Abstract
Antibodies directed at the amyloid-β peptide offer the prospect of disease-modifying therapy for early-stage Alzheimer disease but also carry the risk of brain edema or bleeding events, collectively designated amyloid-related imaging abnormalities. Introduction of the antiamyloid immunotherapies into practice is therefore likely to present a new set of questions for clinicians treating patients with cerebrovascular disease: Which manifestations of cerebrovascular disease should preclude, or permit, antibody treatment? Is it safe to prescribe amyloid immunotherapies to individuals who require antithrombotic treatment, or to administer thrombolysis to antibody-treated individuals with acute stroke? How should severe amyloid-related imaging abnormalities be managed? This science advisory summarizes the data and key considerations to guide these challenging decisions as the medical community collects further data and experience with these groundbreaking agents.
Approval of anti–amyloid-β (Aβ) monoclonal antibody infusion for mild cognitive impairment or mild dementia attributable to Alzheimer disease (AD) marks a fundamental shift in the medical landscape as the first Food and Drug Administration (FDA)–approved disease-modifying therapies for AD. The only major adverse events commonly associated with this class of immunotherapies are amyloid-related imaging abnormalities in the form of vasogenic edema (ARIA-E) or intracranial micro- or macrohemorrhages (ARIA-H). Radiographically detected ARIA is often asymptomatic1–3 and overall does not appear to worsen clinical outcome.4 A subset of ARIA, however, can be severely symptomatic (Figures 1 and 2), or fatal.5–7
Figure 1. Example of symptomatic amyloid-related imaging abnormalities in the form of vasogenic edema. Magnetic resonance imaging slices show large foci of right temporal and frontal lobar edema plus additional bilateral foci, occurring on day 73 of the phase 2 study of lecanemab. The participant was reported to have confusion, disturbance of consciousness, agitation, delusions, and hallucinations. Images from Honig et al.11 Copyright © 2023 The Authors. Published by Wiley Periodicals LLC on behalf of the Alzheimer’s Association. This is an open access article under the terms of the Creative Commons License CC BY-NC-ND 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0), which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
Figure 2. Example of symptomatic amyloid-related imaging abnormalities in the form of intracerebral hemorrhage. Magnetic resonance imaging slices show a left occipital lobar intracerebral hemorrhage detected on day 34 of the open-label extension that followed the phase 2 placebo-controlled trial of lecanemab. Images from Honig et al.11 Copyright © 2023 The Authors. Published by Wiley Periodicals LLC on behalf of the Alzheimer’s Association. This is an open access article under the terms of the Creative Commons License CC BY-NC-ND 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0), which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
The underlying pathogenesis of immunotherapy-related vasogenic edema (ARIA-E) or intracerebral hemorrhage (ICH; ARIA-H) is fundamentally cerebrovascular, placing stroke specialists squarely at the center of a new range of complex medical decisions. Stroke clinicians will need to determine whether patients with cerebrovascular disease or those who have indications for antithrombotic medications are candidates for Aβ immunotherapy, whether patients receiving immunotherapy can be treated with thrombolytics or thrombectomy, and how to treat ARIA when it occurs. This science advisory is not intended as a comprehensive review of ARIA (reviews of ARIA can be found in references 8 and 9) or a guideline to the use of Aβ immunotherapy, but rather presents a set of practical considerations for clinicians consulting on cerebrovascular aspects of anti-Aβ monoclonal antibody infusion. The considerations outlined here are based on currently available data and are thus likely to evolve as results from real-world studies, registries, and phase 4 postmarketing emerge.
Background
Three anti-Aβ monoclonal antibodies are FDA-approved for treatment of mild cognitive impairment or mild dementia attributable to AD (as confirmed by positive amyloid imaging or cerebrospinal fluid testing). Aducanumab, a monoclonal antibody selected for reactivity with Aβ aggregates, was granted accelerated approval on the basis of 1 of 2 phase 3 trials in which high-dose antibody reduced decline in Clinical Dementia Rating Scale Sum of Boxes score1; however, its commercialization has been discontinued by its manufacturer. Lecanemab, a monoclonal antibody reactive to Aβ protofibrils, was initially granted accelerated approval and subsequently full approval on the basis of phase 3 data showing slowing Clinical Dementia Rating Scale Sum of Boxes decline.2 Donanemab, a third monoclonal antibody directed against a pyroglutamate-containing form of Aβ present in AD plaques, slowed decline in the integrated Alzheimer Disease Rating Scale in a phase 3 trial,3 and recently received full FDA approval. ARIA-E and ARIA-H events were associated with drug treatment in each of these phase 3 studies, indicating a class effect. ARIA-E was detected in 35% of participants who received high-dose aducanumab, 12.6% who received lecanemab, and 24% who received donanemab; the corresponding figures for ARIA-H were 28% for high-dose aducanumab, 17.3% for lecanemab, and 31.4% for donanemab. The large majority of these events were asymptomatic or only mildly symptomatic with transient reversible manifestations such as headache, nausea, or altered mental status; however, a subset of ≈1% to 2% of treated individuals had ARIA-E that was classified as a severe adverse event, and ≈0.5% had ICH >1 cm in diameter (Table 1). 10–13 Whether variations in ARIA incidence across studies represent true differences in antibody properties versus trial-specific features of participant selection or design is unclear.
