AAN consensus guidance on implementing anti-amyloid monoclonal antibodies into Alzheimer’s Disease treatment

07 Sep 2023

Recent studies have demonstrated that anti-amyloid monoclonal antibodies (mAbs) can attenuate cognitive and functional deterioration in patients with early symptomatic Alzheimer’s disease (AD).1  One of these mAbs, lecanemab, a humanized immunoglobulin G1 (IgG1) mAb, was verified to diminish amyloid markers and decelerate cognition deterioration in early AD patients after 18 months of treatment in a double-blind, phase 3 trial named CLARITY-AD.2 These promising results indicated that anti-amyloid mAbs could be incorporated into real-life clinical care for early AD patients.1 To expedite their incorporation in clinical practice, the American Academy of Neurology (AAN) published expert consensus guidance on how to optimize anti-amyloid mAbs AD treatment.1

The consensus guidance empathized that two conditions, mild cognitive impairment (MCI) and abnormal brain amyloidosis, should be confirmed before initiating anti-amyloid mAb therapy.1 Assessment for MCI can be performed with a Mini-Mental State Exam (MMSE), where a score of 22-30 indicates MCI.1 For abnormal brain amyloidosis, the consensus recommended performing amyloid positron emission tomography (PET) scan or cerebrospinal fluid (CSF) biomarker tests.1 Although these test methods have limited applicability for all AD patients and rely on, they were deemed necessary for validating their eligibility.1

Aside from this criteria, multiple factors must be taken into account when evaluating the efficacy of anti-amyloid mAb therapy.1 These factors include the extent of cerebrovascular disease and other relevant structural abnormalities, the presence of microhemorrhages and superficial siderosis, as well as the patient’s medical history with cerebral microhemorrhage and ischemic stroke.1 The consensus also advised avoiding administering anti-amyloid mAbs to patients with apolipoprotein E ε4 allele (APOE ε4) gene, a genetic risk factor associated with elevated risks of amyloid-related imaging abnormalities (ARIA), and the co-administration of anticoagulant medication with anti-amyloid mAbs.1 Ultimately, the decision to start anti-amyloid mAbs therapy should involve discussion among clinicians, patients, and caregivers with consideration of possible benefits and risks.1

Once anti-amyloid mAbs therapy is initiated for patients, clinicians should be alerted for potential complications, specifically ARIA.1 In the CLARITY-AD study, 12.6%  of patients in the lecanemab group experienced mild-to-moderate ARIA with edema or effusion (ARIA-E).2 These events were mostly asymptomatic and occurred within the first 3 months of treatment.2 The consensus recommended magnetic resonance imaging (MRI) scans for ARIA detection should include T2-weighted-fluid-attenuated inversion recovery (T2-FLAIR), T2-weighted gradient recalled echo (T2*GRE), and diffusion-weighted imaging (DWI) sequences and suggested a framework for managing varying severities of ARIA.1 Treatment should be suspended if patients were diagnosed with asymptomatic moderate ARIA or exhibited mild-to-moderate symptoms of ARIA.1 High-dose steroids and antiseizure medications can be administered on a patient-specific basis to alleviate symptoms.1 Treatment resumption should only be considered after stabilizing the patient’s conditions.1

In terms of the practicality of anti-amyloid mAbs therapies, the consensus highlighted the importance of training non-dementia-specialist clinicians in conceptual awareness and examination skills, which allow them to perform initial evaluations and identify patients with high-risk factors.1 Public education strategies such as a dedicated website on anti-amyloid mAbs therapies were also suggested to address the heightened inquiries from patients and caregivers while preserving practice resources.1

As for the future of anti-amyloid mAbs, the consensus highlighted a potential candidate for future additions.1 Donanemab is a highly potent anti-amyloid mAb and its United States (US) Food and Drug Administration (FDA) approval is eagerly anticipated.1 The encouraging results of the TRAILBLAZER-ALZ 2 study, a randomized, double-blinded, placebo-controlled phase 3 trial, showed that early AD patients treated with donanemab for less than 72 weeks had significantly higher integrated Alzheimer Disease Rating Scale (iADRS) scores compared to the placebo group (p<0.001).3 The remarkable efficacy in hindering AD progression demonstrated by donanemab has led to speculation of its inclusion in future treatment frameworks.1

To conclude, the emergence of anti-amyloid mAbs has caused massive shifts in the treatment landscape of AD.1 Thus, this expert consensus provides valuable guidance on patient selection, treatment management and community education for anti-amyloid mAbs therapies.1 Additionally, prospects for these therapies are also tackled in this consensus, enabling the development of alternate treatment options for the optimization of patient outcomes.

  1. Ramanan VK, et al. Antiamyloid Monoclonal Antibody Therapy for Alzheimer Disease: Emerging Issues in Neurology. Neurology. 2023.
  2. van Dyck CH, et al. Lecanemab in Early Alzheimer's Disease. N Engl J Med. 2023;388(1):9-21.
  3. Sims JR, et al. Donanemab in Early Symptomatic Alzheimer Disease: The TRAILBLAZER-ALZ 2 Randomized Clinical Trial. JAMA. 2023;330(6):512-527.