Probable lecanemab-associated pontine hemorrhage following cardiovascular intervention: Clinical implications for lecanemab use

Abstract

We report a 76-year-old patient with mild cognitive impairment and APOE ε3/ε3 genotype who developed a rare pontine hemorrhage following treatment with lecanemab, an anti-amyloid-β monoclonal antibody for Alzheimer's disease. She was initially on clopidogrel and rivaroxaban; rivaroxaban was discontinued prior to lecanemab initiation. After two infusions, lecanemab was paused due to angina. She then underwent coronary stenting and was placed on dual antiplatelet therapy (aspirin and clopidogrel). Pontine hemorrhage occurred after twenty days. This case highlights heightened bleeding risk when lecanemab is combined with intensified antithrombotic therapy, even without APOE ε4 or significant cerebral small vessel disease load.

Introduction

Alzheimer's disease (AD) is a common neurodegenerative disorder characterized by progressive impairments in memory and cognitive functions, imposing a substantial burden on both patients and their families. ¹ Epidemiological evidence indicates that, with the accelerating pace of global population aging, the prevalence and incidence of AD are on a steady rise. ² In China, the number of individuals with AD has likewise been expanding rapidly, and the resultant decline in patients’ ability for independent living, along with the rising healthcare costs, poses significant challenges for social welfare and healthcare systems. ³ Consequently, the search for effective interventions and treatments has remained a major focus in both neuroscience and clinical medicine.

Among the proposed mechanisms for AD pathogenesis, the “amyloid cascade hypothesis” has played a central role, positing that misfolding and deposition of amyloid-β (Aβ) peptides are pivotal events in disease progression. ⁴ This has led to the development of passive immunotherapies using monoclonal antibodies to reduce Aβ burden, either by preventing its deposition or enhancing its clearance. However, despite biochemical success in amyloid removal, most monoclonal antibodies have not consistently improved cognitive outcomes, and in some cases, have even been associated with worsening. ⁵ These limitations have generated debate around the translational validity of the amyloid hypothesis.

Among these agents, lecanemab represents a new generation of monoclonal antibodies that selectively binds Aβ protofibrils, thereby reducing the accumulation of soluble oligomers and insoluble fibrillar aggregates in the brain. ⁶ In large-scale Phase III trials, including CLARITY-AD, lecanemab has demonstrated potential benefits in reducing brain Aβ burden and in improving cognitive outcomes, although the clinical meaningfulness of these effects remains a topic of ongoing discussion.^7–9 Due to its encouraging clinical profile, lecanemab was approved for clinical use in China on January 9, 2024, representing a new therapeutic direction for early-stage AD.

However, safety concerns remain. Similar to other anti-Aβ monoclonal antibodies, patients undergoing treatment with lecanemab may develop amyloid-related imaging abnormalities (ARIA), including ARIA-E (edema or effusion) and ARIA-H (hemorrhagic or hemosiderin-related findings).^8,10 Against this backdrop, cerebral microbleeds and more severe intracranial hemorrhage (ICH) have emerged as focal points for clinical concern. Previous studies have indicated that the presence of certain APOE genotypes (especially the ε4 allele), coexisting vascular risk factors, or underlying cerebral amyloid angiopathy (CAA) may further elevate the risk of ICH.^11,12 In addition, with increasing recognition of comorbidities in AD and the resultant need for antiplatelet or anticoagulant therapies in some patients, the risk of hemorrhage could be exacerbated. ¹³ These clinical observations echo longstanding mechanistic concerns raised in earlier literature, including evidence that Aβ may possess important physiological functions in redox balance and vascular protection.^14,15 Specifically, Aβ has been proposed to act as a temporary sealant and local anticoagulant, forming an intravascular ‘scab’ under acidic and metal-rich conditions to help maintain vascular integrity and prevent hemorrhagic complications. ¹⁴ More recent literature further argues that anti-amyloid therapies such as lecanemab may undermine these protective roles, potentially increasing the risk of hemorrhage, edema, and downstream vascular injury in patients receiving antithrombotic therapy. ¹⁶ Nevertheless, current data on how these risks unfold in real-world populations and on the safety of combining lecanemab with other antithrombotic agents remain insufficient and require systematic investigation.