Table 1. Reported Incidence of Symptomatic Amyloid-Related Imaging Abnormalities in Phase 3 Trials and Open-Label Extension
Symptomatic ARIA
Symptomatic ARIA-H (ie, ICH >1 cm), % (number of patients)
0.3 (3)
0.6 (5);
0.6 (4) OLE
0.4 (3);
0.4 (4) OLE
Symptomatic ARIA-E, %
9.1
2.8
5.8;
5.0 OLE
SAE
1.4
0.8
1.5;
1.1 OLE
All numbers refer to double-blind phase 3 studies except where indicated as open-label extension (OLE). ARIA indicates amyloid-related imaging abnormalities; ARIA-E, amyloid-related imaging abnormalities in the form of vasogenic edema; ARIA-H, amyloid-related imaging abnormalities in the form of intracranial micro- or macrohemorrhages; ICH, intracerebral hemorrhage; and SAE, serious adverse event.
The appearance of vasogenic edema and hemorrhagic lesions in ARIA closely resembles that of cerebral amyloid angiopathy (CAA)–related inflammation (CAA-ri),14 suggesting a close relationship between the 2 syndromes. Patients with CAA-ri have been reported to have elevated cerebrospinal fluid concentrations of Aβ autoantibodies,15 indicating that it may represent a spontaneous version of the iatrogenic ARIA syndrome. The observation that markers of CAA such as lobar cerebral microbleeds or cortical superficial siderosis on baseline magnetic resonance imaging (MRI) predict increased future risk of developing ARIA-E (Table 2)12,16 supports a model for ARIA based on binding of administered antibodies to the vascular Aβ deposits that comprise CAA (Figure 3). Aβ immunologically cleared from plaques may also relocate into vessels, exacerbating CAA severity.17
Table 2. Reported Risk Factors for Amyloid-Related Imaging Abnormalities in the Form of Vasogenic Edema1–3,12,16
Risk factors
Recent initiation of immunotherapy (most ARIA occurs within ≈13 wk of initiation)
APOE genotype (greater number of APOE ε4 alleles)
Baseline presence of hemorrhagic lesions (microbleeds or cortical superficial siderosis)
Greater baseline amyloid PET burden
Higher baseline mean arterial blood pressure
Baseline absence of antihypertensive use
ARIA indicates amyloid-related imaging abnormalities; and PET, positron emission tomography.
Figure 3. Mechanistic model for amyloid-related imaging abnormalities. Amyloid-related imaging abnormalities (ARIA) are hypothesized to occur primarily as a result of interaction of antibodies (depicted in purple) with amyloid-β (Aβ) deposits (depicted in green) in the walls of cerebral blood vessels as cerebral amyloid angiopathy (CAA), leading to vascular injury and extravasation of fluid (ARIA in the form of vasogenic edema) or red blood cells (ARIA in the form of intracranial micro- or macrohemorrhages) into the brain parenchyma.
Considerations for Immunotherapy Candidates With Evidence of Preexisting Cerebrovascular Disease
Evidence of CAA
One question that arises from the association between baseline markers of CAA18 and subsequent ARIA is whether to consider excluding individuals with evidence of CAA from Aβ immunotherapy treatment. The clinical trials for aducanumab, lecanemab, and donanemab excluded individuals with >4 cerebral microbleeds, past ICH, or at least 1 (aducanumab and lecanemab) or >1 (donanemab) foci of cortical superficial siderosis (Table 3).5,19–23 Each of these hemorrhagic lesions, when restricted to cortical or lobar locations, suggests advanced CAA pathology.18 The FDA labels for aducanumab and lecanemab19,20 recommend caution in treating individuals outside these parameters used for trial enrollment. Published Appropriate Use Recommendations5,21,22 recommend that such individuals be excluded from immunotherapy treatment.
