-SB score from baseline to week 78.1

Both studies were terminated early by the sponsor based on prespecified interim futility criteria.1,5,6,7 In Study 302 (EMERGE), 1638 patients were randomized 1:1:1 to receive low-dose aducanumab-avwa, high-dose aducanumab-avwa, or placebo.1 High-dose aducanumab reduced clinical decline compared to placebo, as measured by the change in CDR-SB score from baseline to week 78 (statistically significant change from baseline of -0.39 [-22%]).1,2 Secondary efficacy end points, including change in MMSE, Alzheimer's Disease Assessment Scale-Cognitive Subscale 13 (ADAS-Cog 13), and Alzheimer's Disease Cooperative Study - Activities of Daily Living Inventory (Mild Cognitive Impairment version) (ADCS-ADL-MCI), were significantly reduced with high-dose aducanumab versus placebo.1,2 Low-dose aducanumab did not produce statistically significant effects when compared with placebo.1,2 A subgroup of patients within the trial were enrolled in an amyloid positron emission tomography (PET) substudy (488 were enrolled; 302 were evaluated at week 78).1,2 Imaging found that the mean change from baseline to week 78 in brain amyloid beta PET composite as measured by standardized uptake value ratio (SUVR) was significantly reduced in the high-dose and low-dose groups compared to placebo, with greater efficacy noted with the high-dose group demonstrating a dose-dependent effect.1,2

In Study 301 (ENGAGE), 1647 patients were randomized 1:1:1 to receive low-dose aducanumab-avwa, high-dose aducanumab-avwa, or placebo.1,2 There was no significant difference detected for the primary efficacy end point between aducanumab-treated patients and placebo.1,2 Similar to Study 302, the mean change from baseline to week 78 in brain amyloid beta PET composite SUVR was significantly reduced in the high-dose and low-dose aducanumab groups compared to placebo within the subgroup of patients who were enrolled in an amyloid PET substudy (585 were enrolled; 374 were evaluated at week 78).1,2

Results of a phase 1b, double-blind, placebo-controlled dose-ranging study (Study 103; PRIME) were also used to support the efficacy of aducanumab.1,3 The study enrolled a similar demographic of patients as that in Study 301 and Study 302; patients had stage 3 or stage 4 Alzheimer's disease with confirmed presence of amyloid pathology, a global CDR score of 0.5 or 1.0, and a MMSE score between 20 and 30.1,4 Enrollment distribution was 43% stage 3 patients and 57% stage 4 patients.1 Patients were randomized to either a fixed dosage of aducanumab-avwa (1, 3, 6, or 10 mg/kg), a dosage titrated to 10 mg/kg over 44 weeks, or placebo for 12 months.1 The mean change from baseline to week 54 in brain amyloid beta composite SUVR was significantly reduced in the aducanumab-avwa 3-, 6-, and 10-mg/kg groups compared to placebo.1,4 The study was not powered to detect changes in cognitive decline; the change in CDR-SB from baseline to 1 year was dose-dependent with the least change observed with aducanumab-avwa 10 mg/kg compared to placebo.1,4

Clinical Perspective

Alzheimer's disease is the most common type of dementia in the US, but treatment options are limited.5 Prior to the approval of disease modifying agents, such as the monoclonal antibodies aducanumab and lecanemab-irmb, which target brain amyloid plaques, the only approved pharmacological treatments for cognitive symptoms associated with Alzheimer's disease were cholinesterase inhibitors (e.g., donepezil, galantamine, rivastigmine) and memantine, an N-methyl-d-aspartate (NMDA) receptor antagonist.20,21 These treatments are used for symptomatic management of dementia; however, there is no evidence that these drugs alter the course of the underlying dementia process.20,21

