System readiness and the patient care pathway for Alzheimer's disease diagnosis and treatment

Abstract

Promising therapeutic interventions that target the underlying pathophysiology are changing the landscape of Alzheimer's disease (AD) research. The AD care pathway must be transformed to meet the challenge of bringing these new therapies to the increasing number of people living with AD within the existing healthcare framework. Challenges include identifying patients who may benefit from treatment interventions early in the course of the disease, ensuring that diagnostic tools are accessible and accurate, and developing capabilities to monitor the effectiveness of interventions over time. These challenges must be addressed at all levels, from primary care settings to tertiary treatment centers; this will require collaborative efforts between health systems, drug manufacturers, and research institutions to navigate this evolving landscape and ensure system readiness for patients and their families with AD. The Spring 2024 Alzheimer's Association Research Roundtable (AARR) meeting gathered industry representatives and clinicians to discuss insights, challenges, and solutions that will help researchers and health systems identify patients in the early stages of AD and deliver emerging therapies efficiently and safely. In this paper, we provide highlights from the Spring 2024 AARR meeting.

1. INTRODUCTION

Anti‐amyloid monoclonal antibodies are emerging as promising therapeutic interventions that target one aspect of Alzheimer's disease (AD) pathophysiology. These treatments are reshaping the landscape of AD diagnosis, treatment, and care by demonstrating the potential for slowing disease progression. However, effectively delivering these therapies to the growing population of individuals living with AD within the current healthcare frameworks has proved challenging, indicating the need for transformative system‐wide changes. Key challenges in this evolving therapeutic landscape include identifying patients who could benefit from such interventions early in the course of the disease, ensuring widespread access to accurate and efficient diagnostic tools, and developing the capacity to monitor the effectiveness and safety of these therapies.

To meet these challenges, healthcare systems need to prioritize readiness by raising awareness among healthcare providers, shifting to earlier‐stage diagnosis and treatment, and establishing infrastructure for administering infusions and managing potential side effects like amyloid‐related imaging abnormalities (ARIA). A coordinated, comprehensive strategy is essential – one that spans all levels of healthcare, from early detection in community and primary care settings to specialized management provided at tertiary centers. This calls for robust collaboration among clinical specialties, healthcare systems, pharmaceutical companies, research institutions, governmental and private insurers, and policymakers to enhance system readiness and support effective care delivery to patients and their families.

The Spring 2024 Alzheimer's Association Research Roundtable (AARR) was a unique platform to explore these topics in depth. The meeting provided an important opportunity to discuss the best practices, challenges, and potential solutions to help healthcare providers and health systems deliver emerging AD therapies efficiently and safely. This meeting brought together a diverse group of experts, including scientific leaders from the AARR membership, academia, large healthcare systems, clinicians treating patients with AD, the National Institutes of Health (NIH), the Centers for Medicaid and Medicare Services (CMS), and the United States Food and Drug Administration (FDA). These discussions focused on system readiness in the United States healthcare system; while some considerations will apply more broadly, other issues will need to be addressed in the context of other systems. In this manuscript, we provide a summary of key discussions from the meeting, including insights into current challenges and potential strategies proposed by leaders in the field, with the ultimate aim of advancing AD care and accelerating progress toward improved outcomes for those living with the disease.

2. EARLY AD DIAGNOSIS AND PATIENT CARE PATHWAY: THE ROLE OF PRIMARY CARE

The core attributes of primary care, as outlined by the National Committee for Quality Assurance (NCQA) and embodied in the patient‐centered medical home (PCMH) model, emphasize comprehensive and longitudinal care, patient‐centeredness, coordinated care, quality, and accessibility. ¹ These principles make primary care an ideal setting for managing chronic conditions like AD, where early diagnosis, ongoing monitoring, and care coordination are critical. Nevertheless, while primary care is often the first point of contact for patients with cognitive impairment, significant challenges exist that complicate the integration of AD diagnosis and management into primary care. Such challenges include time constraints, the broad range of health issues managed by primary care providers (PCPs), and the need to stay current with rapidly advancing diagnostic and therapeutic developments in AD. To address some of these challenges, the Spring 2024 AARR meeting highlighted the Georgia Memory Net as an example of an initiative to integrate AD care into primary care (Supplemental Text 1).

The imperative to improve current primary care practices while simultaneously exploring innovative and transformative approaches is crucial in the evolving landscape of AD treatment and diagnosis. The potential for advancements in cognitive assessment within primary care is especially important, offering a pathway to more personalized care. This may include leveraging artificial intelligence and large language models to analyze patient‐reported data longitudinally, thereby identifying subtle cognitive changes as early indicators for intervention. Below, we discuss the importance of cognitive testing in primary care as well as other considerations for enhancing the transition from primary care to specialty care, such as improved referral pathways and enhanced training for PCPs.

