Anti-Amyloid Antibody Therapy for Mild Cognitive Impairment in Alzheimer Disease With Confirmed Aβ Pathology
Alzheimer disease (AD) is a complex and gradually progressive neurodegenerative condition with a prevalence that is rising worldwide. Recent data project a doubling of AD cases in Europe and a tripling globally by 2050 that will pose significant societal and economic impacts.1 Moreover, AD is surging among older Americans, affecting 6.7 million people aged 65 years and older, with this figure projected to double by 2060. It was the 6th-leading cause of death, with 121,499 deaths, in 2019. Deaths have spiked by more than 145% since 2000, emphasizing the need for urgent action.2 Figure 1 shows the current trends in AD.1,2
Clinically, AD spans mild cognitive impairment (MCI) to severe dementia. Its pathology is characterized by the accumulation of amyloid-beta (Aβ) plaques and neurofibrillary tau tangles in the brain. Notably, Aβ deposition often precedes clinical symptoms, underlining the crucial need for early detection and intervention.3
While nonpharmacologic strategies such as lifestyle adjustments are important in managing cognitive decline, pharmacotherapy remains pivotal. A comprehensive approach to AD necessitates targeted interventions addressing amyloid and tau pathology as well as inflammation and metabolic dysregulation.1
Collaborative efforts and global initiatives are indispensable in tackling the escalating AD crisis. Disease-modifying therapies (DMTs), particularly those targeting Aβ and tau proteins, are at the forefront of these endeavors, with anti-amyloid monoclonal antibodies (mAbs) showing remarkable promise.1
Mechanism of Action of Anti-Amyloid mAbs
Anti-amyloid mAbs primarily engage the immune system to reduce Aβ plaques in the brain, a hallmark of AD.3 By activating microglia, the brain’s immune cells, they prompt phagocytosis of fibrillar Aβ, facilitating its degradation. Each mAb targets specific Aβ species, with all US Food and Drug Administration (FDA)-approved mAbs demonstrating significant reductions in plaque Aβ, as confirmed by amyloid positron emission tomography (PET) scans.4
However, current methods for measuring Aβ in plasma and cerebrospinal fluid (CSF) primarily detect monomeric Aβ, with no established techniques for quantifying other Aβ species. Consequently, the full therapeutic impact of targeting nonplaque Aβ species remains to be elucidated.4
The recent FDA approvals of aducanumab and lecanemab as DMTs are significant milestones in AD treatment. They represent a pivotal advancement in directly targeting Aβ pathology, offering newfound optimism for slowing disease progression, particularly in individuals with early-stage AD, including those with MCI.5,6
Aducanumab
Aducanumab, a human immunoglobulin gamma 1 (IgG1) mAb, was the first Aβ-targeting mAb and DMT approved for AD. It targets an N-terminal epitope within the Aβ42 peptide, showing higher affinity for fibrillar aggregates compared to monomers.4
FDA Approval and Indication
The FDA granted aducanumab accelerated approval in June 2021.4 It is indicated for the treatment of AD and should be started in patients with MCI or the mild dementia stage of the disease, which is the population studied in clinical trials. Its accelerated approval was based on reduction in amyloid plaques in patients treated with aducanumab.5
Clinical Trials and Efficacy
Phase 3 trials — notably PRIME (ClinicalTrials.gov identifier: NCT01677572), ENGAGE (ClinicalTrials.gov identifier: NCT02477800), and EMERGE (ClinicalTrials.gov identifier: NCT02484547) — established aducanumab’s clinical profile. Participants in the ENGAGE and EMERGE trials had baseline Mini-Mental State Examination (MMSE) scores of 24-30, positive amyloid PET scans, and Clinical Dementia Rating Sum of Boxes (CDR-SB) global scores of 0.5. These trials evaluated aducanumab’s efficacy at varying doses over 76 weeks, focusing on CDR-SB score differences between the drug and placebo groups.4
Initial futility analyses led to a temporary halt in the trials. However, further data analysis revealed promising outcomes in the high-dose arm of the EMERGE trial, with significant decreases in CDR-SB scores and secondary endpoints related to cognitive and functional assessments being met. The ENGAGE and EMERGE studies demonstrated dose-dependent reductions in Aβ pathology evidenced by amyloid PET and downstream biomarkers such as CSF and plasma p-tau levels.4
Safety and Adverse Events
Aducanumab shows therapeutic promise, with long-term extension studies affirming sustained reductions in Aβ plaques and continued clinical benefits, bolstering its disease-modifying potential. However, it also raises safety concerns that are particularly notable in the high-dose arm, with adverse events including amyloid-related imaging abnormalities (ARIA) and intracerebral hemorrhage.4
FDA Approval and Controversy
The FDA’s approval based on amyloid plaque reduction triggered debate in light of previous anti-amyloid mAb failures to demonstrate clear clinical efficacy. Although the EMERGE trial evidenced a modest decline in CDR-SB scores among high-dose recipients, real-world adoption has been limited due to safety concerns and clinical uncertainties, especially regarding ARIA.3
Lecanemab
Lecanemab, a humanized IgG1 antibody derived from mouse mAb158, specifically targets Aβ protofibrils. It received FDA accelerated approval in January 2023 and full approval in July 2023 for the treatment of AD.1,4 Treatment with lecanemab should be initiated in patients with MCI or the mild dementia stage of the disease, which is the population in which treatment was initiated in clinical trials.6
Clinical Trials and Efficacy
