Note: This article was updated 10/18/23 to reflect information on a CMS decision on amyloid PET.
Radiologists should be prepared for an influx of Alzheimer’s disease (AD) and other dementia patients in the coming years. Prevalence of these cases is growing, and new and emerging treatments that offer hope to these patients for extending their quality of life require imaging — specifically MRI and PET — for diagnosis, treatment eligibility and ongoing monitoring of the disease.
The key will be to produce data that is easily shared among physicians, regulators, payers and, of course, patients. With that in mind, a group of organizations from medical specialties and academic bodies collaborated to create the Alzheimer’s Network for Treatment and Diagnostics (ALZ-NET), a national real-world data registry for evidence gathering, information sharing and education across clinical and research communities. The goal is to encourage inclusive research aimed at improving patient care and outcomes in AD.
More than 6 million Americans are living with AD or related dementia, according to the Alzheimer’s Association. Care for this massive cohort could be hindered by a nationwide radiology staff shortage and varying levels of experience in the imaging of AD patients. The field of treatments is growing, with more than 140 AD therapies being tested in clinical trials and some in late phases awaiting regulatory review from the U.S. Food & Drug Administration (FDA).
Imaging serves a vital role in AD diagnosis and routine safety monitoring — one that is increasingly important. “If there are no breakthrough treatments or other interventions that stop or dramatically slow progression of the disease, it is expected that by 2050, we are going to have more than double the current prevalence of the disease,” says John E. Jordan MD, MPP, FACR, a Los Angeles area-based private practice neuroradiologist, chair of the ACR Commission on Neuroradiology, a member of the ALZ-NET Imaging Committee and an ALZ-NET project advisor.
“This is a major issue,” Jordan says. “In addition to the suffering of AD and dementia patients and their families, the cost of care for these patients is extremely high. It is long-term and labor-intensive care. The ACR has been playing a central role in clinical research and information exchange to advance study findings and meet imaging demands in the AD domain.”
The College has shown real leadership in advancing the diagnosis and treatment of these diseases, and has spearheaded advocacy efforts around regulatory policies, Jordan says. These actions are critical to making sure the medical community has the information it needs to provide patients with the best possible care.
“The ACR is responsible for data management, imaging analysis and curation of a growing imaging repository,” Jordan says. “Imaging committee members have been working in concert to provide guidance to radiologists and other clinicians on image interpretation, standardized reporting and acquisition protocols to foster a better understanding of the efficacy and safety of AD therapeutics.”
The Collective Value of ALZ-NET
Recognizing the growing need for collaboration in collecting real-world clinical and imaging data on individuals being evaluated for treatment or those receiving FDA-approved therapies for Alzheimer’s disease, several groups launched ALZ-NET in 2022. They included the Alzheimer’s Association, the ACR, the American Society of Neuroradiology (ASNR), the Department of Biostatistics at Brown University School of Public Health, and the Critical Path Institute, along with other clinical research and imaging experts.
The provider-enrolled network was created to track, monitor and support clinical, safety and long-term outcomes about individuals from a variety of backgrounds and communities — information including cognition, function, adverse events and resource utilization. ALZ-NET investigates the efficacy and safety of AD therapies over an extended period and outside of the context of a randomized controlled trial. Data will be broadly shared with the research community and other stakeholders.
ALZ-NET offers a centralized location of recommended acquisition protocols for PET, MRI and variations of the modalities — providing resources that outline appropriate training, recommended scanner type, required sequences, and reporting guidelines and templates. ALZ-NET also serves as a platform for patients to access the latest news on AD, community engagement, Medicare billing and locating a dementia care expert within the network.
We want to enable sites to be a part of ALZ-NET and continue to grow as we collect the data that is critical to answering future questions around patient care.
The network builds on approaches from successful research networks in other therapeutic areas and from the Imaging Dementia-Evidence for Amyloid Scanning (IDEAS) study and its successor New IDEAS — proving that large-scale real-world data collection in dementia practices is feasible for addressing critical research questions. The studies focused on investigating the clinical utility of brain amyloid PET scans.
FDA-approved brain amyloid PET detects amyloid plaques in the brain, a core neuropathological feature of AD. Amyloid PET is associated with changes in subsequent management of diagnostically challenging patients with cognitive disorders. This modality can detect one of the hallmark brain changes related to Alzheimer’s — amyloid accumulation — in those with mild cognitive impairment or dementia of uncertain cause.
While ALZ-NET will leverage the existing infrastructure of the IDEAS Study Program, more participating sites are needed for their expertise in the diagnosis and extended treatment of AD and other dementias. Interested and participating sites should have an established and appropriate multi-disciplinary dementia care team providing optimal medical management with access to imaging, infusion and emergency services, as well as an understanding of diverse patient populations and strong community relationships.