2.1. Cognitive testing in primary care

Approximately 60% of patients with dementia go undiagnosed in the community ² and 34% in primary care. ³ These numbers increase to 90% in some middle‐ and low‐income communities. ⁴ Time constraints, along with uncertainty related to diagnosing and managing dementia, have been suggested as the leading reasons for failure to diagnose. ⁵ , ⁶ , ⁷ In its last updates, the United States Preventive Task Force recognized that cognitive assessment tools could increase the detection of cognitive impairment. ⁸ In line with this, the Spring 2024 AARR delved into exploring the test performance of cognitive screening tools for mild cognitive impairment (MCI) and dementia in primary care. ⁴ Among the tools reviewed were paper‐and‐pencil cognitive tests, including the Mini‐Mental State Examination (MMSE), the Short Form (16‐item) Informant Questionnaire on Cognitive Decline (IQCOD), the Ascertain Dementia (AD8) questionnaire, the General Practitioner Assessment of Cognition (GPCOG), the Short Form of the Montreal Cognitive Assessment (s‐MoCA), the Mini‐Cog, the Memory Impairment Screen (MIS), and the Quick Dementia Rating System (QDRS) (Supplemental Text 2).

In addition to traditional paper‐and‐pencil cognitive tests noted in Supplementary Text 2, several digital tools are under development, with some evidence indicating they may outperform paper‐and‐pencil tests. ⁹ Two tests are specifically being developed for use in primary care, including the 5‐Cog – a culturally neutral 5‐min test that has a sensitivity of 0.96 and a specificity of 0.71, ¹⁰ , ¹¹ and the My Cog – a 10‐min test that has a sensitivity of 0.79 and a specificity of 0.82 – for detecting dementia or cognitive impairment. ¹² These tests and many others are currently being tested in the clinic and home environments for practical implementation.

Physicians and healthcare providers in the primary care setting are increasingly tasked with diagnosing and caring for patients with cognitive impairment. To facilitate improved diagnostic detection via cognitive tools, attention needs to be given to the time required for administration, ease of scoring, and diagnostic accuracy. Additionally, establishing appropriate cut‐off scores for race/ethnicity and education and language adaptations are needed to make the use of these tools more generalizable to the population. Finally, it is worth noting that while many of these cognitive tests demonstrate good diagnostic accuracy, they may not be adequate for detecting cognitive impairment at a sufficiently early stage to enable the timely use of emerging disease‐modifying AD therapies. This highlights the need to consider coupling these tools with other biomarker tests to improve early detection.

2.2. Optimizing primary care pathways and enhancing the transition to specialty care

AD has emerged as the third most expensive disease in the United States, following cardiovascular disease and cancer, with annual treatment costs estimated between US$50 and US$100 billion. As the number of individuals diagnosed with AD continues to rise, managed care organizations are expected to bear a larger portion of these expenses. To mitigate this burden, it will be crucial to implement early diagnostic and management programs, particularly as novel disease‐modifying therapies like anti‐amyloid monoclonal antibodies become more widely available.

Optimizing primary care pathways in the United States will necessitate an evaluation and re‐examination of the implementation of the Medicare Annual Wellness Visit. There is notable variability in the performance of these visits, particularly across rural regions, with disparities in content and quality. Although detection of cognitive impairment is a required component of the wellness visit, no standardized recommendations exist for how the cognitive assessment should be performed or what testing tools, if any, should be employed. ¹³ There are also no recommendations for subsequent steps following the identification of cognitive impairment. Consequently, there is a need for standardization and enhancement of assessment procedures and care linkages within the context of annual wellness visits.

Efforts are under way to standardize diagnostic protocols in the primary care setting to ensure early and accurate diagnosis. These include developing diagnostic algorithms, utilizing digital cognitive assessments, incorporating blood‐based and imaging biomarkers, and exploring other innovative diagnostic technologies. Programs such as Project ECHO‐based ¹⁴ dementia conferences and other educational initiatives are also being implemented to enhance the knowledge and confidence of PCPs in diagnosing and managing cognitive disorders. However, these initiatives face significant challenges. PCPs are often overburdened and time‐constrained, and there is a nationwide shortage of dementia care specialists. Additionally, access to non‐pharmacological support and caregiver education is limited, and existing reimbursement models disincentivize innovative approaches to care.

To overcome these barriers, the United States healthcare system will need to explore not only the development of novel care algorithms and diagnostic tools but also reimagine how primary care and specialty teams collaborate and how subspecialists are reimbursed. A hub‐and‐spoke model, where dementia specialists provide oversight while advanced practice providers (APPs) and allied specialists deliver day‐to‐day care, could help address the growing demand for dementia care. This model could reduce waiting times for specialized dementia care, allow for a more efficient distribution of resources, and enable PCPs to play a greater role in the diagnostic process. Shifting from a traditional fee‐for‐service reimbursement to value‐based models would better support this integrated approach, encouraging coordination across primary and specialty care. As the demand for dementia care continues to grow, implementing flexible reimbursement models that recognize both the direct and consultative roles of dementia specialists will be essential to ensure comprehensive and timely management of AD patients across the healthcare system.