After termination of the phase 3 studies that were conducted with aducanumab, additional analysis of data was performed to determine the importance of the statistically significant treatment effect of the high-dose group compared with placebo in Study 302 and to identify reasons for the conflicting evidence of efficacy between the 2 studies.6,7 With guidance from the FDA, the sponsor conducted further post-hoc analyses of the phase 3 data and the phase 1b dose-ranging study.5,6 These analyses were unable to determine why there were discrepant findings between Study 301 and 302.6 The baseline demographics of the studies were largely similar and unlikely to explain the differences in outcomes.2,3,6 While a reduction in amyloid beta plaques was observed with aducanumab, there has been controversy and disagreement on the appropriateness of this surrogate marker as evidence of an improved clinical outcome.5,6 Within the FDA approval process, the Peripheral and Central Nervous System Drugs Advisory Committee overwhelmingly voted that the evidence was insufficient to support the effectiveness of aducanumab for Alzheimer's disease.5,6 Despite the uncertainty of the clinical trial data, the FDA subsequently approved aducanumab via the accelerated approval pathway, which allows access to treatments for serious diseases with an unmet need when there is a residual uncertainty at the time of approval regarding the drug's ultimate benefit.7 The FDA's accelerated approval pathway requires use of a valid surrogate marker that is likely to predict clinical benefit; the surrogate end point utilized in the accelerated approval of aducanumab was the reduction of amyloid beta plaques.5,7 A reduction in amyloid beta plaques with aducanumab was clearly and consistently demonstrated across trials.7 However, experts have disagreed on whether this is an appropriate surrogate end point.3,6,7,8,9 Several organizations and expert panels have published appropriate use criteria or position statements expressing concerns over the available evidence supporting use.10,11,12

General

Pretreatment Screening

• Confirm the presence of amyloid beta pathology prior to initiating treatment.
• Obtain a recent (within 1 year) brain MRI.1

Patient Monitoring

• Discontinue the infusion if signs or symptoms of a hypersensitivity reaction (e.g., angioedema, urticaria) occur.1
• Obtain an MRI prior to the 5th, 7th, 9th, and 12th infusions.1
• Monitor for symptoms suggestive of ARIA; if symptoms occur, perform clinical evaluation, including MRI if indicated.1

Administration

Aducanumab is administered by IV infusion once every 4 weeks.1 The commercially available injection solution must be diluted prior to administration.1

Aducanumab should be administered through a sterile, low-protein binding 0.2- or 0.22-micron inline filter.1

If an infusion is missed, resume administration at the same dose as soon as possible and at least 21 days apart.1

Store unopened vials of aducanumab at 2-8°C in the original packaging to protect the drug from light; do not freeze.1 Unopened vials may be stored at room temperature up to 25°C for a maximum of 3 days.1 Unopened vials in the original packaging that are removed from refrigeration may be returned to the refrigerator if the total time at room temperature does not exceed 24 hours.1

Dilution

Aducanumab must be diluted with 0.9% sodium chloride injection prior to administration.1

Determine the number of vials needed based on the patient's actual body weight and recommended dosa each vial contains an aducanumab-avwa concentration of 100 mg/mL.1 Inspect each vial visually prior to use; the solution should be clear to opalescent, colorless to yellow, and free of particulates.1

Withdraw the required volume of aducanumab-avwa and add to infusion bag containing 100 mL of 0.9% sodium chloride injection; other diluents should not be used.1 Discard any partially used vials; each vial is intended for single use only.1 Mix the final diluted solution for infusion by gentle inversion; do not shake.1

After the drug is diluted, immediate use is recommended.1 If immediate administration is not possible, the diluted solution may be stored at 2-8°C for up to 3 days or at room temperature up to 30°C for up to 12 hours.1

Allow the diluted solution to warm to room temperature prior to infusion if necessary.1 Inspect the diluted solution prior to administration; do not use if discolored or if opaque or foreign particles are present.1

Rate of Administration

Administer IV infusions of aducanumab over approximately 1 hour.1

Dosage

Alzheimer's Disease

Calculate dose of aducanumab-avwa based on actual body weight.1

Initial Titration

Titrate dosage of aducanumab-avwa according to the following schedule; IV infusions of the drug should be administered every 4 weeks:1

• Infusion 1 (at week 0) and infusion 2 (at week 4): 1 mg/kg
• Infusion 3 (at week 8) and infusion 4 (at week 12): 3 mg/kg
• Infusion 5 (at week 16) and infusion 6 (at week 20): 6 mg/kg

Maintenance Dosing

The recommended maintenance dosage of aducanumab-avwa starting with infusion 7 (at week 24) is 10 mg/kg administered as an IV infusion every 4 weeks.1 Doses should be separated by at least 21 days.1

