Newswise — Amsterdam, May 24, 2023 – In a notable case study featured in the Journal of Alzheimer's Disease, researchers document post-mortem discoveries in a 65-year-old woman diagnosed with Alzheimer's disease (AD) who underwent three open label infusions of the experimental drug lecanemab, an anti-amyloid beta (Aβ) antibody. Merely four days following the final infusion, she exhibited stroke symptoms and succumbed to multifocal intracerebral hemorrhage despite medical intervention efforts. Neuropathological observations indicated therapy-induced Aβ phagocytosis, impacting both the brain tissue and cerebral vasculature.
The predominant theory extensively investigated in relation to the pathogenesis of Alzheimer's disease (AD) is the amyloid cascade hypothesis. According to this hypothesis, the disease is driven by an abundance of neurotoxic Aβ, leading to subsequent neurofibrillary degeneration, neuronal loss, and progressive neurological decline. Consequently, targeting Aβ to reduce its levels emerges as a rational approach for therapeutic intervention.
The individual enrolled in a phase III clinical trial investigating the effectiveness and safety of lecanemab, an experimental humanized monoclonal therapy designed to target soluble Aβ protofibrils. The study revealed a significant 27% decrease in the rate of cognitive deterioration over an 18-month period. However, it is important to note that previous clinical trials have indicated the possibility of adverse reactions associated with experimental therapies targeting Aβ.
"The significance lies in the fact that, even though clinical trials focusing on Aβ have been conducted for over two decades and known adverse reactions both clinically and through imaging (such as amyloid-related imaging abnormalities, or ARIA), we had minimal understanding of the cellular responses to these experimental antibodies or the mechanism behind amyloid clearance prior to this case," explained Dr. Rudolph J. Castellani, the lead investigator and Professor of Neuropathology in the Department of Pathology at Northwestern University Feinberg School of Medicine in Chicago, IL, USA.
In this instance, the patient passed away during the "subacute" phase of the reaction to lecanemab, following only three infusions of the drug. This specific finding had not been previously documented during this stage of the treatment protocol. Despite the absence of significant systemic cardiovascular comorbidities upon autopsy examination, analysis of the brain confirmed that the anti-Aβ therapy triggered an unprecedented amyloid phagocytic syndrome. This syndrome affected numerous small blood vessels in the cerebral cortex, which exhibited a high presence of cerebral amyloid angiopathy (CAA). Consequently, this condition appeared to be responsible for the manifestation of stroke symptoms and subsequent hemorrhage, even in the presence of attempts to intervene and treat the stroke.
Dr. Castellani remarked, "In my view, it is evident in this case that the patient's response to the anti-Aβ therapy resulted in clinical symptoms and created a condition that led to hemorrhage despite therapeutic intervention, highlighting the possibility of a potentially fatal drug interaction. This raises the question of whether patients receiving anti-Aβ treatments can be adequately assessed for the extent of cerebral amyloid angiopathy (CAA), which can vary from minimal to abundant in Alzheimer's disease, as observed in this case. Additionally, it raises concerns about avoiding adverse outcomes that could prove lethal. On a positive note, there seemed to be some degree of Aβ clearance, and possibly even a reduction in phosphorylated tau, which has not been previously reported. In summary, while improvement was achieved, it came at the cost of collateral damage to small blood vessels affected by CAA."
Co-investigator Dr. Pouya Jamshidi from the Department of Pathology at Northwestern University Feinberg School of Medicine expressed a word of caution, stating, "While this case presents the initial report on the neuropathological observations following lecanemab treatment, the distinct pattern and distribution of pathology are so pronounced that it is difficult to imagine this being an isolated incident."
According to Dr. M.-Marsel Mesulam, the Ruth Dunbar Davee Professor of Neuroscience and Chief of Behavioral Neurology in the Department of Neurology at Northwestern University Feinberg School of Medicine, as well as the namesake for the Mesulam Center for Cognitive Neurology and Alzheimer's Disease at Northwestern, the availability of lecanemab marks a new phase in the treatment of Alzheimer's disease (AD). However, the benefits of the drug are modest when viewed at the group level, and the individual patient's response remains uncertain. This case report suggests that the side effects, even if infrequently symptomatic, can have devastating consequences. Therefore, it becomes crucial to screen patients for cerebrovascular disease and determine their apolipoprotein E status before prescribing the medication. Additionally, patients may need to be informed that anticoagulant treatment for stroke, if such an event occurs, could carry even greater risks.
Dr. Castellani further commented, "It is evident that there is a delicate and challenging balance between targeting Aβ and triggering a harmful response from the host, particularly concerning the blood vessels affected by cerebral amyloid angiopathy (CAA). Improved biomarkers that can accurately evaluate the extent of CAA are urgently required. While neuroimaging and APOE genotyping play a crucial role in assessing the risk, they fail to detect many cases of severe CAA."
Dr. George Perry, Editor-in-Chief of the Journal of Alzheimer's Disease and Semmes Distinguished University Chair in Neurobiology at The University of Texas at San Antonio, emphasized the need for thorough and meticulous examination of individuals experiencing adverse effects from these experimental drugs. This scrutiny is crucial in order to minimize the potential risks of brain damage and mortality.
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