3. INTEGRATING BIOMARKERS INTO CLINICAL PRACTICE

For much of the 20th century, AD could only be definitively diagnosed post mortem through autopsy, with no clinical criteria available to guide diagnosis during life. This changed in 1984 when the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (now known as the Alzheimer's Association) introduced the first clinical criteria for AD, which enabled diagnosis at the dementia stage but was limited to clinical symptoms without biological confirmation and only a diagnosis of possible or probable AD. ¹⁵ Over the years, however, significant advances in biomarker technology have revolutionized the diagnostic landscape. In 2011, updates to the criteria expanded the diagnostic framework by recognizing the continuum of AD and incorporating biomarkers in symptomatic individuals while also acknowledging the existence of a preclinical phase for the first time. ¹⁵ , ¹⁶ , ¹⁷ By 2018, the diagnostic framework further evolved with the introduction of the AT(N) criteria, which recommended categorizing AD based solely on biological markers. ¹⁸ Most recently, the 2024 updated criteria for diagnosis and staging of AD by a workgroup of the Alzheimer's Association incorporate fluid biomarkers – both plasma and cerebrospinal fluid (CSF) – and imaging biomarkers to expand the criteria beyond AT(N) to include vascular, inflammatory, and copathological markers. ¹⁹ This development allows for more nuanced disease staging and greater accessibility to testing that provides a more comprehensive understanding of AD and comorbid pathologies.

Despite biomarker advancements in research and clinical trials, a substantial gap remains between these developments and the standard of care most patients receive. Bridging this gap requires integrating biomarkers for early diagnosis into clinical care, harmonizing protocols, and expanding access to biomarker testing. Additionally, healthcare provider education and the implementation of quantitative approaches to maximize the utility of biomarkers, such as advanced imaging techniques, are essential for enhancing the quality of care and ensuring more accurate diagnoses and treatment. Furthermore, a paradigm shift in AD care is needed, with an emphasis on prevention through midlife risk assessment and lifestyle modification rather than diagnosis solely at symptomatic stages. This shift would require the development of more scalable and efficient tools, standardized cognitive and functional assessments, and the incorporation of biomarkers into preventive care strategies.

The AARR meeting highlighted the real‐world application of amyloid positron emission tomography (PET) imaging in the Imaging Dementia – Evidence for Amyloid Scanning (IDEAS) study, which assessed the clinical utility of amyloid PET scans in a real‐world setting under a coverage‐with‐evidence‐development framework. The IDEAS study demonstrated excellent agreement between visual reads of amyloid PET scans from community physicians with those from expert panels, supporting the high reliability of visual amyloid PET scans in routine clinical practice. ²⁰ Blood‐based biomarkers (BBMs) are also rapidly advancing, offering the potential for scalable diagnostic tools in clinical care. However, more work is required before these biomarkers can be fully validated for real‐world use. ²¹ Studies have also indicated that combining digital cognitive assessments with BBMs can improve diagnostic accuracy. ²² Additionally, the integration of proteomic panels is expected to further refine disease staging, with panels assessing multiple biomarkers, such as tau epitopes, providing more granular insights into disease progression. ²³ Beyond amyloid and tau, these proteomic approaches allow for the identification of diverse disease mechanisms, such as synaptic dysfunction or immune activation, potentially enabling personalized therapeutic approaches. ²⁴ , ²⁵

Taken together, the future of AD diagnosis and treatment lies in a comprehensive approach that integrates biomarkers into the patient journey, from risk assessment in midlife to treatment response monitoring. This approach would personalize care, respect patient preferences and values, and enable early intervention strategies based on individual risk profiles.

3.1. BBMs and readiness in primary care settings

BBMs offer several advantages over CSF analysis and PET imaging for the diagnosis of AD‐related cognitive impairment, especially at the population level. BBMs are less invasive, easier to obtain, and more accessible in primary care, particularly in rural or underserved areas where advanced imaging facilities are often unavailable. Additionally, BBMs could streamline the diagnostic process, enabling earlier identification of AD patients in primary care settings. However, while some AD BBMs are clinically available, and certain immunoassays can be reimbursed by insurance, most research on BBMs has been conducted in specialized clinical settings, and insurance coverage is not yet widely available. Consequently, many questions remain regarding their implementation and utility in real‐world primary care settings. ²⁶

Although BBMs hold great diagnostic promise, limited data suggest that patients in primary care settings may not yet be accepting of these tests. Preliminary results of a 12‐month study conducted by Indiana University and Atrium Health were presented at the AARR meeting; this study tested the integration of digital cognitive assessments and BBMs in primary care. The findings suggested that among over 200 symptomatic patients identified through digital cognitive assessment, 60% refused a BBM test, while 8% agreed to the test but did not follow up for the disclosure discussion. These findings highlight the importance of qualitative research to better understand why patients may decline BBM testing and to explore whether these reasons vary by race, ethnicity, education, socioeconomic status, or other demographic factors. Additionally, clinical guidelines are urgently needed to guide the use of BBMs in various populations, such as those with multiple chronic conditions known to affect biomarker levels or those with limited life expectancy. Current recommendations suggest that BBMs should be used only in symptomatic individuals, ²⁷ but there is a need for broader guidance on their application in asymptomatic individuals and those at higher risk for AD, especially if disease‐modifying treatments for asymptomatic individuals are approved in the future.