There is a multi-year agreement in place between the Alzheimer’s Association and the College for ACR’s Center for Research and Innovation™ (CRI) to serve as the operations center for ALZ-NET. The ability to collect and manage multidisciplinary data in the context of a real-world data project starts with meaningful research. CRI supports, designs and manages research studies to translate new evidence into clinical practice. The center is a partner and resource hub for ACR members, academia and industry on clinical trial design and management, precision diagnostics and treatments.
"We are thrilled to serve as the operational center for ALZ-NET and continue our longstanding, successful partnership with the Alzheimer’s Association,” says Andrew March, director of clinical trials administration for CRI. “We are building on our previous collaborations through the IDEAS studies, which established a robust network of more than 1,000 dementia care practices and imaging facilities across the country.”
IDEAS and Imaging Education
The original IDEAS study, with more than 18,000 participants between 2016 and 2018, provided data supporting the value of amyloid PET brain scans. Published in 2019, the study found that amyloid PET scans changed patient management — including medications prescribed and referrals to counseling — in nearly two-thirds of cases. Amyloid PET scans also altered diagnosis of the cause of cognitive impairment for one in three participants.
The New IDEAS study, sponsored by the Alzheimer’s Association and managed by the ACR, builds upon the original IDEAS study but with an added focus on the recruitment of a racial and ethnically diverse population to allow for better understanding of the impact of amyloid PET scans on change management and health outcomes where there is limited information.
New IDEAS participants also have the option to contribute plasma and DNA (via saliva) samples to the New IDEAS biorepository, funded by the Alzheimer’s Association, to allow researchers to test and validate new genetic and blood biomarkers for dementia that are applicable and accurate for a diverse, real-world population. New IDEAS is still active and accepting new applications to become a participating PET imaging facility or dementia practice.
The need for more research and better tools to provide earlier and more accurate diagnosis of AD and other dementia is critical. The urgency is even higher with new treatments having recently received FDA approval, and more on the horizon, which require clinicians to recognize the presence or absence of brain amyloid to make treatment decisions. Per appropriate use recommendations (AURs), patients require confirmation of amyloid in the brain (most commonly via PET scan) and an MRI prior to treatment, then regular safety monitoring through MRIs over the course of treatment. Detection of amyloid-related imaging abnormalities (ARIA) events in routine safety imaging is relatively new to radiologists, and these abnormalities could be easily misdiagnosed, resulting in compromised patient safety.
“For brain MRI, ARIA is a new entity. Many different pathologies can look similar, and you need the correct clinical context,” says Ana M. Franceschi, MD, PhD, a neuroradiologist with Northwell Health in New York City who specializes in the advancement of brain PET/MRI and hybrid imaging techniques in dementia and neurodegenerative disease. Franceschi is chair of the ACR Commission on Neuroradiology’s Dementia Workgroup and a member of the commission’s research committee and the ALZ-NET imaging committee.
There are concerns around the difficulty of picking up on these relatively subtle findings, Franceschi says. “As a result, there is a lot of interest in exploring potential AI-assisted detection of ARIA in the clinical setting. You can use AI for quantification, be it for MRI or PET modalities. For MRI, we’re not just interested in volumetrics (measures of key brain structure volumes), but with recent regulatory approval of monoclonal antibodies, we also want to see how AI might detect micro hemorrhages, for example, that can be a side effect of these therapies,” she says. “This type of side effect is fairly common among patients who are on monoclonal antibodies — so physicians need to be educated on recognizing and grading it and reporting it appropriately so that a neurologist can take appropriate next steps in patient management.”
Robust data sets, as with ALZ-NET, provide not only a plethora of cases for educational purposes, but also open up more research possibilities — figuring out necessary sequences for optimal detection and understanding what is needed or redundant, what is absolutely necessary and what is the minimum you can accept, Franceschi says.
Her group has been focusing on imaging protocols for several modalities, including brain MRI and the different types of PET scans. “We placed a lot of emphasis on the need for education. It was not just the protocols in terms of the sequences that we would prefer to have, but also what information we might want or need from the reports that are generated for these scans,” Franceschi says. “Because of the large potential influx of patients and cases, there is some concern that there may not be enough trained radiologists and/or scanners to serve everyone. As a result, there is great interest in terms of what sequences are necessary and whether you can perform ‘fast’ ARIA protocols to get more volume into the same number of times slots.