Table 3. Considerations for Patients With Preexisting Cerebrovascular Disease
Baseline markers
Clinical trials (aducanumab, lecanemab, donanemab)1–3,16
FDA label (aducanumab, lecanemab, donanemab)19,20,23
Appropriate Use Recommendations (aducanumab, lecanemab)5,21,22
Baseline markers of cerebral amyloid angiopathy
Intracerebral hemorrhage >1 cm in diameter
Excluded
“Caution should be exercised” for findings excluded in the clinical trials
Exclude
Microbleeds on baseline MRI
Allowed ≤4, excluded >4
“Caution should be exercised” for findings excluded in the clinical trials
Exclude for >4 microhemorrhages
Cortical superficial siderosis on baseline MRI
Excluded (aducanumab, lecanemab); 1 allowed (donanemab)
“Caution should be exercised” for findings excluded in the clinical trials
Exclude for any focus of cortical superficial siderosis
APOE genotype
Performed for all participants
“Consider testing for APOE ε4 status to inform the risk of developing ARIA”
APOE genotyping recommended
Baseline markers of ischemic stroke or ischemic brain injury
History of ischemic stroke or infarction on baseline MRI
Excluded (aducanumab, lecanemab)
“Caution should be exercised” for findings excluded in the clinical trials
Exclude for >2 lacunar infarcts or stroke involving a major vascular territory
White matter disease
Excluded for severe white matter disease42,43
“Caution should be exercised” for findings excluded in the clinical trials
Exclude for severe (Fazekas grade 3)42 white matter hyperintensities
ARIA indicates amyloid-related imaging abnormalities; FDA, Food & Drug Administration; and MRI, magnetic resonance imaging.
Several considerations arise in identifying which individuals with markers of CAA to exclude from amyloid immunotherapy. An analysis of baseline microbleeds associated with donanemab reported progressively increasing risk of ARIA-E across categories of 0, 1, and 2 to 4 microbleeds,12 suggesting a dose-dependent relationship with CAA severity. It will be important to consider in practice that microbleed count depends on sensitivity of T2*-weighted MRI method, with greater numbers of lesions detected using higher-sensitivity techniques, such as susceptibility-weighted imaging or higher (3 to 7 T) magnetic field strength.24 There are no data on whether more recently identified nonhemorrhagic MRI markers of CAA, such as severe perivascular spaces in the centrum semiovale or white matter hyperintensities in a multispot pattern,18 are also associated with increased ARIA risk, which is an important question for future registry data collection. It is plausible that APOE genotypes containing the APOE ε4 allele confer increased ARIA risk25 (Table 2) through their association with greater CAA severity,26 although additional mediating mechanisms are likely.
The phase 3 lecanemab trial2 also excluded individuals with cerebral aneurysms or vascular malformations, but did not require vascular imaging for study entry or specify diagnostic criteria. There have been no reports of or hypothesized mechanisms for aneurysm or vascular malformation rupture related to amyloid immunotherapy.
Evidence of Ischemic Lesions
Individuals with past ischemic stroke or severe white matter hyperintensities were excluded from immunotherapy trials (Table 3). This exclusion is not thought to be attributable to ARIA risk (which does not appear to be elevated in these patients),12 but rather because of the possibility that these individuals’ cognitive impairment had a substantial vascular component, limiting their potential benefit from Aβ removal. An additional consideration in individuals with evidence of ischemic lesions is that they might be more likely to require antithrombotic agents or acute stroke treatment during their course of immunotherapy, raising concerns for ICH6 (see following).
Considerations for Immunotherapy Candidates With Indications for Anticoagulant, Antiplatelet, or Thrombolytic Agents
The occurrence of symptomatic ICH as a small subset of ARIA-H events (Table 1 and Figure 2) raises concerns that concomitant use of antithrombotic or thrombolytic agents may increase the likelihood or severity of ICH. Analysis of individuals receiving concomitant lecanemab and anticoagulation reported symptomatic ICH in 2 of 83 (2.4%) in the phase 3 randomized study and 4 of 139 (2.9%, excluding the additional thrombolytic-related ICH discussed in the following) in the phase 3 plus open-label extension.13 If these proportions of ICH on anticoagulation are replicated in future studies, they would represent a substantial counterweight to the benefits of immunotherapy, given the nearly 50% short-term mortality risk of anticoagulant-related ICH.27 Antiplatelet monotherapy appears to be reasonably well-tolerated with immunotherapy; lecanemab clinical trial data suggest no excess risk of ARIA when antiplatelet therapy is combined with antiamyloid therapy.13 Immunotherapy trial data are not available regarding the effects of dual antiplatelet therapy; however, in patients with cardiovascular or cerebrovascular disease, dual versus single antiplatelet therapy appears to increase risk for intracranial hemorrhage ≈1.4-fold.28 FDA labels have advised “additional caution” in use of concomitant antithrombotic agents, and Appropriate Use Recommendations have recommended against concomitant use of anticoagulants until more data demonstrating safety are available (Table 4).