Ethical considerations are also paramount when incorporating BBMs into routine care. The inclusion of BBM results in patients’ medical records could have implications for their ability to obtain long‐term care or life insurance. ²⁸ These potential legal and financial implications must be clearly communicated to patients before testing, which poses an additional challenge for PCPs who often operate under time constraints. This further underscores the need for education and preparation among healthcare providers to manage these discussions effectively and the need for updated reimbursement models.

Given the shortage of AD/dementia specialists, primary care will play a crucial role in AD diagnosis. However, further research is needed to determine how best to implement BBMs in primary care, including determining the appropriate patient populations and timing for their use. Studies assessing the accuracy of BBMs in diverse populations of older adults with multiple chronic conditions and varying degrees of cognitive impairment are also essential. Finally, implementation research is also needed to identify barriers and facilitators for the widespread adoption of AD BBMs in primary care. ²⁹ , ³⁰

3.2. Optimizing the use of amyloid PET quantification in clinical routine settings

The prescribing information for both lecanemab and donanemab mandates confirmation of amyloid pathology before initiating therapy. Additionally, the prescribing information for donanemab recommends discontinuation of therapy once amyloid plaques have been reduced to minimal levels, as verified through amyloid PET imaging. In the United States, amyloid PET scans are routinely interpreted using a binary visual assessment to determine the presence or absence of amyloid plaques. However, the Centiloid (CL) scale – a continuous, tracer‐independent, and unbounded measure anchored between 0 and 100 CL – has gained increasing acceptance for quantifying cortical amyloid load. This scale is now a key outcome measure in pivotal studies of anti‐amyloid therapies.

As part of the AARR forum, 35 global experts were surveyed to identify an appropriate CL threshold for initiating therapy in patients with MCI or mild AD. Seventy percent of the panel recommended a CL range of 24 to 30 for this purpose. It was noted that while there may be some variability (“noise”) in the CL metric, a threshold of 24 CL aligns closely with visual read methodology, which is based upon a multisite pathology verification study, ³¹ while 30 CL was suggested as a more conservative threshold, ensuring the presence of neuritic amyloid with greater certainty. ³²

Experts also advocated for the use of FDA‐cleared software for routine clinical practice, emphasizing that CL quantification should complement, rather than replace, traditional visual inspection. Nuclear medicine specialists on the panel reiterated the importance of conducting image quality checks alongside CL quantification. The CL method will be a valuable adjunct to support visual reads and provide clarity for cases where amyloid levels in scans are near the pathological threshold, aiding in the consistent management of patients receiving anti‐amyloid therapies.

4. INTEGRATING AD TREATMENTS IN CLINICAL PRACTICE

Implementing anti‐amyloid therapies across clinical settings in the U.S. has led to the development of diverse practice models, as showcased by various initiatives at the AARR meeting, including memory clinics, community centers, and academic institutions across the U.S. that illustrate varied models for delivering anti‐amyloid therapies to patients (Supplemental Text 3). Lessons learned from these experiences showed that there is no one‐size‐fits‐all approach; each center has tailored its methods based on institutional structure, available resources, and patient needs. Centers have adopted different strategies, from leveraging nurse practitioners and other advanced practice providers to delegating specific tasks like scheduling or coordinating clinic visits. Some centers have integrated multidisciplinary teams that include behavioral neurologists, geriatric psychiatrists, neuropsychologists, nurses, and support staff. To streamline workflows, some centers have established new protocols specific to infusion and monitoring, including additional staff training for handling these complex treatments. Furthermore, experiences with registries like the Alzheimer's Network for Treatment and Diagnostics (ALZ‐NET) have enabled early patient enrollment, streamlined data collection, and support for insurance authorization.

Effective implementation of anti‐amyloid therapies in clinical practice requires addressing challenges related to monitoring and management of side effects such as ARIA and considerations regarding communication of the benefits and risks of these therapies with patients and caregivers. Models of care that emphasize equitable access and patient‐centered communication, particularly in clinics serving underrepresented populations, are critical to reducing health disparities. In this section, we discuss approaches for patient‐centered communication of the benefits, risks, and expectations of anti‐amyloid therapies, as well as best practices for ARIA management and the value of real‐world data to improve the clinical workflow.

4.1. Patient‐centered communication of the benefits, risks, and expectations of anti‐amyloid therapies for AD

The approval of anti‐amyloid therapies by the FDA has introduced a transformative landscape in the treatment of AD, presenting clinicians and healthcare providers with the challenge of effectively communicating the complexities of these novel therapies. This includes addressing the risks, benefits, burdens, and costs associated with disease‐modifying treatments, as well as providing necessary support to patients, families, and healthcare providers.