Therapy Interruption for Toxicity

Dosage interruption may be required for patients with amyloid related imaging abnormalities-edema (ARIA-E), amyloid related imaging abnormalities-hemosiderin deposition (ARIA-H), or intracerebral hemorrhage.1 Recommendations for dosage interruption in patients with ARIA-E are provided in Table 1.1

Recommendations for dosage interruption in patients with ARIA-H are provided in Table 2.1

If intracerebral hemorrhage >1 cm in diameter develops during treatment with aducanumab, suspend dosing until MRI demonstrates radiographic stabilization and symptoms, if present, resolve.1 Use clinical judgment in considering whether to continue treatment after radiographic stabilization and resolution of symptoms or permanently discontinue aducanumab.1

Special Populations

The manufacturer makes no specific dosage recommendations for geriatric patients or for patients with renal or hepatic impairment.1

Contraindications

• None.1

Warnings/Precautions

Amyloid Related Imaging Abnormalities (ARIA)

A boxed warning about the risk of ARIA is included in the prescribing information for aducanumab-avwa.1 Monoclonal antibodies directed against aggregated forms of beta amyloid, including aducanumab, can cause ARIA, characterized as amyloid related imaging abnormalities-edema (ARIA-E), which can be observed on MRI as brain edema or sulcal effusions, and amyloid related imaging abnormalities-hemosiderin deposition (ARIA-H), which includes microhemorrhage and superficial siderosis.1 ARIA can occur spontaneously in patients with Alzheimer's disease.1 ARIA-H associated with monoclonal antibodies directed against aggregated forms of beta amyloid generally occurs in association with an occurrence of ARIA-E.1 ARIA-H of any cause and ARIA-E can occur together.1

ARIA usually occurs early in treatment and is usually asymptomatic, although serious and life-threatening events, including seizure and status epilepticus, can occur.1 When present, symptoms associated with ARIA may include headache, confusion, visual changes, dizziness, nausea, and gait difficulty.1 Focal neurologic deficits may also occur.1 Symptoms associated with ARIA usually resolve over time.1

In clinical studies of aducanumab-avwa, symptomatic ARIA occurred in 10% of patients treated with the drug; serious symptoms were reported in 0.3% of these patients.1 ARIA-E was considered mild if FLAIR hyperintensity was confined to the sulcus and/or cortex/subcortical white matter in one location < 5 cm; moderate if FLAIR hyperintensity was 5 to 10 cm, or involved more than 1 site, each measuring <10 cm; and severe if FLAIR hyperintensity measured >10 cm, often with significant subcortical white matter and/or sulcal involvement (with possibility of one or more separate sites of involvement).1 ARIA-H microhemorrhage was considered mild if there were no more than 4 new incident microhemorrhages; moderate if there were 5 to 9 new incident microhemorrhages; and severe if there were at least 10 new incident microhemorrhages.1 ARIA-H superficial siderosis was considered mild if there was 1 focal area; moderate if there were 2 focal areas; and severe if there were >2 focal areas.1

In Studies 301 (ENGAGE) and 302 (EMERGE), 454 of 1105 (41%) of patients treated with aducanumab-avwa with a planned dose of 10 mg/kg experienced ARIA-E and/or ARIA-H compared to 111 of 1087 (10%) of patients treated with placebo.1 In clinical studies, 35% of patients treated with aducanumab-avwa 10 mg/kg and 3% of patients treated with placebo developed ARIA-E, and 28% of patients treated with the drug and 9% of patients treated with placebo developed ARIA-H.1 The risk ofARIA, including symptomatic and serious ARIA, is increased in apolipoprotein E ε4 (ApoEε4) homozygotes.1 Approximately 15% of Alzheimer's disease patients are ApoE ε4 homozygotes.1 The incidence ofARIA was higher in ApoE ε4 homozygotes (16%) thanin heterozygotes (11%) and noncarriers (5%) among patients treated with aducanumab.1 However, the incidence of serious adverse reactions with ARIA-E, including risk of death, persistent or significant disability or incapacity, hospitalization, or other medically important event that may require intervention to prevent serious outcomes, was similar for ApoE ε4 carriers and noncarriers (2% in homozygotes, 1% in heterozygotes, 2% in noncarriers).1

