Intracerebral hemorrhage following mild ARIA-H in an APOE ε2 carrier receiving lecanemab

Abstract

Objective

Report a case of an apolipoprotein E (APOE)ε2 carrier receiving lecanemab who developed late onset intracerebral hemorrhage (ICH) following amyloid-related imaging abnormalities-hemorrhage (ARIA-H).

Method

We detail the history and neuroimaging findings of a 73-year-old male with Alzheimer’s disease (APOEε2/ε3 status) who developed ICH after mild ARIA-H and suffering a fall.

Results

The patient developed mild ARIA-H after his 13th infusion that was proceeded by left temporo-occipital hemorrhage following his 14th infusion.

Discussion

Although APOE ε2 is known to be protective against Alzheimer’s disease, it has also been shown to increase risk for hemorrhage with cerebral amyloid angiopathy. This case serves as an opportunity to examine the complex role that APOE ε2 plays in both protection against Alzheimer’s disease and contribution to increased hemorrhagic risk with lecanemab.

Introduction

Alzheimer’s disease (AD) is the most common cause of dementia worldwide, projected to afflict more than 150 million people worldwide by the year 2050[1]. Lecanemab, an FDA-approved treatment for early stage AD, is a monoclonal antibody designed to target amyloid-β protofibrils to reduce amyloid plaque burden, modestly decreases cognitive/functional decline relative to placebo, but it may also cause amyloid-related imaging abnormalities (ARIA) in 21.5% of patients [2, 3]. ARIA-E (edema) and H (hemorrhage) risk increases with the number of the apolipoprotein E (APOE) ε4 alleles [4]. Consequently, Lecanemab Appropriate Use Criteria recommend exercising caution in APOE ε4 homozygotes [4].

The APOE ε2 genotype is protective against AD [5], but studies have linked this allele to increased lobar hemorrhage risk in the setting of cerebral amyloid angiopathy [6]. Minimal data exists relating APOE ε2 carrier status to lecanemab safety.

We describe a case of an APOE ε2 carrier who developed ARIA-H following the 13th lecanemab infusion (> 6 months from drug initiation) that resulted in lobar hemorrhage.

Case history

A 73 year-old right-handed male with well-controlled hypertension, dyslipidemia, and type II diabetes diagnosed with A+/T+/N + AD[7] based on positive spinal fluid biomarkers (Table 1) on aspirin 81 mg (for coronary artery disease risk factors), lisinopril, fluoxetine, and insulin (Humolog/Lantus) was found to have baseline Mini–mental state examination (MMSE) 29/30 with APOE ε2/ε3 status. He never had any neurosurgical interventions. Initial MRI brain prior to lecanemab infusion was closely reviewed, and found to be negative for cerebrovascular disease (Fig. 1A). Particularly, there were no cortical superficial siderosis, visible perivascular spaces in the centrum semiovale or basal ganglia, significant confluent white matter disease (Fazekas grade 1), multispot pattern of white matter hyperintensities, or microbleeds suggestive of any underlying cerebral amyloid angiopathy (CAA). The patient had previously been started on donepezil 10 mg and memantine 10 mg bid. The decision was made to initiate lecanemab, which was tolerated without infusion reactions or ARIA-related symptoms. After the 13th infusion (26 weeks of treatments after first lecanemab dose), a surveillance MRI brain showed 3 new microhemorrhages involving the left occipitotemporal lobe, consistent with mild ARIA-H (Fig. 1B). There was no other evidence of CAA-related findings on MRI at this time as well. Given that there were fewer than 5 microhemorrhages and the patient was asymptomatic, lecanemab infusions were continued.