To address some of these complexities, the Alzheimer's Association Clinical Meaningfulness Workgroup has provided recent recommendations to guide healthcare professionals in discussing treatment eligibility, benefits, risks, apolipoprotein E (ApoE) genotyping, treatment costs, and expectations of anti‐amyloid therapies with patients and caregivers. ³³ These recommendations emphasize the importance of personalized, patient‐centered communication, offering practical language examples to help healthcare providers navigate these conversations. For example, it was noted that risk and benefit conversations must be individualized and presented transparently to avoid creating false expectations. ARIA‐related risks in particular should be explained in clear, accessible terms so that patients and caregivers fully understand potential complications and the need for ongoing monitoring. Additionally, it is essential to communicate that while these therapies may slow disease progression, they do not provide a cure or improve current symptoms.

Patients should be given adequate time to absorb the information, ask questions, and make informed decisions, with opportunities for follow‐up consultations as needed. The use of tailored, patient‐centered language that addresses individual risk profiles helps empower patients in the decision‐making process. Ultimately, the creation of new care models that accommodate these evolving treatment paradigms is critical. Iterative improvements in care delivery should prioritize patient safety, clear communication, and timely action to ensure optimal outcomes for individuals receiving treatment for AD.

4.2. Managing ARIA: best practices for treating clinicians, radiologists, and emergency teams

ARIA is the most significant adverse event associated with amyloid‐lowering immunotherapy. It involves edema and hemorrhagic complications such as microbleeds and superficial siderosis, which occur as amyloid deposits are cleared, particularly from the walls of small arterioles. ARIA typically presents early in treatment and is usually transient and asymptomatic. ³⁴ , ³⁵ However, in a small percentage of cases, it can become serious and life‐threatening. ³⁶ , ³⁷ , ³⁸ To minimize the risk of severe outcomes, careful patient selection and close monitoring are essential.

The primary risk factors for ARIA include APOE ε4 allele count, underlying cerebral amyloid angiopathy (CAA) and the dose of the immunotherapy. ³⁴ Carriers of the APOE ε4 allele, especially homozygotes, are at a significantly higher risk for ARIA, including more severe and recurrent episodes. Testing for the ApoE genotype is recommended to assess risks and guide safety management. Patients with evidence of significant CAA or other safety concerns on baseline magnetic resonance imaging (MRI) are not ideal candidates for treatment. ³⁴ , ³⁵ Hypertension may also be a factor in developing ARIA, ²⁰ , ³⁹ and cooperation between anti‐amyloid treating physicians and primary care clinicians will be important for managing this risk factor.

The lecanemab Appropriate Use Recommendations ⁴⁰ provide clear guidance for ARIA management, advising suspension of treatment in cases where ARIA is symptomatic or shows moderate to severe radiographic findings. Regular follow‐up MRI is essential to track the resolution of edema and stabilization of hemorrhagic findings. Once these issues have been resolved, a discussion with the patient and family is necessary to determine whether treatment can be safely resumed.

Collaboration between clinicians and radiologists is crucial for the early detection of ARIA, and emerging artificial intelligence (AI)‐based software may assist radiologists in achieving consistently accurate scan interpretation. Coordination between outpatient and emergency care teams is also critical in managing serious ARIA cases. Emergency clinicians must be aware that ARIA can present as a stroke mimic and that the use of thrombolytics could have life‐threatening consequences or even death. ³⁶ Electronic medical record (EMR) alerts and medical alert cards can help facilitate this awareness, as noted earlier in the case examples in Section 4.1. In cases where ARIA is suspected, urgent MRI is necessary to evaluate both ARIA and ischemic stroke, as the radiographic manifestations of ARIA are rarely visible on computed tomography scans. Prompt initiation of supportive treatment, management of seizures, and consideration of high‐dose corticosteroids is essential once ARIA is diagnosed. Although ARIA is generally transient and manageable, careful patient selection, close monitoring, and prompt intervention in more serious cases is key to reducing the risk of severe outcomes.

4.3. Utilizing insights from clinical trials and real‐world evidence

Utilizing insights from clinical trials and real‐world evidence (RWE), including registries like ALZ‐NET, can help accelerate progress in AD treatment development and improve patient outcomes. Although clinical trials provide crucial data on drug efficacy, dosing, side effects, and benefit‐risk ratios, many unanswered questions remain. To address these gaps, RWE is a key element in understanding how new treatments work in everyday practice, particularly in diverse populations over extended periods. Unlike clinical trials, which focus on controlled environments, RWE allows for insights into broader, more varied healthcare settings, providing generalizability that is often missing from traditional trials. This kind of evidence is critical in understanding how treatments perform across different subpopulations, revealing nuances that may not have been captured in clinical trials but are crucial for optimizing patient care. Furthermore, RWE offers insights into how infrastructure challenges affect patient outcomes and helps refine measures of cost‐effectiveness, which are important for securing payer support.