The timing of ARIA-E radiographic events most often occurred early in treatment (within the first 8 doses); however, ARIA can occur at any time during treatment.1 In patients who had ARIA-E with a planned 10 mg/kg dose of aducanumab-avwa, the severity was classified as mild, moderate, and severe in 10%, 20%, and 4% of patients, respectively.1 Overall, 98% of patients had resolution of ARIA-E after detection; resolution occurred in 68% of patients by 12 weeks and 91% of patients by 20 weeks.1 The maximum radiographic severity of ARIA-H microhemorrhage in patients treated with aducanumab was mild in 14% of patients, moderate in 3% of patients, and severe in 3% of patients.1 The maximum radiographic severity of ARIA-H superficial siderosis in patients treated with aducanumab was mild in 7% of patients, moderate in 4% of patients, and severe in 3% of patients.1 Among patients treated with aducanumab, the incidence of severe radiographic ARIA-E was highest in ApoE ε4 homozygotes (11%), compared to heterozygotes (4%) or noncarriers (2%).1 Among patients treated with aducanumab, the incidence of severe radiographic ARIA-H (microhemorrhage or superficial siderosis) was highest in ApoE ε4 homozygotes (20%), compared to heterozygotes (4%) or noncarriers (2%).1

In addition to ARIA, intracerebral hemorrhages >1 cm in diameter, including fatal events, have occurred in patients treated with aducanumab.1

The overall incidence of seizure, independent of ARIA, in clinical studies was 0.5% in the aducanumab group and 0.8% in the placebo group in clinical studies.1 Status epilepticus was also reported in the placebo-controlled and long-term extension studies in patients treated with the drug.1

Patients who were receiving antiplatelet or anticoagulant agents other than aspirin (325 mg or less daily) were excluded from the clinical studies; however, some patients required the use of a higher dose of aspirin or another antiplatelet or anticoagulant agent during the studies for an intercurrent medical event.1 Patients who received aducanumab and an antithrombotic agent did not have an increased risk of ARIA-H or intracerebral hemorrhage compared to patients who received placebo and an antithrombotic agent.1 The majority of exposures were to aspirin; few patients were exposed to other antiplatelet drugs or anticoagulants, limiting any meaningful conclusions about the risk of ARIA or intracerebral hemorrhage in patients taking other antiplatelet drugs or anticoagulants.1 Because intracerebral hemorrhages greater than 1 cm in diameter have been observed in patients taking aducanumab, additional caution should be exercised when considering the administration of anticoagulants or a thrombolytic agent (e.g., tissue plasminogen activator) to a patient already being treated with aducanumab.1 Caution should be exercised when considering the use of aducanumab in patients with risk factors for intracerebral hemorrhage, in particular for those who require anticoagulant therapy.1

Consider the benefit of aducanumab for the treatment of Alzheimer's disease and potential risk of serious adverse events associated with ARIA when deciding to initiate treatment.1 Testing for ApoE ε4 status should be performed prior to initiation of treatment to inform the risk of developing ARIA.1 Prior to testing, discuss with patients the risk of ARIA across genotypes and the implications of genetic testing results.1 Inform patients that if genotype testing is not performed they can still be treated with aducanumab; however, it cannot be determined if they are ApoE ε4 homozygotes and at higher risk for ARIA.1 An FDA-authorized test for the detection of ApoE ε4 alleles to identify patients at risk of ARIA if treated with aducanumab is not currently available.1 Currently available tests used to identify ApoE ε4 alleles may vary in accuracy and design.1 The recommendations on management of ARIA do not differ between ApoE ε4 carriers and noncarriers.1

Perform baseline brain MRI and periodic monitoring with MRI during aducanumab treatment.1 Enhanced clinical vigilance for ARIA is recommended during thefirst 8 doses, particularly during titration.1 IfARIA is observed on MRI, perform a careful clinical evaluation prior tocontinuing treatment.1

Recommendations for dosing in patients with ARIA-E depend on clinical symptoms and radiographic severity.1 Recommendations for dosing in patients with ARIA-H depend on the type of ARIA-H and radiographic severity.1 There is limited experience in patients who continued dosing through symptomatic ARIA-E, or through asymptomatic moderate to severe ARIA-E.1 There are limited data in dosing patients who experience recurrent ARIA-E.1

The Alzheimer's Network for Treatment and Diagnostics (ALZ-NET) is a voluntary provider-enrolled patient registry that collects information on treatments for Alzheimer's disease, including aducanumab.1 Providers may obtain information about the registry at [Web] or contact [email protected].1

