Building an Infrastructure to Administer Amyloid-Targeting Treatments

Amyloid-targeting treatments (ATTs) for Alzheimer disease (AD) have been approved by the Food and Drug Administration (FDA), are available (and generally covered by payors), and are effective at slowing AD progression, but they are associated with safety risks (chiefly amyloid-related imaging abnormalities [ARIAs]).^1,2 Physicians and health care systems must develop an infrastructure to ensure appropriate treatment and monitoring.³

There are currently 2 FDA-approved ATTs in the United States: lecanemab (Leqembi; Eisai, Nutley, NJ; accelerated approval January 2023, traditional approval July 2023) and donanemab (Kisunla; Eli Lilly, Indianapolis, IN; approved July 2024). These therapies mark a dramatic pharmacologic change for the treatment of mild cognitive impairment and mild dementia due to AD, and they have different infrastructural requirements. ATTs require a more extensive diagnostic, treatment, and monitoring process and increased participation of health care personnel compared with previous therapies (eg, acetylcholinesterase inhibitors, memantine, neuropsychiatric management) (Table). It is crucial that AD be diagnosed and disclosed in a timely manner. Initial clinical visits should focus on the clinical stage of the disease, overall health and comorbid conditions, and caregiver support. Later visits should include discussions with patients based on genetic and imaging findings, evidence of amyloid in cerebrospinal fluid samples or positron emission tomography images, and careful and thoughtful selection for therapy which requires informed patient consent. After beginning ATT therapy, individuals with AD require appropriate MRI monitoring, infusion scheduling, ARIA management, and ongoing discussions with physicians to ensure compliance, expectations, and understanding. 

The paradigm shift associated with the emergence of ATTs has created the need for new clinical systems and workflows, interdisciplinary teams, and technical expertise for effective ATT administration.⁴ Treating physicians find themselves in various stages of motivation and readiness; however, individuals and families interested in pursuing ATT are often placed on a waiting list. In this article, we describe the components of an optimal ATT program, including workflow, staffing, oversight, and billing considerations; flexibility needs; and troubleshooting pointers. An optimal ATT program can help physicians maximize patient wellbeing, autonomy, and safety. Every program should be built for optimal flow while anticipating potential barriers which could disrupt patient care (Figure 1).

Figure 1. Optimal patient flow will be challenged at every step. A system built for optimal patient flow should anticipate potential barriers which could disrupt patient care, and accommodate overwhelmed, limited, or inconsistent caregivers.
Abbreviations: AD, Alzheimer disease; ARIA, amyloid-related imaging abnormality; LP, lumbar puncture; PET, positron emission tomography.

Infrastructure Requirements
Knowledgeable and Dedicated Physicians
The diagnosis and treatment of individuals with AD requires a team of dedicated neurologists, geriatricians, and psychiatrists. The responsibilities of this interdisciplinary team include ordering appropriate laboratory studies (eg, preliminary MRI and biomarker testing), discussing AD test results, identifying individuals who are eligible for ATT, initiating anti-amyloid medications appropriately, and managing treatment. 

Along with close collaboration with infusion nurses, radiologists, scheduling staff, primary care doctors, other specialists, and billing staff (Figure 2), clinical expertise remains the chief requirement of physicians in this new age of AD treatment. Some inclusion and exclusion criteria to consider for individuals who may be candidates for ATT are fairly simple (eg, do not dose a patient who has 10 microhemorrhages), whereas other situations require nuanced decision making. For instance, physicians may need to determine which treatment recommendations to make for a patient who presents with preserved daily function (eg, managing medications, finances, driving, handling appliances) with a language variant and Mini-Mental State Examination score of 17. Additional factors may include concerns about patient and caregiver competency with respect to decision-making, and caregiver proximity to the patient (eg, a caregiver who lives 1 hour away). Caregivers are of vital importance: they need to help patients navigate MRI and infusion appointments and insurance hurdles, monitor and report possible side effects (eg, infusion reactions, symptomatic ARIAs), and navigate new medical and psychosocial challenges that arise during treatment.

Clinical demands will grow as ATTs become more increasingly used. At one center (University of Alabama at Birmingham), wait times increased from 245 days to 490 days with lecanemab approval.⁵ Adding and training advanced practice practitioners in practices may be necessary if it is not feasible to hire additional physicians. 

Figure 2. Key stakeholders involved in the administration of anti-amyloid targeting therapies (not including patients and caregivers).
Abbreviations: APP, advanced practice practitioners; CSF, cerebrospinal fluid; ED; emergence department; PET, positron emission tomography. 

Infusion Centers
Infusion centers are essential for administering ATTs which require intravenous delivery. Existing centers likely have the capacity to handle a modest increase in patients requiring infusions and can expand to ensure they meet the needs of their local populations. Independent infusion centers or those under the direction of rheumatology, oncology, or multiple sclerosis centers, are possible locations where these ATT infusions could be administered. All patients with AD require reliable clinical protocols to maximize their safety and comfort. As such, it is important to provide training for infusion center staff on potential side effects (eg, identification of ARIAs and checklist questions are crucial) (Figure 3). 

Figure 3. Sample checklist for a patient with a new medical condition
Created with MedTraker.com.

MRI and Radiology Services
A baseline MRI scan is used to assess treatment eligibility for individuals suspected of AD dementia, and regular MRI scans obtained posttreatment are used to monitor for ARIAs. Partnering with radiologists skilled in ARIA interpretation to establish clear protocols for clinical information and to facilitate detection and reporting of ARIAs is optimal. Access to MRIs can be ensured with advance scheduling, and forming partnerships with imaging centers can help establish an appropriate monitoring schedule.