In the context of disease‐modifying therapies for AD, critical questions, such as whether new therapies extend life, when patients should stop treatment, and the timing of and appropriate reasons for treatment discontinuation, can be answered through RWE. Moreover, RWE helps address what matters most to patients, such as how long they can remain independent or manage their daily lives. These insights are essential for personalizing care and ensuring that treatments align with patient priorities. Registries like ALZ‐NET play a pivotal role in collecting and tracking real‐world outcomes of AD treatments, allowing streamlined data collection and integration of RWE directly into the clinical workflow.

Despite the clear benefits, collecting RWE poses challenges. Although having detailed information is important for a sophisticated understanding of treatment effects and patient outcomes, collecting extensive information in the real world presents significant challenges to clinicians and their staff. Claims data and EMRs offer valuable information and can avoid manual data entry, but have additional limitations, including delays and incomplete datasets. Simplifying the clinical information that must be entered and improving the collection and utilization of unstructured data from EMRs are priorities. Another significant barrier to RWE collection is the mentality of stakeholders assuming that data collection is someone else's responsibility. Healthcare professionals are urged to take an active role in gathering high‐quality RWE to advance the field.

In summary, there is an immediate need to collect and analyze RWE in AD. The era of amyloid‐targeting therapies presents a unique opportunity to understand these treatments' real‐world implications. High‐quality evidence is necessary to improve patient outcomes and ensure the safe, effective use of these novel therapies, and broad engagement from all stakeholders is essential to achieving this goal.

5. COST‐EFFECTIVENESS ANALYSIS IN VALUING AD TREATMENTS

The AARR meeting addressed the challenges of valuing AD treatments through cost‐effectiveness analysis (CEA) and the limitations inherent in this approach. Existing doubts and skepticism about the value of AD drugs largely stem from the reliance on CEA as the primary metric for assessing their worth. Although commonly used, this method may not be ideal for evaluating neurodegenerative diseases like AD.

Several challenges and misconceptions regarding CEA were discussed. First, there is the myth that cost effectiveness equates to cost saving. In reality, however, cost effectiveness refers to whether the incremental cost of a treatment is justified by its incremental benefit in terms of value for money. Another challenge is the assumption that quality‐adjusted life years (QALYs), the central metric used in CEA, are universally accepted and consistently applied. In practice, QALYs are difficult to measure and vary significantly across countries. Additionally, the belief that all countries outside the United States rely solely on QALYs for reimbursement decisions is inaccurate. Many high‐income countries use a more comprehensive approach, starting with the clinical benefit of treatment compared to standard care and then considering economic and societal factors. This more flexible method is better suited to addressing the specific characteristics of individual drugs rather than focusing exclusively on QALYs. ⁴¹

AD treatments often receive low valuations in CEA due to factors such as the nature of the disease, the elderly population it affects, and its slow progression. For example, the lifetime gross value of a treatment that slows disease progression by 30% – when initiated at the MCI stage – has been estimated at $134,418 (2021 US$), or around US$20,000 per treatment year. Despite this, the QALY gain remains modest at 0.75, reflecting the natural limitations of a slowly progressing, age‐related condition. These factors make the lifetime benefits of AD treatments appear small in CEA. Moreover, AD is not a costly medical condition in itself; most associated costs come from social care, not medical care. As a result, the traditional CEA framework may not accurately capture the full value of AD treatments. ⁴²

It was also argued that the incremental cost‐effectiveness ratio (ICER) framework inherently undervalues innovation in areas like AD because drug prices in this field start from a relatively low baseline. In contrast, fields like immunology, where baseline drug prices are already high, benefit from incremental cost evaluations. This discrepancy distorts innovation incentives, encouraging pharmaceutical companies to invest in areas with established high prices, leaving fields like AD, which lack historical precedents for expensive treatments, at a disadvantage. ⁴²

Taken together, the CEA approach may undervalue AD treatments due to its limitations in capturing the full scope of innovation and societal impact. A broader evaluation framework that incorporates long‐term innovation potential, societal fairness, and the transformative value of breakthrough treatments is necessary to drive progress in AD therapies.

6. REIMBURSEMENT FOR EMERGING AD THERAPEUTICS

Drug reimbursement and coverage have been critical aspects of medical innovation, particularly when addressing novel therapies for conditions like AD. Currently in the United States, monoclonal antibodies targeting amyloid plaques for AD treatment fall under a CMS national coverage determination (NCD), which includes specific requirements for both providers and patients to qualify for coverage. It is important to note that payers in the United States also closely adhere to CMS NCD guidelines when determining coverage and reimbursement for any condition or disease with a companion NCD, often developed alongside the approval of new therapies or diagnostics by the FDA. Given the complexity of coverage and the high cost associated with these therapies, the AARR meeting provided an overview of the factors that influence these decisions, provided by a seasoned policy and reimbursement professional. The discussion focused on the key stakeholders involved in the coverage process and outlined important considerations for ensuring that patients receive the full benefit of these innovative treatments.