Hypersensitivity Reactions

One patient receiving aducanumab-avwa during clinical trials experienced angioedema and urticaria during the IV infusion.1 Discontinue the IV infusion promptly and initiate appropriate therapy if any signs or symptoms consistent with hypersensitivity reactions are observed.1

Immunogenicity

In Studies 301 (ENGAGE) and 302 (EMERGE), up to 0.6% (15/2689) of patients receiving aducanumab-avwa every 4 weeks developed anti-drug antibodies over a period of 41 months of treatment in the combined placebo-controlled and long-term extension periods.1 However, the available data are too limited to make definitive conclusions regarding the effect of antibodies on pharmacokinetics, safety, or efficacy of aducanumab.1

Specific Populations

Pregnancy

There are insufficient data to inform a drug-associated risk for major birth defects, miscarriages, or other adverse maternal or fetal outcomes if aducanumab is used during pregnancy.1 Animal studies in rats have not detected adverse effects on embryofetal or pre- or postnatal development; however, aggregated amyloid beta, the target of aducanumab, is not present in rats.1

Lactation

It is not known whether aducanumab is distributed into human milk; the effects on nursing infants or on milk production also are not known.1

Consider the benefits of breast-feeding along with the importance of aducanumab to the woman and any potential adverse effects on the breast-fed infant from the drug or underlying maternal condition.1

Pediatric Use

Safety and efficacy of aducanumab have not been established in pediatric patients <18 years of age.1

Geriatric Use

In Studies 301 (ENGAGE) and 302 (EMERGE), the mean age of patients was 70 years; 79% and 32% of patients were ≥65 years of age and ≥75 years of age, respectively.1 Notable differences were not observed in the safety profile between these age groups, and there were no additional safety concerns in patients ≥65 years of age versus younger patients.1

Hepatic Impairment

The pharmacokinetics of aducanumab have not been studied in patients with hepatic impairment; aducanumab is not expected to be metabolized by hepatic enzymes.1

Renal Impairment

The pharmacokinetics of aducanumab have not been studied in patients with renal impairment; aducanumab is not expected to be eliminated renally.1

Common Adverse Effects

Most common adverse reactions (≥10% and higher incidence compared to placebo) include ARIA-E, headache, ARIA-H microhemorrhage, ARIA-H superficial siderosis, and fall.1

There is no information regarding drug interactions with aducanumab in the prescribing information for the drug.1

Description

Aducanumab is a human IgG₁ monoclonal antibody that targets aggregated forms of amyloid beta.1 Amyloid beta plaque accumulation in the brain is a hallmark feature of Alzheimer's disease.1,3 Clinical studies have demonstrated the ability of aducanumab to reduce amyloid beta plaques in a dose- and time-dependent manner in patients with Alzheimer's disease; however, the exact role of amyloid beta plaques in the pathogenesis of cognitive decline is unclear.9 It is hypothesized that accumulation of amyloid beta plaques leads to several downstream effects including the formation of neurofibrillary tangles and loss of cholinergic neurons, which contributes to short-term memory loss.3 Accumulation of amyloid beta plaques is thought to occur 1-2 decades before the onset of clinical symptoms.1 However, there is controversy regarding the appropriateness of using a reduction in amyloid load as a surrogate marker for cognitive decline.9

Exposure to aducanumab increases proportionally with increasing doses.1 Steady-state concentrations are obtained by week 16 following repeated dosing every 4 weeks.1 Aducanumab is expected to be metabolized in the same manner as endogenous IgG₁ through degradation into small peptides and amino acids via catabolic pathways.1 The terminal half-life of aducanumab is 24.8 days.1