Fig. 1

Neuroimaging findings. 3 T Axial MRI SWI images showed no evidence of microhemorrhage prior to initiation of lecanemab (A), but demonstrated ARIA-H in the left occipitotemporal lobe after the 13th infusion (B). After 14th infusion, the patient had a fall leading to head injury, at which point no abnormalities were appreciated on CT head (C), but developed intracerebral hemorrhage 1 week later (D; T2 FLAIR sequence)

One week after his 14th infusion, the patient suffered a mechanical ground level fall, hitting the top of his head on the door that led to a head laceration (but no loss of consciousness). He initially presented to the local emergency room (ED), where a CT head was negative for evidence of intracerebral hemorrhage (Fig. 1C). He was discharged home free of symptoms. Subsequently he developed progressive headache, somnolence and nausea, returning to the ED one week later, and found to have a left occipitotemporal lobe intracerebral hemorrhage on both CT head and MRI brain. The patient was normotensive (presenting blood pressure 127/64) and neuroimaging was negative for any vascular abnormalities underlying the bleed. His aspirin was immediately discontinued. He was discharged after overnight monitoring without any interventions (Fig. 1D) and lecanemab was discontinued indefinitely.

When the patient was seen in the clinic approximately 1 month after the event, he was noted to be largely asymptomatic, although had a drop in the MMSE score to 26 (losing points for verbal recall and serial 7s compared to initial exam).

Discussion

We report a 73 year-old APOE ε2 male with biomarker-confirmed early stage AD who developed mild ARIA-H in the setting of lecanemab that evolved into a lobar hemorrhage following a mechanical ground level fall that led to a head injury. To the best of our knowledge, this is the first reported case of symptomatic ARIA-H in a carrier of APOE ε2 allele, as none of the patients enrolled in the CLARITY trial who developed intracerebral hemorrhage carried the allele [3].

Even though the APOE ε2 gene is protective against Alzheimer’s disease (with APOE ε2/ε2 or ε2/ε3 carriers having fewer amyloid-beta plaques as well as build-up of neurofibrillary tangles [6]), studies have also found consistently that APOE ε2 carries increased risk of CAA and CAA-related intracranial hemorrhage [8,9,10] with recent meta-analysis showing strong association between APOE ε2 and cortical superficial siderosis [11]. The mechanism behind the increased risk for CAA-related bleed is unknown, but direct vasculopathic changes [12, 13] via promotion of amyloid deposition [11] is thought to play a role.

Although generally well-tolerated [2, 3], there have been few reports of adverse events with lecanemab, including cerebral β-amyloid-related arteritis as well as severe hemorrhages after thrombolytics [14,15,16]. Interestingly, neuropathologic examination of one of the cases revealed phagocytic response to not only parenchymal amyloid-β (contributing to amyloid-β clearance), but also vascular amyloid-β as well, suggesting potential mechanisms on how ARIA may develop in response to lecanemab [15]. Hence, carriers of the allele may have a higher risk of amyloid-β vessel wall binding with lecanemab, potentially leading to a higher risk of CAA and intracerebral hemorrhage. Indeed, this raises the question on whether ARIA and CAA share common pathways in the pathogenesis [17]. For instance intracerebral hemorrhage can develop in areas of microbleeds in some CAA patients over time [18], akin to what occurred in our current case.

It is our presumption that the patient’s APOE ε2 status may have resulted in the delayed onset of mild ARIA-H (e.g. 6 months after initial lecanemab infusion) followed by lobar hemorrhage as the CLARITY AD trial showed that most incidences of ARIA occurred within the first 4 months of the therapy. Our patient’s intracerebral hemorrhage was not detected immediately after the mechanical fall on head CT, but rather 1 week afterwards (Fig. 1C, D); hence it seems less likely that the trauma was the direct cause of the bleed. He was taking daily aspirin, but even in patients taking antiplatelet or anticoagulation therapy, the ICH risk is estimated to be 0.2–1.5%[19]. The intracranial hemorrhage occurred in the left temporo-occipital area of asymptomatic ARIA-H, thus suggesting that lecanemab as well as the patient’s APOE ε2 carrier status may have contributed via effects on vascular amyloid-β.

This case study suggests that APOE ε2 carrier status may need to be taken into account when considering the risk versus benefit of amyloid monoclonal antibody treatment in early-stage AD.

Table 1 Alzheimer’s Disease Biomarker Data. Patient biomarker data from cerebrospinal fluid studies. Test performed by the Mayo Clinic