Reimbursement in the United States is determined by the U.S. FDA and CMS, where the FDA must first approve the therapeutic modality, followed by a coverage decision by CMS. This process governs federal coverage of new therapeutics via Medicare, and the commercial space usually follows suit. For example, if CMS issues a NCD with evidence development, then the commercial market follows suit and covers the product based on the NCD requirements. Coverage also takes into account other clinical quality tools, such as guidelines and quality measures. Finally, at the payer and pharmacy benefit manager (PBM) level, CMS guidance and clinical data are further parsed by the Pharmacy and Therapeutics (P&T) Committee for coverage and formulary placement determinations.

Formulary decision processes in general involve three analytic steps, which include therapeutic assessment, P&T Committee assessment, and value assessment. ⁴³ Regardless of process or assessment stage, the following factors greatly impact and determine the type of coverage: clinical trial data, longitudinal registries, RWE, adverse events, and risk profile, along with drug characteristics such as being a first‐in‐class novel product versus a follow‐on product. Once these are addressed and analyzed, the actual approval can be either full approval or accelerated approval. It should be noted that accelerated approvals may not benefit Medicare populations since accelerated trials often do not include Medicare populations or complex comorbid patients.

Given the CMS NCD on monoclonal antibodies directed against amyloid approved by the FDA for the treatment of AD and concerns regarding coverage of these therapies, understanding P&T Committee clinical assessment factors will benefit providers navigating patient care while obtaining reimbursement for infusions. P&T Committees evaluate all the clinical evidence from a risk‐benefit perspective, including adverse event profiles in clinical trials. In addition, they also evaluate clinical guidelines, that is, Grade A evidence, which is based on robust clinical data, and can include longitudinal registries and RWE.

However, access to coverage is best addressed from a patient's perspective. This is where coverage under Medicare Part B for an infused drug versus coverage under Medicare Part D for a small molecule and/or patient‐administered product becomes important. Part B reimburses providers based on the average sales price (ASP) of the drug plus an additional 6% for infusion services, which include provider services, infusion equipment, and medical supplies. However, patients are responsible for 20% coinsurance on all these services, along with additional coinsurance and copays for items related to the procedure and venue, such as charges for the facility, equipment, and supplies. ⁴⁴ According to the NCD, the infusion must be preceded by imaging studies, which adds to the patient's medical bill and owed amounts. Currently, disease‐slowing AD therapies at present are available only by infusion and are financially burdensome. However, potential future therapies that could be self‐administered or do not require infusions will be covered under Part D. These therapies will increase affordability because once the Medicare Part D drug deductible and copays reach a $2000 out‐of‐pocket maximum, the patient will transition to the “catastrophic phase” of coverage and no longer have additional treatment expenses. ⁴⁵

Overall, it is important for providers to be knowledgeable about the current reimbursement conditions and the costs to the patient in order to ensure that patients receive the full benefit of innovative treatments for AD. Furthermore, as stated in prior sections, healthcare professionals should be encouraged and empowered to participate in RWE collection to contribute to the ongoing process of accumulating robust clinical data that will inform payer evaluations and the reimbursement landscape.

7. LEVERAGING LESSONS FROM MULTIPLE SCLEROSIS

Multiple sclerosis (MS) is a common immune‐mediated demyelinating disease of the central nervous system that can affect daily functioning. Timely interventions with advanced and often infused therapies, with the potential for serious side effects, are needed to avoid significant physical and neurological disability. At the AARR Spring 2024 meeting, discussants highlighted parallels with MS and the potential to draw on the past two decades of MS treatment evolution as a framework for addressing emerging opportunities and challenges in the evolving landscape of AD therapy, particularly in the realm of disease‐modifying therapies.

The goal of these discussions was to provide a unique perspective on the MS clinical journey over the past 20 years, illustrating how advancements in MS diagnosis and treatment may offer insights into the trajectory of AD management. Since the FDA approval of Betaseron (interferon beta1b) in 1994, the field of MS has seen an explosion of therapeutic innovations. ⁴⁶ , ⁴⁷ , ⁴⁸ , ⁴⁹ , ⁵⁰ Coupled with recent improvements in imaging and clinical care, these advancements have led to significant reductions in relapse rates and improved long‐term outcomes for MS patients. Many individuals who might have otherwise required mobility aids, such as canes or wheelchairs, have been able to maintain a higher quality of life as a result of these breakthroughs. ⁵¹ , ⁵² , ⁵³ , ⁵⁴

A similar trajectory of advancements in the field of AD is anticipated, where the advent of anti‐amyloid therapies presents a new frontier in disease modification. However, as in MS, the timing of intervention is critical. The importance of timely evaluation and diagnosis of MCI or early AD through a comprehensive diagnostic workup cannot be overstated. Early diagnosis in AD, as in MS, is critical for maximizing the benefits of emerging disease‐modifying therapies, as early intervention may significantly alter the disease trajectory and delay the accumulation of disability. This requires a comprehensive diagnostic workup, including cognitive assessments, APOE genotyping, MRI scans and PET imaging, CSF analysis, and/or use of emerging BBMs.

