Fatal Iatrogenic Cerebral Amyloid-Related Encephalitis in a patient treated with lecanemab for Alzheimer’s disease: neuroimaging and neuropathology

We report the case of an elderly woman in good general health aside from early-stage Alzheimer’s disease who was enrolled in a randomized controlled trial of the novel therapeutic monoclonal antibody lecanemab where she was treated with the placebo, and subsequently in the open label extension study where she received lecanemab infusions every two weeks. After the third infusion, she suffered a seizure followed by aphasia and progressively worsening encephalopathy. Magnetic resonance imaging revealed multifocal cerebral edema and an increased burden of cerebral microhemorrhages compared to pre-trial imaging, consistent with Amyloid Related Imaging Abnormality (ARIA). She was treated with an antiepileptic regimen and high-dose intravenous corticosteroids but continued to worsen and expired after five days in the hospital. The family requested an autopsy and consented to evaluation of her brain for research. Post-mortem MRI confirmed extensive microhemorrhagic changes in the temporal, parietal and occipital lobes, some of which were visible on gross inspection of the brain. Autopsy confirmed APOE genotype of E4/E4 and the presence of typical neuropathological features of Alzheimer’s disease along with severe cerebral amyloid angiopathy with inflammatory features, including perivascular lymphocytic infiltrates, reactive macrophages and fibrinoid degeneration of vessel walls. There were deposits of β-amyloid in meningeal vessels and penetrating arterioles with numerous microaneurysms. Cerebral microhemorrhages were associated with arterioles harboring β-amyloid deposits and having degenerative morphologies. We conclude from these results that the patient likely died as a result of severe cerebral amyloid angiopathy with marked microvascular degeneration and meningoencephalitis. Further study of the mechanism of ARIA and the neuropathological changes associated with plaque clearance are needed. ### Competing Interest Statement MJD receives research related support from Philips North America; is a paid consultant for Pfizer Inc, Alterity, Global Blood Therapeutics, Graphite Bio, and LymphaTouch; is a paid advisory board member for Novartis and Bluebird Bio; receives research funding from Pfizer Inc; and is the President/CEO of Biosight, LLC which operates as a clinical research organization. AC reports receiving funding from the Bodossaki Foundation and the Frechette Family Foundation and consulting fees from Imperative Care. MSS reports receiving funding from the American Federation of Aging Research, the National Institutes of Health and consulting fees from Labaton-Sucharow LLP and Raymond James. The other authors declare no competing interests. ### Funding Statement This study was made possible by philanthropic support from the family and friends of Louis Stephen Zuzga Moran and the family and friends of Douglas B. Janney, Jr. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Vanderbilt University Medical Center's institutional review board granted ethical approval of this study as part of our ongoing Observational Study of CAA and Related Disorders (OSCAAR), approval number 180287. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All relevant data are included in this article and the associated supplemental material.