Table 4. Considerations for Patients Requiring Antithrombotics or Thrombolytics
Agents
Clinical trials (aducanumab, lecanemab, donanemab)1–3,16
FDA label (aducanumab, lecanemab, donanemab)19,20,23
Appropriate use recommendations (aducanumab, lecanemab)5,21,22
Anticoagulants
Excluded (aducanumab, lecanemab phase 2 core study); allowed if stable dose (lecanemab phase 2 OLE and phase 3, donanemab)
“Additional caution should be exercised when considering the administration of antithrombotics or a thrombolytic agent (eg, tissue-type plasminogen activator)”
Exclude from immunotherapy until data demonstrating safety are available
Antiplatelets
Allowed
See above
Allowed at standard monotherapy doses
Thrombolytics
Not specified
Above plus “treating clinicians should consider whether [focal neurologic] symptoms could be due to ARIA-E before giving thrombolytic therapy”
Avoid thrombolytics until data demonstrating safety are available
ARIA-E indicates amyloid-related imaging abnormalities in the form of vasogenic edema; FDA, Food & Drug Administration; and OLE, open-label extension.
Considerations around administration of thrombolytic agents to immunotherapy-treated patients are further complicated by the unpredictability and major clinical effects of the events that trigger their emergent use: stroke, pulmonary embolism, and myocardial infarction. In the absence of extensive data on thrombolysis in the setting of Aβ immunotherapy, much attention has focused on reports of fatal multifocal ICHs in 1 lecanemab-treated patient and 1 donanemab-treated patient after intravenous administration of alteplase or tenecteplase, respectively.6,29 The former event occurred in a 65-year-old woman who presented with a stroke-like syndrome 4 days after her third dose of open-label lecanemab with postmortem pathology demonstrating severe CAA-ri6; the latter was a 72-year-old man with stroke-like symptoms 9 days after a fifth dose of open-label donanemab who did not have postmortem examination.29 The FDA labels for aducanumab and lecanemab advise “additional caution” when considering thrombolysis, whereas the FDA label for donanemab notes that “because ARIA-E can cause focal neurologic deficits that can mimic an ischemic stroke, treating clinicians should consider whether such symptoms could be due to ARIA-E before giving thrombolytic therapy.”23 The Appropriate Use Recommendation for lecanemab5 recommends against use of thrombolytics until further data demonstrate safety (Table 4). An additional practical step in anticipation of unexpected events is advance care planning discussions between the patient and physician regarding the patient’s preference.30 In stroke care practice, it will be important to consider the possibility that acute ARIA-related symptoms might appear as a stroke mimic requiring urgent MRI for correct diagnosis, particularly in the context of ARIA risk factors, such as APOE ε4/ε4 genotype or recent initiation of immunotherapy (see Table 2). An additional important consideration for practice is that mechanical thrombectomy performed without thrombolytic administration for large-vessel occlusion does not appear to increase risk for symptomatic ICH even in the presence of cerebral microbleeds31 and is therefore likely a safe option to be considered when evaluating possible acute stroke in patients receiving immunotherapy. The considerations discussed here and methods for identifying individuals being treated with amyloid immunotherapy should be disseminated across the acute stroke team.
Considerations for Treating and Preventing Incident ARIA
FDA recommendations for management of ARIA are to suspend dosing for moderate to severe ARIA-E or ARIA-H MRI findings (defined as appearance of a hyperintense lesion at least 5 cm in greatest dimension or multiple hyperintense foci, at least 5 new cerebral microbleeds, or at least 2 new foci of cortical superficial siderosis), moderate to severe ARIA-E clinical symptoms (defined as sufficient to affect daily activities), or any symptomatic ARIA-H (including all ICHs), and to base the decision to resume dosing on resolution of imaging findings and symptoms and on clinical judgement.19,20,23 The Appropriate Use Recommendations suggest the additional option of anti-inflammatory treatment, such as corticosteroids.5,21 Looking to the experience with CAA-ri, a retrospective observational study found that patients with CAA-ri whose initial clinical presentations were treated with anti-inflammatory agents (most commonly intravenous methylprednisolone 1 g daily for 3 to 5 days; then, oral prednisone 60 mg daily tapered to discontinuation over several months) were more likely to have clinical and neuroimaging improvement and demonstrated longer time to CAA-ri recurrence than those who were untreated.32 These observations offer some support for high-dose steroid treatment for severe ARIA-E, with the caveat that results from the endogenously generated immune response in spontaneous CAA-ri may not fully generalize to the exogenously generated syndrome of ARIA.