“One of the things our committee finds very exciting is the sheer volume of cases that we will have access to through ALZ-NET,” Franceschi says. “I think the possibilities to do translational research that is clinically meaningful, impacting patients’ daily care and improving patient outcomes, is what is most exciting. We have a chance to improve patient care and ensure that medications and therapies are introduced in a safe and effective manner. Combining both structural imaging (MRI) with molecular imaging (amyloid/tau brain PET) makes the possibilities endless in terms of what we can achieve.”
Partners in Research and New Therapies
The IDEAS study is a great example of how diagnostic certainty can impact patient management and lead to improved outcomes for individuals and their families, says Heather M. Snyder, PhD, vice president of medical and scientific relations for the Alzheimer’s Association. There are many benefits of an accurate diagnosis at the earliest point in time, she adds. “This means we need a trained workforce that can meet the needs of patients in terms of access to imaging technologies and with the skills to read and understand what the images are or are not telling us.”
One of the challenges to imagers and patients is access. “If you look at a map of where PET is done, it isn’t available everywhere,” Snyder says. “You may be practicing somewhere that does not have a PET scanner, so you don’t have significant exposure to that modality. That is something we and the ACR and ASNR are looking at — to build out educational tools and opportunities for those segments of the workforce until the technology becomes more available in clinical practice across the country.”
The ALZ-NET partnership creates resources for the radiology community and links all of the multidisciplinary needs that people with AD and other dementia will require. Through the collaboration, the partners are poised to handle the future.
“The Alzheimer's Association and ACR have a longstanding relationship built on mutual synergy, working on IDEAS and New IDEAS together, and now moving that relationship forward through ALZ-NET,” Snyder says. “We want to enable sites to be a part of ALZ-NET and continue to grow as we collect the data that is critical to answering future questions around patient care. What will that care look like as we expand the number of therapies out there? How do we start thinking about combination therapies and who is or is not responding to them?
“We anticipate that as the number of ALZ-NET sites and participants grow, we will have an opportunity to support an even larger network,” Snyder says. “It’s about building evidence to inform future care and to ensure that discussions with healthcare providers are happening based on real-world data.”
The collaborative nature of ALZ-NET will ultimately lead to better healthcare. “We are proud of the support to date from all our partners around the public sharing of data, and we intend to share information more broadly within the research community,” Snyder says. “We know from other spaces — oncology is a great example — that this will accelerate work in the field that will help everyone better understand the tenets of the disease.”
Driving Regulatory Determinations with the Best Data
The road to beating AD and other dementias is paved with real-world data that influences the approval or denial of new technologies and treatments. CMS policy decisions are driven by data and the best evidence, Jordan says. CMS decides to provide Medicare coverage for items and services on the condition that they are furnished in the context of approved clinical studies or with the collection of additional clinical data. Coverage with evidence development (CED) is a coverage policy innovation intended to get certain approved treatments to beneficiaries more quickly while collecting information about health outcomes.
In other words, the best evidence must be put forward to make a coverage determination for expensive technologies. “ALZ-NET is designed to provide regulatory-grade data that is robust enough to inform policy decisions — and the network has the attention of CMS and the FDA,” Jordan says.
CMS recently published a decision memo stating that it would allow Medicare coverage determinations for amyloid PET to be made by Medicare Administrative Contractors (MACs). “This would reverse its decade-old national coverage determination that allowed conditional coverage of amyloid PET,” Franceschi says. Medicare coverage has been limited by CMS to one PET scan for the entire life of a Medicare patient under the terms of CED — thereby markedly limiting patient access to this modality.
The ACR, the Alzheimer’s Association and other groups have advocated removing that restriction and providing broader access to beta-amyloid PET imaging for AD diagnosis, management and evaluation of newly approved therapies. The College strongly urged CMS to reconsider leaving coverage determinations to the discretion of local MACs and instead implement a national coverage ruling. If left to local determination, a final ruling for coverage of amyloid PET could be significantly delayed and highly variable across geographic regions, further exacerbating existing inequities to access. Swift and broad coverage of amyloid PET is imperative at this time when anti-amyloid therapies are being approved by the FDA and highly sought after by patients and their families.
As a result, in large part because of these efforts, CMS announced Oct. 13 that it will no longer require CED for beta-amyloid PET and will allow MACs to determine coverage for these exams. This final decision means Medicare beneficiaries can potentially benefit from multiple scans over a Medicare patient’s life to monitor the extent of amyloid plaque deposits and to track the side effects of newly approved Alzheimer’s treatments. This is a significant success based on the foundational research by the ACR CRI.
Another positive development around the treatment of AD may unfold by year’s end or in early 2024, when the FDA is expected to approve donanemab, according to Jordan. The monoclonal antibody therapy has been shown in a phase 3 clinical trial to slow the rates of cognitive and functional decline in participants who have mild cognitive impairment or early Alzheimer’s — and is at least as effective, and possibly more so, than lecanemab, which was approved by the FDA in July, Jordan says.