Awareness in Primary Care, Stroke Neurology, and Emergency Medicine
Primary care physicians often encounter individuals who might benefit from ATTs. These providers should be educated on early AD detection and referral pathways. The oft-used phrase in stroke care that “time is brain” also applies to the diagnosis and treatment of individuals with AD, because earlier identification ensures more appropriate and effective treatment.

Tissue-type plasminogen activator administration poses risks to people taking ATTs, and stroke neurologists and emergency physicians should be aware of this potential danger. Potential solutions to help limit the danger of such interactions include wallet cards, medical alert bracelets, or electronic medical record drug–drug interaction warnings.

Anticoagulant use is also dangerous for people taking ATTs. Because anticoagulants are often used to treat atrial fibrillation, cardiologists should have some familiarity with ATT medications and need to be consulted about recommending alternative treatment approaches, such as atrial appendage closure devices or antiplatelet treatment, before ATT treatment can be initiated.  

Tracking Systems
A system to track elements relevant to ATT treatment and monitoring is essential. This could include electronic medical records with alerts. Commercial options include MedTraker.com (Atlantic Zeiser, Emmingen-Liptingen, Germany) which is free to use and tracks required follow-ups, MRIs, and monitoring for symptomatic ARIAs before each dose (Figure 3). A robust tracking system used by the treatment team ensures adherence to therapy protocols and active recognition and management of potential side effects.

Staffing
An ATT clinic requires staffing capable of accommodating the need of the patient population. For example, with 10 patients in treatment, the team does not require an antiamyloid coordinator; with >50 patients, this role is a necessity. An optimal ATT administration team should include a doctor, receptionist, telephone scheduler, billing specialist, anti-amyloid coordinator (tasked with MRI and infusion scheduling, registry requirements, and revenue management), and, if drug is infused onsite, an infusion nurse. The Centers for Medicare & Medicaid Services (CMS) mandates, but does not fund, a registry as a condition for coverage of ATTs. Although the registry is well-intentioned, it places an additional burden on staff. Additionally, without a blinded control group the registry cannot generate safety or efficacy data. Infusion sites could consider a scribe to help with data entry into electronic medical records and the CMS registry. 

Onsite Care vs Outsourcing
Delays to the delivery of ATT treatment occur for a variety of reasons (eg, the need for approvals, committee meetings, and order sets) and can hinder patient care. During delays, patients with early symptomatic AD who may be ATT candidates will have disease progression. ATT treatment benefits can be diminished in individuals with AD progression, and individuals who transition into the moderate stage of dementia may become ineligible for treatment.

A possible solution to prevent delays is to outsource patient care. However, medical administrators may not be agreeable to outsourcing care because this would decrease revenue. The need for patients to seek external care outside the institution is referred to as “leakage.”⁶ The ability to care for patients onsite in a timely manner aligns the goals of physicians and administrators by preventing “leakage” and optimizing patient care. 

Financial Considerations
Implementation of ATTs requires substantial time and interdisciplinary input which is not recognized by payors. Non-340B institutions may experience tight financial margins, limiting financial incentives for clinicians to prescribe this new treatment class.⁷ In addition, some physicians are hesitant to prescribe ATTs due to perceptions about the potential risks of treatment and costs associated with treatment.⁸

Insurance companies may not cover the costs of ATTs, even for those drugs which are approved by the Food and Drug Administration, which can generate confusion for physicians and patients when considering treatment with these therapies.⁹

To limit coverage, insurance companies have mischaracterized lecanemab’s phase 3 trial results and have used Medicare’s denial of aducanumab as a confounder.  One medical insurance director said, “Re-evaluation made it clear to us that the existing evidence does not allow for conclusions to be drawn about the safety and effectiveness of Leqembi.”¹⁰ This mirrors the following statements from the CMS: “At this time there is no antiamyloid that does demonstrate a clinically meaningful benefit,” and “CMS needs evidence that an antiamyloid mAb for the treatment of AD demonstrates improved health outcomes, with reasonable risk of harm, in broader community practice and in the broader Medicare population, that are similar to results achieved in successful but narrowly-designed RCTs seeking to establish safety and efficacy for FDA approval.”¹¹

A strong counterapproach is required to properly challenge insurance coverage denials. In the authors’ practice, each first pass and appealed denial must have a signed statement in accordance with ALCOA principles (Attributable, Legible, Contemporaneous, Original, and Accurate). Third parties may refuse to sign denials. Despite insurers’ claims of using a “peer-to-peer” process, it is important to note that insurers are not directly involved in the care of patients and lack decision rights. As such, the information they utilize to accept or reject coverage for certain therapies is based on an incomplete picture of patients’ needs.

Regardless, discussions between physicians and payors must adhere to ALCOA principles, with contemporaneous documentation, including names (with spelling), National Provider Identifiers, and state license numbers. 

Physicians interact with various stakeholders and should explain details of the disease and the diagnosis to patients and their families, document medical decision making, and justify treatment with routine clinical care. Physicians must also be familiar with insurance appeals processes and, at times, the need to contact state representatives, their state insurance commissioner, and journalists. 

Conclusion
Patients with AD can be assessed and treated with medications that slow disease progression when diagnosis occurs early in the disease process. An emphasis on patient safety, monitoring, and wellbeing as well as the creation of a stable infrastructure for administering ATTs are all factors which help ensure that patients with AD receive timely, safe, and effective care.