For care of patients with ARIA-H presenting as symptomatic ICH, there is no reason to deviate from existing ICH guidelines.33 Evacuation of the types of lobar ICHs that are often related to CAA does not appear to carry increased risk of surgical complication.34,35
Identifying modifications of treatment protocols that reduce risk or severity of ARIA appears a promising future direction for optimizing Aβ immunotherapy. An intriguing recent observation that both lower mean arterial pressure and use of an antihypertensive medication—potentially an indication of better blood pressure control—at initiation of donanemab treatment independently predicted reduced ARIA-E incidence12 raises the possibility that blood pressure may interact with the vascular pathways that generate ARIA. Previous studies among patients with probable CAA have suggested association of hypertension with increased risk of ICH recurrence36 and greater white matter atrophy,37 highlighting likely interactions between blood pressure and small vessels with CAA.
Conclusions and Future Steps
To summarize key vascular considerations related to amyloid immunotherapy:
1.
ARIA is a common effect of Aβ immunotherapy. Whereas ARIA is often asymptomatic, it is symptomatic in a substantial subset of patients, and occasionally is associated with irreversible brain injury or neurologic impairment. Knowledge about potential presenting symptoms, including headache, altered mental status, partial or generalized seizures, and focal neurologic deficits, is potentially relevant to all clinicians providing care for patients with stroke.
2.
There is solid evidence that ARIA risk can be stratified by presence of CAA markers, such as cerebral microbleeds, cortical superficial siderosis, and APOE genotype. Detection of these markers therefore provide a good basis for personalized decision-making that incorporates the risk of severe ARIA along with the individual’s projected benefits from immunotherapy.
3.
Limited data indicating associations of higher baseline blood pressure and absence of antihypertensive medication use with increased risk of donanemab-related ARIA-E12 support close adherence to guidelines for detection and treatment of hypertension38 for patients treated with immunotherapy.
4.
Anticoagulation likely increases the risk of severe ARIA in the form of symptomatic ICH. Personalized decision-making for patients with coexisting early AD and nonvalvular atrial fibrillation (with elevated CHA2DS2-VASc score) requires incorporating this risk (which can only be estimated imprecisely on the basis of sparse existing data), the individual’s projected benefit of immunotherapy, and the American Heart Association class I recommendations favoring anticoagulation for primary and secondary stroke prevention.39,40
5.
Limited data are available to guide individual-level decisions regarding thrombolysis, but dictate vigilant scrutiny for ARIA as the potential cause of stroke-like symptoms. Risk of thrombolysis-related ICH might be stratified in the acute care setting by an individual’s likelihood of ARIA as determined by factors such as recency of immunotherapy initiation, APOE genotype, and baseline CAA markers (Table 2). Review of recent monitoring MRIs and performance of immediate MRI are reasonable approaches to identifying the presence of ARIA and its possible presentation as an acute stroke mimic. Pending further data demonstrating the safety of thrombolysis in this setting, treating clinicians might reasonably consider a high level of caution or avoidance of thrombolytic use in patients receiving immunotherapy. Mechanical thrombectomy without thrombolytics for patients with established clinical indications is likely safe and should be performed.
6.
Treatment of symptomatic or radiographically advanced ARIA centers on suspending immunotherapy and considering lessons from the response of CAA-ri to anti-inflammatory treatment.
Optimizing the benefit to risk tradeoff of Aβ immunotherapy for AD will require better predictors of severe or life-threatening ARIA, mechanism-based prevention and treatment strategies, and delineation of the decision tipping point for determining when benefit outweighs risk. Development and validation of novel approaches and evidence-based treatment algorithms41 in each of these areas will be advanced by collection of real-world data on treated individuals as required by the Centers for Medicare & Medicaid Services for Medicare coverage of lecanemab. The Centers for Medicare & Medicaid Services–approved ALZ-NET Alzheimer’s National Registry for Treatment and Diagnostics (www.alznetproviders.org) has committed to collecting and sharing (in de-identified form) the full range of patient-level data, outcomes, biomarkers, and neuroimaging studies required for creating firm guidance for implementing this new approach to AD-modifying therapy.