A phase 2b trial (ClinicalTrials.gov identifier: NCT01767311) involving 856 participants over 18 months was aimed at determining optimal dosing and efficacy parameters. Participants had to meet stringent eligibility criteria, including confirmed Aβ pathology and a minimum MMSE score. The trial used a Bayesian adaptive dose-finding design to evaluate the primary endpoint: the change from baseline on the AD Composite Score (ADCOMS). Although the trial did not meet its primary endpoint at 12 months, later analyses indicated significant efficacy: the 10 mg/kg biweekly dose achieved a 64% probability of slowing ADCOMS decline by 25% more than placebo.4
The phase 3 CLARITY AD trial (ClinicalTrials.gov identifier: NCT03887455), a randomized, double-blind, placebo-controlled study, enrolled 1795 participants. Eligibility criteria included age, diagnosis of MCI or mild AD as per US National Institute on Aging and Alzheimer’s Association (NIA-AA) criteria, memory impairment, and Aβ positivity. The primary endpoint was a change from baseline on the CDR-SB at 18 months.4 Lecanemab demonstrated a notable slowing of decline on the CDR-SB compared to placebo, with a 25% reduction in disease progression, equating to a delay of approximately 4 to 5 months in clinical deterioration over 1.5 years. Secondary outcomes also showed improvements in cognitive measures and reductions in amyloid plaque levels.3
Safety and Adverse Events
Although lecanemab has demonstrated promising outcomes, it is linked with adverse events. The mAbs such as lecanemab that are designed to target aggregated Aβ forms may induce ARIA, which can manifest as either ARIA-E (edema) or ARIA-H (hemosiderin deposition). These ARIA events, often asymptomatic and occurring early, can have serious consequences, including intracerebral hemorrhages, particularly within this class of medications.6
Approximately 15% of AD patients are ApoE ε4 homozygotes and thus predisposed to a heightened risk of ARIA when treated with lecanemab. Pretreatment ApoE ε4 testing can assist in assessing this risk. Patients should be informed about the potential for ARIA across genotypes and the significance of genetic testing, although treatment is still viable without it.6
Comparative Efficacy and Safety
A meta-analysis conducted after FDA approval highlighted potential advantages of lecanemab over aducanumab in terms of efficacy and safety. Lecanemab’s selective binding to large, soluble Aβ protofibrils may account for its higher efficacy and lower risk of side effects compared to aducanumab, which binds to plaques.1 Table 1 compares the indications, mechanisms of action, and adverse events of aducanumab and lecanemab.5,6
Transitioning From Clear Indications to Personalized Risk Assessment
Eligibility for anti-amyloid mAb therapy requires a nuanced evaluation of clinical indicators and personalized assessments. Studies like CLARITY AD focus on patients with early symptomatic AD, emphasizing the need to confirm abnormal brain amyloidosis via PET scans or CSF biomarker testing. While PET scans provide specificity, CSF biomarkers — though more accessible — involve invasive procedures. Patient selection must exclude non-AD diagnoses or multi-etiologic cognitive impairment, with comprehensive assessments essential for identifying risks such as ARIA. Genetic factors, notably the APOE ε4 allele, increase ARIA risks, highlighting the importance of genetic testing before treatment.3
Administering Treatment: Medication Infusions, Safety Oversight, and Response Plans
Administering anti-amyloid mAb therapy requires interdisciplinary efforts to ensure consistent access and safety. Collaboration with specialized teams and adherence to evolving guidelines refine patient selection, ensuring safe and effective treatment. Coordinating patient selection and scheduling infusions demands meticulous planning, with ARIA symptoms requiring vigilant monitoring. Safety MRI scans before specific infusion milestones are crucial for accurate detection. Managing ARIA severity follows established guidelines that emphasize comprehensive care planning and access to appropriate resources.3
When clinical markers are combined with personalized assessments, treatment options are aligned with individualized care goals, and safe administration is ensured through interdisciplinary collaboration, anti-amyloid mAbs offer promising avenues for AD treatment.
References
1. Wu W, Ji Y, Wang Z, et al. The FDA-approved anti-amyloid-β monoclonal antibodies for the treatment of Alzheimer’s disease: a systematic review and meta-analysis of randomized controlled trials. Eur J Med Res. 2023;28(1):544. doi:10.1186/s40001-023-01512-w
2. 2023 Alzheimer’s disease facts and figures. Alzheimers Dement. 2023;19(4):1598-1695. doi:10.1002/alz.13016
3. Ramanan VK, Armstrong MJ, Choudhury P, et al; AAN Quality Committee. Antiamyloid monoclonal antibody therapy for alzheimer disease: emerging issues in neurology. Neurology. 2023;101(19):842-852. doi:10.1212/WNL.0000000000207757
4. Cummings J, Osse AML, Cammann D, Powell J, Chen J. Anti-amyloid monoclonal antibodies for the treatment of alzheimer’s disease. BioDrugs. 2024;38(1):5-22. doi:10.1007/s40259-023-00633-2
5. Aduhelm®. Prescribing information. Biogen, Inc; 2023. Accessed May 18, 2024. https://www.biogencdn.com/us/aduhelm-pi.pdf
6. Leqembi®. Prescribing information. Eisai R&D Management Co, Ltd; 2023. Accessed May 18, 2024. https://www.leqembi.com/-/media/Files/Leqembi/Prescribing-Information.pdf?hash=77aa4a86-b786-457a-b894-01de37199024
Posted by Haymarket’s Clinical Content Hub. The editorial staff of Neurology Advisor had no role in this content’s production.
Reviewed June 2024