An essential aspect of optimizing AD care lies in the development of specialized, multidisciplinary care teams analogous to those established for MS management. However, the current shortage of dementia specialists, neurologists, and geriatricians poses a significant barrier. The establishment of specialized AD care centers with an interdisciplinary team of providers who are trained in dementia care is critical to streamlining the care process and maximizing the available resources. Integration of an infusion center as a place not only for patients to receive pharmacological treatment but also to foster socialization and comfort is similarly critical. Furthermore, strong partnerships between local academic centers, hospital systems, non‐profit advocacy organizations like the Alzheimer's Association, industry, and other key members of the healthcare team can significantly improve access, efficiency, and, ultimately, the care of AD patients.

In summary, the MS field provides valuable lessons for advancing AD care, particularly in the context of disease‐modifying therapies. The advancements in MS have highlighted the value of early diagnosis, multidisciplinary care, a patient‐centered approach, and the need for adaptive reimbursement models. By integrating these lessons, the AD field has the opportunity to develop a comprehensive approach to the effective implementation of emerging therapies within healthcare systems.

8. SUMMARY

The availability of disease‐modifying treatment (in the form of amyloid‐targeting therapeutics) is changing the landscape of the AD field, both in terms of future research endeavors and clinical practice. In its current state, the AD care pathway has profound limitations in terms of efficient and effective screening for cognitive changes, formulating timely and accurate diagnoses, and effectively setting up treatment pathways for eligible patients. The Spring 2024 Alzheimer's Association Research Roundtable (AARR) meeting gathered industry representatives and clinicians to discuss insights, challenges, and solutions that will help address these limitations. Participants identified professional audiences among those involved in the AD care delivery framework whose participation will be crucial, including PCPs, general neurologists, memory specialists, general radiologists, and neuroradiologists, as well as healthcare management and reimbursement experts/payors. Several novel or emerging technologies were prioritized as likely to help address current challenges in AD care delivery, including blood‐based AD biomarkers, digital cognitive assessment tools, AI‐assisted interpretation of neuroimaging, and automation solutions to optimize clinical care workflow. Successfully identifying people with mild symptoms in primary care and community settings not only is crucial to bringing new therapies to individuals and their families living with AD but will require the coordinated efforts of health systems (ranging from primary care to tertiary care centers), drug manufacturers, research institutions, medical professional societies, federal regulators, and insurers.

CONFLICT OF INTEREST STATEMENT

B.J.S. has received grants, contracts, or consulting fees from Eisai, Eli Lilly, and Roche. A.B. is a full‐time employee and minor shareholder at Eli Lilly and Company. S.B. is a full‐time employee of Hoffman–LaRoche. C.C. has received funding from the NIA, ANF, and HRSA, and consulting fees from Braincheck, Otsuka, Eli‐Lilly, and NovoNordisk. G.F. is an employee of GE Healthcare who holds the Marketing Authorisation for VizamylTM.DG. D.G. has received grants or consulting fees from Biogen, Bristol Myers Squibb, Cassava, Eli Lilly, Eisai, Abbvie, Davos Alzheimer's Collaborative, NIA, Alzheimer's Association, Genentech/Roche, Nutricia, NovoNordisk, WIRB‐Copernicus. R.K. is a full‐time employee of Johnson & Johnson Innovative Medicine. S.M. has received research contracts/grants to USC from Biogen, C2N, Eisai, and Roche. M.M. has received grants from the NIH, Alzheimer's Association, Davos Alzheimer's Collaborative, and consulting fees from Athira, Biogen, Eisai, Lilly, Merck, Roche, Siemens Healthineers, and Novo Nordisk. D.M. is a full‐time employee of the Pharmaceutical Care Management Association. J.M. is a full‐time employee of Biogen. H.O. has received grants, contracts, or consulting fees from Biogen, Eisai, Optina, American College of Radiology, NIA/NOH, Alzheimer's Association, Eli Lilly, Woolsey, Ecofibre, Commonwealth Health Research Board. G.D.R. has served on scientific advisory boards and/or as a consultant for Eli Lilly, Genenetech/Roche, GE Healthcare, Alector and Merck, payments from Efficient LLC, JAMA Neurology (Associate Editor), Miller Medical Communications, paid for participation on a Data Safety Monitoring Board or Advisory Board for Johnson & Johnson. D.R. has received honoraria for educational events from Northwestern University, AAAS, IMPACT AD. J.S. has received honoraria from Biogen, Eisai, Eli Lilly, Arrowhead Pharmaceuticals, and Global Learning Collaborative on Alzheimer's Disease Topics. H.S., S.M., G.W., C.J.W., and M.C.C. are full‐time employees of the Alzheimer's Association. Author disclosures are available in the supporting information.

CONSENT STATEMENT

Consent (i.e., all human subjects provided informed consent) was not applicable.

Supporting information

Supporting Information

Supporting Information

Snider BJ, Biffi A, Bozeat S, et al. System readiness and the patient care pathway for Alzheimer's disease diagnosis and treatment. Alzheimer's Dement. 2025;11:e70094. 10.1002/trc2.70094