Attack on the Cerebral Vasculature with Anti-Amyloid Immunotherapy in Alzheimer’s Disease: A Pathological Perspective


Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder and a major cause of dementia worldwide. Though research over the years has identified characteristics of the disease such as the presence of amyloid plaques between neurons and the buildup, known as tangles, of another toxic protein, tau, inside neurons, questions remain about what causes the disease and how best to treat it in a clinically meaningful way. Disease-modifying candidate therapies currently in clinical trials have largely aimed to deplete accumulation of amyloid β (Aβ). In a recent study published in the Journal of Alzheimer’s Disease, Professor Rudolph Castellani, along with a team of researchers from Northwestern University (Dr. Elisheva Shanes, Dr. Matthew McCord, Dr. Nicholas Reish, Dr. M-Marsel Mesulam, Dr. Pouya Jamshidi and Dr. Margaret Flanagan), presented a compelling case report that highlight the complexities and challenges of anti-Aβ immunotherapy. The case highlights the need for more in-depth understanding of the mechanisms and potential risks associated with these experimental treatments. The case is a 65-year-old woman with a known APOE ε4/ε4 genotype, a well-established genetic risk factor for AD. The patient participated in a phase III clinical trial investigating the efficacy and safety of lecanemab, a humanized monoclonal antibody designed to target soluble Aβ protofibrils. Notably, the study does not provide information on whether the patient received the drug or a placebo during the clinical trial phase. The patient developed acute ischemic stroke symptoms after receiving three intravenous infusions of lecanemab as part of an open-label extension phase following the clinical trial, necessitating therapeutic intervention with tissue plasminogen activator. Tragically, the patient suffered extensive intracerebral hemorrhage and passed away several days later. The autopsy findings reported by the authors revealed a unique and striking pathology within the brain that was not explained by simple hemorrhagic conversion of a vascular territory ischemic infarct. Numerous cortical and subcortical hemorrhages were present throughout the cerebral hemispheres. Importantly, the patient was in excellent cardiovascular health, had no risk factors for stroke other than age, and had no atherosclerosis in the general autopsy. The authors’ histopathological analysis of brain tissue samples demonstrated several important findings: for instance, there was necrotizing vasculitis involving blood vessels with cerebral amyloid angiopathy in a distribution that paralleled the multifocal hemorrhage noted macroscopically and on neuroimaging. Transmural vasculitis was present in 25 out of 35 brain samples, and there was a clear, transmural fibrinoid necrosis of blood vessel walls particularly in regions with accompanying hemorrhageThe vascular inflammation was exclusively observed in areas involved by CAA. Of note, the fibrin that replaced blood vessel walls is a substrate for tissue plasminogen activator, which provides a convincing pathological substrate and mechanism for the fatal hemorrhagic complication.  Furthermore, the researchers provided compelling evidence of phagocytosis of Aβ plaque cores. Interestingly, the researchers also noted variations in phosphorylated tau immunolabeling between different brain regions. There appeared to be relatively less phosphorylated tau in the superior temporal gyrus compared to the frontal cortex, raising the possibility that Aβ-targeting therapy might influence tau pathology.

According to the authors, the observed Aβ phagocytosis by macrophages suggests that this mechanism may contribute to Aβ clearance with anti-Aβ immunotherapy. This finding aligns with the notion that immunotherapies can mobilize the brain’s immune response to target Aβ aggregates. The differential distribution of Aβ and phosphorylated tau pathology noticed between brain regions suggests that the therapeutic effects of anti-Aβ antibodies may vary across different brain areas and that these treatments might influence tau pathology. Moreover, the presence of vasculitis and fibrinoid necrosis in areas affected by CAA raises concerns about potential neurovascular complications associated with anti-Aβ therapy. This finding warrants careful monitoring of clinical trial subjects and further investigation into the mechanisms underlying these vascular changes. Finally, the case’s APOE ε4/ε4 genotype raises questions about whether certain genetic factors might influence the risk of complications associated with anti-Aβ immunotherapy. Patients with APOE ε4 alleles may be more susceptible to adverse effects, suggesting that genetic factors could play a role in the variability of treatment outcomes. In conclusion, the study by Professor Rudolph Castellani and colleagues highlights both Aβ plaque engagement and iatrogenic CAA engagement of insoluble Aβ fibrils after three infusions with anti Aβ-therapy, which precipitated clinical symptoms and the adverse reaction to thrombolysis. This case highlights the potential risks and benefits associated with anti-Aβ immunotherapy, but in particular the need for better understanding of CAA for safer and more effective treatments for AD. The extent to which anti-Aβ therapy-induced vasculitis underlies so-called amyloid-related imaging abnormalities, or ARIA, also warrants further investigation. Completely unexplored is the long-term morbidity with respect to the cortical vasculature in patients receiving such therapy. More research is needed.

Attack on the Cerebral Vasculature with Anti-Amyloid Immunotherapy in Alzheimer's Disease: A Pathological Perspective - Medicine Innovates

About the author

Dr. Rudy Castellani is a professor in the Division of Neuropathology at the Northwestern University Feinberg School of Medicine, and the Neuropathology Core Director for the Northwestern University Alzheimer’s Disease Research Center. Dr. Castellani has authored or co-authored over 300 research articles, reviews, and chapters, with focus on neurodegenerative diseases and neurotrauma. He is the recipient of the 2010 Alzheimer medal from the Journal of Alzheimer’s disease. He was an invited expert panelist and only pathologist to serve at the International Consensus Conference on Concussion in Sport in Berlin in 2016 and Amsterdam in 2022.


Castellani RJ, Shanes ED, McCord M, Reish NJ, Flanagan ME, Mesulam MM, Jamshidi P. Neuropathology of Anti-Amyloid-β Immunotherapy: A Case Report. J Alzheimers Dis. 2023;93(2):803-813. doi: 10.3233/JAD-221305.

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