AMSTERDAM, May 24, 2023 – In a compelling case study published in the Journal of Alzheimer's Disease, researchers reported on a 65-year-old patient with Alzheimer's disease who was treated with lecanemab, an experimental anti-β-amyloid (Aβ) antibody drug, after receiving three infusions.
On the fourth day after the last infusion, she developed symptoms of stroke and died a few days later from a multifocal intracerebral hemorrhage, despite therapeutic interventions. Neuropathological examination revealed that treatment-induced Aβ phagocytosis involved in fibrous Aβ in brain parenchymal tissues as well as the cerebrovascular system.
The most widely accepted theory for the pathogenesis of Alzheimer's disease is the amyloid cascade hypothesis, which hypothesizes that excess accumulation of Aβ is a neurotoxin that drives the AD process, with neurofibrillary tangles, neuronal loss, and neurodegeneration as subsequent events. Therefore, Aβ reduction is considered a reasonable therapeutic strategy.
The patient participated in a phase III clinical trial evaluating the efficacy and safety of lecanemab, a humanized monoclonal therapy believed to target soluble Aβ fibrils. The trial showed a 27% reduction in cognitive decline at 18 months. Previous clinical trials have shown potential adverse effects of experimental therapies targeting Aβ.
The patient died during the "subacute" phase of treatment after receiving only three infusions of lecanemab. Discoveries at this stage have not been previously reported. Although autopsy did not reveal significant systemic cardiovascular complications, brain examination confirmed that anti-Aβ therapy led to an unprecedented form of Aβ phagocytosis syndrome, affecting numerous small blood vessels in the cerebral cortex rich in cerebral amyloid angiopathy (CAA). This appears to be the cause of stroke symptoms and causes bleeding in stroke intervention attempts.
In this case, the patient's response to anti-Aβ therapy resulted in clinical symptoms and provided a substrate for bleeding for therapeutic intervention, raising the issue of potentially fatal drug interactions. The question arises as to whether the extent of CAA in patients receiving anti-Aβ therapy can be adequately assessed (CAA in Alzheimer's disease ranges from mild to none, to abundant as in this case), and whether adverse or even fatal outcomes can be avoided. On the positive side, there appears to be partial clearance of Aβ and possibly even phosphorylated tau protein, which has not been previously reported. In short, the targeted effect was achieved, but at the cost of collateral damage to the small vessels involved in the CAA.
Although this is the first case to describe the neuropathological findings of lecanemab in detail, the pattern and distribution of lesions is so remarkable that it is hard to believe that this is an isolated phenomenon. The advent of lecanemab marks a new phase in the treatment of AD. The benefit at the population level is limited and unknown to individual patients. Even when symptoms are rare, side effects can be extremely devastating, as shown in this case report. Screening for cerebrovascular disease and apolipoprotein E status is essential for prescribing medications. In addition, patients may need to be informed that anticoagulation may be an option, but with greater risks, if a stroke occurs.
Clearly, there is a delicate and dangerous balance between Aβ targeting and potentially deleterious host responses, particularly when it comes to the blood vessels of CAA. There is an urgent need for better biomarkers that can accurately assess the extent of CAA. Neuroimaging and APOE genotype testing, while important for risk stratification, remain undetected in many cases of severe CAA.
文献参考——Neuropathology of Anti-Amyloid-β Immunotherapy: A Case Report,” by Rudolph J. Castellani, Elisheva D. Shanes, Matthew McCord, Nicholas J. Reish, Margaret E. Flanagan, M-Marsel Mesulam, and Pouya Jamshidi