In light of these concerns, this case report focuses on the safety challenges encountered when using lecanemab in real-world settings, particularly regarding potential mechanisms behind rare hemorrhagic complications in patients with cardiovascular or other chronic comorbidities. By presenting and analyzing a rare case of pontine hemorrhage, we aim to provide insights for clinicians assessing the risks of combining lecanemab with comorbid conditions. Not only is this case notable for its unusual hemorrhage location, but it also underscores the complexity introduced by multiple concomitant medications and comorbidities, highlighting the importance of individualized risk assessment and multidisciplinary collaboration in clinical decision-making.

Case presentation

We report a 76-year-old female with mild cognitive impairment (MCI) due to AD (confirmed by both Aβ and tau positivity on positron emission tomography). She was an APOE ε3/ε3 homozygote. For past history, she had coronary artery disease, deep vein thrombosis (DVT), and stable breast cancer. She had been on dual antithrombotic therapy with clopidogrel (antiplatelet 75 mg daily) and rivaroxaban (anticoagulant 20 mg daily) over six months prior to anti-amyloid therapy. Rivaroxaban was paused due to stable DVT before initiating lecanemab. Notably, pre-treatment magnetic resonance imaging (MRI) revealed only two temporal cerebral microbleeds (CMBs) (Figure 1A) but no pontine microbleed or obvious cerebral small vessel disease load.

Figure 1.

Neuroimaging findings. Panel A demonstrates a susceptibility-weighted imaging (SWI) sequence revealing cerebral microbleeds (CMBs) in the temporal lobe (arrow), with no evidence of pontine abnormalities. Panel B displays hyperdense lesion in the left pontine region on computed tomography (CT), indicating acute pontine hemorrhage. Panel C and D illustrate the same hemorrhagic lesion visualized on SWI and T2-weighted fluid-attenuated inversion recovery (T2-FLAIR) sequence respectively.

She subsequently received two lecanemab infusions (10 mg/kg) without immediate complications. Brain MRI after either infusion did not reveal a significant edema or increased CMBs. However, due to recurrent angina, lecanemab was temporarily paused. She then underwent coronary stenting for angina, after which dual antiplatelet therapy was initiated (aspirin 100 mg daily and clopidogrel 75 mg daily).

Twenty days following stenting, she developed sudden dizziness with diplopia. Emergent brain imaging indicated the occurrence of pontine hemorrhage (Figure 1B-D). Head and neck computed tomographic angiography suggested atherosclerosis, but no abnormal vascular malformations (such as arteriovenous malformations) or aneurysms were found. After adjusting antithrombotic therapy (aspirin retention, clopidogrel discontinuation) and rehabilitation treatment, the patient's ICH was gradually absorbed but remained intermittent dizziness. Physical examination still showed mild abduction limitation of the left eye, but no obvious diplopia symptoms.

Discussion

This ICH, occurring on a background of normal blood pressure and no previous significant pontine CMBs, does not conform to the profile of hypertensive ICH. Imaging excluded cavernous hemangioma (absence of “popcorn sign” or “mulberry like” lesions) and metastasis (no enhancement). Although, the patient had been on clopidogrel and rivaroxaban for over six months without any significant bleeding events, a pontine hemorrhage ultimately occurred after initiation of lecanemab and subsequent reintroduction of dual antiplatelet therapy (aspirin and clopidogrel) following coronary stenting. This sequence of events suggests a potential synergistic effect between anti-amyloid therapy and intensified antithrombotic exposure.

Additionally, the hemorrhage site itself is atypical. Pontine hemorrhages are relatively uncommon and typically associated with severe hypertension or structural anomalies (e.g., cavernous hemangiomas). In this case, the patient's blood pressure remained well-controlled and imaging ruled out such structural pathologies. This rare presentation raises concern about the vulnerability of deep brain regions in patients receiving vascularly active therapies such as lecanemab, especially in the setting of concurrent antithrombotic treatment.

