The multifaceted role of Vascular Neurologists in the care of candidates for anti-amyloid immunotherapy

The approval of aducanumab, lecanemab, and donanemab for mild cognitive impairment and mild dementia due to Alzheimer's disease has implications that cut across neurological subspecialties.  A timely Science Advisory from the American Heart Association Stroke Council highlights key roles vascular neurologists may play in the selection of individuals being considered for treatment with anti-amyloid immunotherapy and in the care of patients receiving this treatment.¹ The value of vascular neurologists in the treatment course of these patients stems from the risk these patients have of developing amyloid-related imaging abnormalities (ARIA) as an adverse effect of the medication.² The members of the writing group did a wonderful job at summarizing available evidence on the risk of ARIA and identifying the situations in which the participation of vascular neurologists can be crucial for the selection of safe candidates for anti-amyloid treatment and for the management of these patients once they are receiving this therapy. In this commentary we will further distill their discussion and translate it into practical considerations for daily practice.

While vascular neurologists may not prescribe anti-amyloid therapy frequently, they have unique expertise in cerebrovascular MRI grading, acute stroke management and stroke prevention, and management of cerebral amyloid angiopathy related inflammation (CAAri). Consequently, vascular neurologists can best fulfill the following tasks:

Assisting in identifying safe candidates for anti-amyloid therapy

Vascular neurologists may use help select optimal candidates for these immunotherapies in two ways: 1) characterizing baseline vascular burden, both hemorrhagic (microbleeds, superficial siderosis) and ischemic (multiple infarcts, subcortical white matter ischemia), that may contribute to the cognitive impairment and would not be amenable to disease modification with anti-amyloid therapy; in other words, helping differentiate between Alzheimer disease for which amyloid reduction would help and vascular dementia for which amyloid reduction should have minimal, if any, beneficial effect. 2) stratifying the risk of ARIA by determining the presence and severity of cerebral amyloid angiopathy (CAA) changes. This may play a role in both determining suitability for treatment as well as eventually choosing among anti-amyloid agents with different side effect profiles.

Deciding on the safety of antithrombotic and thrombolytic therapy in patients receiving an anti-amyloid drug

For these decisions, evidence can only be extrapolated from what we know regarding patients with CAA and the limited evidence from the randomized controlled trials that led to the approval of anti-amyloid drugs for clinical use.^3-5 Antiplatelet monotherapy appears safe, but little is known about the risk of hemorrhagic complications with dual antiplatelet therapy and there is concern that this risk may be excessive with anticoagulation. The vascular neurologist is ideally positioned to refer individuals with atrial fibrillation who are otherwise excellent candidates for anti-amyloid immunotherapy to undergo left atrial appendage occlusion.⁶ Patients with other indications for anticoagulation will demand individual risk-benefit assessment with combined input from behavioral and vascular neurologists.

Patients receiving anti-amyloid therapy who present with symptoms of acute ischemic stroke require the expertise of vascular neurologists to clarify the diagnosis and decide the best treatment plan. The first step is differentiating acute stroke from symptomatic ARIA. In the absence of a documented arterial occlusion that can explain the acute symptoms, these patients may require additional imaging (CTP or ideally MRI with perfusion-weighted imaging) to reach a firm diagnosis. Intravenous thrombolysis may not be safe in patients being treated with anti-amyloid therapy (we have opted not to offer it at our institution), but endovascular thrombectomy should be pursued when it is possible to reach the site of occlusion.

Of note, Appropriate Use Recommendations recommend against use of anticoagulation or intravenous thrombolysis in patients receiving anti-amyloid immunotherapy while the FDA label advises "additional caution" when considering anticoagulant or thrombolytic use for these patients. 

Helping with the treatment of symptomatic ARIA

Symptomatic ARIA can result from vasogenic edema (ARIA-E) or hemorrhage (ARIA-H). These presentations mimic what we see with CAAri⁷ and we, as vascular neurologists, have expertise in handling these cases. Starting steroids may be easy, but deciding how much and for how long is more challenging. Similarly, in the unfortunate cases of large hemorrhages, vascular neurologists need to be in charge of medical care (blood pressure control, management of brain swelling) and decide whether to refer the patient for hematoma evacuation. Whether strict treatment of hypertension can minimize the risk of ARIA is unclear, but it makes sense to pursue this goal particularly in patients who develop asymptomatic ARIA changes on MRI or have any baseline changes suggestive of CAA.

Looking into the future

Vascular neurologists can also play a key role in answering some major ongoing questions: 1) Are anticoagulants safe in patients receiving anti-amyloid immunotherapy? 2) Are thrombolytics contraindicated if a patient on anti-amyloid therapy presents with acute neurological deficits and MRI reveals no ARIA? 3) What biomarkers can be used to predict and monitor ARIA?  4) Can strict blood pressure control diminish the risk of ARIA? 5) What is the long-term bleeding risk of individuals who develop ARIA-H after treatment?  6) What is the optimal management strategy of symptomatic ARIA?

Anti-amyloid immunotherapy has come to stay and the number of patients receiving this treatment is expected to rise exponentially in the near future. As vascular neurologists, we can and should help optimize the safe and effective use of this new treatment.