Advice to Patients

• Advise patients that aducanumab can cause amyloid related imaging abnormalities (ARIA).1 ARIA typically presents as temporary swelling of areas in the brain that usually resolves over time.1 Some patients may also develop small spots of bleeding in or on the surface of the brain.1 Inform patients that most cases are asymptomatic, but some patients may experience symptoms such as headache, confusion, dizziness, vision changes, and nausea; instruct patients to notify their healthcare provider if these symptoms occur.1 Inform patients that they will be scheduled for MRI scans to monitor for ARIA.1
• Inform patients that events of intracerebral hemorrhage >1 cm in diameter have been reported infrequently in patients taking aducanumab, and that the use of anticoagulant or thrombolytic medications while taking aducanumab may increase the risk of bleeding in the brain.1
• Inform patients that although ARIA can occur in any patient treated with aducanumab, there is an increased risk in patients who are apolipoprotein E ε4 (ApoE ε4) homozygotes and that testing for ApoE ε4 status should be performed prior to initiation of treatment to inform the risk of developing ARIA.1 Prior to testing, discuss with patients the risk of ARIA across genotypes and the implications of genetic testing results.1 Inform patients that if testing is not performed, it cannot be determined if they are ApoE ε4 homozygotes and at a higher risk for ARIA.1
• Advise patients that the Alzheimer's Network for Treatment and Diagnostics (ALZ-NET) is a voluntary provider-enrolled patient registry that collects information on treatments for Alzheimer's disease, including aducanumab.1 Encourage patients to participate in the ALZ-NET registry.1
• Inform patients that aducanumab can cause hypersensitivity reactions, such as angioedema and urticaria.1
• Advise women to inform their clinician if they are or plan to become pregnant or plan to breast-feed.1
• Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary and herbal supplements, as well as any concomitant illnesses.1
• Advise patients of other important precautionary information.1

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

1. Biogen Inc. Aduhelm™ (aducanumab-avwa) for injection prescribing information. Cambridge, MA; 2023 Aug.

2. Food and Drug Administration. Center for Drug Evaluation and Research clinical review of aducanumab. 2021 Jun. From FDA website. [Web]

3. Tampi RR, Forester BP, Agronin M. Aducanumab: evidence from clinical trial data and controversies. Drugs Context . 2021; 10 [PubMed 34650610]

4. Sevigny J, Chiao P, Bussière T et al. The antibody aducanumab reduces Aβ plaques in Alzheimer's disease. Nature . 2016; 537:50-6. [PubMed 27582220]

5. Esang M, Gupta M. Aducanumab as a Novel Treatment for Alzheimer's Disease: A Decade of Hope, Controversies, and the Future. Cureus . 2021; 13:e17591. [PubMed 34646644]

6. Alexander GC, Emerson S, Kesselheim AS. Evaluation of Aducanumab for Alzheimer Disease: Scientific Evidence and Regulatory Review Involving Efficacy, Safety, and Futility. JAMA . 2021; 325:1717-1718. [PubMed 33783469]

7. Dunn B, Stein P, Cavazzoni P. Approval of Aducanumab for Alzheimer Disease-The FDA's Perspective. JAMA Intern Med . 2021; 181:1276-1278. [PubMed 34254984]

8. Barenholtz Levy H. Accelerated Approval of Aducanumab: Where Do We Stand Now. Ann Pharmacother . 2021; :10600280211050405. [PubMed 34595939]

9. Planche V, Villain N. US Food and Drug Administration Approval of Aducanumab-Is Amyloid Load a Valid Surrogate End Point for Alzheimer Disease Clinical Trials. JAMA Neurol . 2021; 78:1307-1308. [PubMed 34515750]

10. Cummings J, Aisen P, Apostolova LG et al. Aducanumab: Appropriate Use Recommendations. J Prev Alzheimers Dis . 2021; 8:398-410. [PubMed 34585212]

11. Watson LC, Juman R, AMDA Board of Directors.. AMDA Position Statement on Aducanumab. J Am Med Dir Assoc . 2021; 22:1777. [PubMed 34456010]

12. Institute for Clinical and Economic Review. Aducanumab for Alzheimer's disease: effectiveness and value. Final evidence report and meeting summary. 2021 Aug. From ICER website [Web]

20. APA Work Group on Alzheimer's Disease and other Dementias., Rabins PV, Blacker D et al. American Psychiatric Association practice guideline for the treatment of patients with Alzheimer's disease and other dementias. Second edition. Am J Psychiatry . 2007; 164:5-56. [PubMed 18340692]

21. Rabins PV, Rovner BW, Rummans T et al. Guideline Watch (October 2014): Practice Guideline for the Treatment of Patients With Alzheimer's Disease and Other Dementias. Focus (Am Psychiatr Publ) . 2017; 15:110-128. [PubMed 31997970]