Moreover, published literature points to a link between lecanemab and ARIA, particularly ARIA-H (hemorrhagic manifestations).^6,7 While baseline antithrombotic therapy has not been clearly identified as an independent risk factor for ICH, combining lecanemab with intensified antithrombotic or thrombolytic regimens (e.g., tissue plasminogen activator) could further increase the hemorrhagic risk. ⁶

Although this patient was a non-APOE ε4 carrier, sporadic hemorrhagic events associated with lecanemab have been documented in both clinical trials and real-world reports, hinting that the drug's mechanism requires further scrutiny.^{7–8,17–19} Other possible causes, including brain metastases, arteriovenous malformations, and aneurysms, were ruled out. Given that dual antithrombotic therapy alone had not led to ICH during the preceding six months, lecanemab, newly introduced and potentially affecting vascular integrity or an underlying CAA, seems a more plausible contributor to this event.

Data from the CLARITY-AD trials (core study and open-label extension) have documented seven cases of isolated ICH and three cases of ICH concurrent with ARIA-E following lecanemab infusions, with only two of those patients being non-APOE ε4 carriers. ⁸ Although logistic regression analyses indicate that baseline antithrombotic therapy does not necessarily increase ICH risk,^7,8 recent literature points to an overall unfavorable risk-benefit ratio in certain subgroups.^20,21 Extreme caution is advised when considering the addition of thrombolytic agents in patients already receiving lecanemab.^22,23 Elevated ICH risk appears largely tied to definite or possible CAA, especially among APOE ε4 or ε2 carriers or those with hemorrhage-prone radiological features.^{17–19,22–23} It is thus striking that our patient, with no pre-existing pontine CMBs or high-risk genotypes, experienced this rare pontine hemorrhage. To the best of our knowledge, this is the first reported instance of an isolated, mild pontine hemorrhage following lecanemab infusions. These observations echo earlier theoretical concerns about the interplay between anti-amyloid therapy and cerebrovascular compromise,^14–16 and raise practical considerations about patient selection in real-world settings.

Notably, our patient also developed angina shortly after the initiation of lecanemab therapy. While this may be coincidental, Aβ has been shown to possess anticoagulant and vascular protective properties, particularly under conditions of low pH and high concentrations of metal ions. ²⁴ These conditions promote Aβ aggregation into structures that help maintain microvascular integrity, a concept first demonstrated experimentally and later discussed as a potential “vascular scab” mechanism. ¹⁴ In the heart, Aβ deposits have been identified in cardiomyocytes and interstitial tissue, ²⁵ raising the possibility that Aβ clearance may affect coronary microvascular stability. The temporal association in this case suggests that lecanemab-mediated removal of vascular Aβ could have contributed to microvascular perfusion imbalance or local thrombosis, ultimately resulting in angina.

This unusual clinical scenario highlights the importance of individualized treatment decisions when considering lecanemab, particularly in patients with cardiovascular comorbidities who may require concurrent or intensified antithrombotic therapy. Given the potential for hemorrhagic complications even in patients without classic radiologic or genetic risk factors, careful multidisciplinary evaluation and longitudinal monitoring are strongly advised. In our own cohort of other nine patients (including five APOE ε4 carriers and three on baseline antiplatelet therapy; ≤6-month follow-up), no hemorrhagic events have been observed so far. Nevertheless, in individuals with unstable vascular conditions and who might eventually need more complex or aggressive antithrombotic treatments, thorough evaluation is essential before and during lecanemab therapy. Collaboration among neurology, cardiology, and other relevant specialties, coupled with vigilant monitoring of clinical and radiological findings, is critical for balancing the drug's cognitive benefits against the risk of severe hemorrhagic complications.

Conclusion

This case underscores the importance of individualized risk assessment when considering lecanemab in patients with vascular comorbidities, particularly those requiring antiplatelet or anticoagulant therapy. Caution is required when such therapies are initiated or intensified following lecanemab infusions. Notably, intracerebral hemorrhage may still occur even in the absence of typical risk factors such as APOE ε4 genotype or extensive small vessel disease. Moreover, hemorrhagic complications may manifest in atypical locations (such as deep brainstem) beyond cerebral cortex and lobes. These findings highlight the need for close interdisciplinary monitoring and may inform future guidelines on the safe use of anti-amyloid therapies in complex real-world populations.