Yet another win in the Alzheimer’s arena came this summer when the AMA issued Current Procedural Terminology (CPT®) codes for AI-related brain MRI quantification, Franceschi says. “That was big news because the CPT codes allow for the potential use of these AI tools in the setting of AI-assisted ARIA detection. So overall, this is a very exciting time.”
The Future of AD Resources and Management
The positive steps and good news are painting a bright picture for the future of AD management and the role radiology will play in it, says Charlie Apgar, executive vice president for clinical research and innovation for ACR.
“I am absolutely amazed by our physician leadership and our exceptional staff who have dedicated so much time and effort to IDEAS, New IDEAS and now ALZ-NET as our collaborative effort with the Alzheimer’s Association continues to evolve and expand,” Apgar says. “The progress that has been made over the past few years is astounding, and there is now tremendous hope that more than 6 million patients and families who are dealing with Alzheimer’s or other dementias may benefit from tests that detect the disease and therapies that slow progression of the disease in its early stages. Radiology has been and remains an essential partner in this process, and we have much to be proud of.”
Data sharing is key, along with the exchange of best practices, says March from the CRI. “We plan to develop a national imaging facility network early next year and to begin direct data collection and templated reports for routine Alzheimer’s imaging,” March says. “There will be greater access to training and resources, and we hope to incorporate some AI-based applications to assist in the assessment of the safety of AD therapeutics. A longer-term goal is to create opportunities for imaging facilities to be recognized and distinguish themselves as providing excellent AD imaging care.”
A collaborative approach is helping ensure ideas for improvement are shared along with data and best practices. “ALZ-NET will continue to grow its network and is creating a data access committee to explore the very important concept of sharing the data that we are gathering,” Jordan says. “It is so important to share with other researchers and clinicians, and collaboration for downstream projects is a high priority of the ACR. We need to educate our providers and our imagers to foster the best practices and ideally improve patient outcomes.”
Promoting health equity is another key component of the work by the ACR’s neuroradiology commission’s dementia workgroup and ALZ-NET. “We know that that many of the patients living with AD are from underserved communities with few resources, and we’re very keen on reaching them,” Jordan says. That is the crux of the New IDEAS study, he says, to make sure that there is appropriate representation in diverse patient populations where it is difficult to make generalizations if they are excluded from clinical studies. “In terms of advancing health equity through the imaging of these patients, we’re primarily referring to the PET scans and MRIs that many of them don’t have access to.”
The radiology community will need to be innovative when it comes to handling the influx of AD patients and the scans they will require. “We need additional tools and technology to help with workforce issues, and things like AI might help ease the burden of the daunting amount of work that’s forthcoming,” Jordan says. “Radiologists are absolutely expected to play a critical role in the imaging and management of a growing number of AD patients. The ACR and its partners are committed to meeting the demand by preparing neuroradiologists and general radiologists for new therapeutics and advances in brain imaging. We hope to contribute to improved outcomes for AD patients in a significant way.”
Alzheimer’s Association – Read about the latest trends and statistics on Alzheimer’s Disease.
Alzheimer’s Network – Learn more about ALZ-NET, the collaborative effort to improve brain outcomes.
ALZ-NET Imaging Education and Resources – Explore guidance, recommendations and resources.
ALZ-NET Patient and Caregiver site – Refer to patients and caregivers for treatment and diagnosis through ALZ-NET.
ACR recorded webinar – “Alzheimer’s Disease and Amyloid-Related Imaging Abnormalities,” available on the ACR website, is about learning to recognize the amyloid-related imaging abnormalities (ARIA) associated with Alzheimer’s disease, including risk factors, clinical presentation and management. The webinar is sponsored by the ACR® Commission on Neuroradiology.
Alzheimer’s Association recorded webinar – “An Introduction to Amyloid-Related Imaging Abnormalities (ARIA) and Its Management” is intended to help medical professionals understand ARIA, along with its risk factors and clinical management.
ALZ-NET recorded webinar – “Engaging Health Systems in ALZ-NET: Transforming Clinical Practice, Research, Treatment and Care,” presented by the Alzheimer’s Association, introduces ALZ-NET and the urgent need for a cohesive approach to evidence-based diagnosis, treatment and quality care for individuals and their families affected by Alzheimer’s disease and all other dementia.
Understanding ARIA recorded webinar – “Understanding Amyloid-Related Imaging Abnormalities: A Case-Based Conversation” is presented by the medical resource portal Understanding ARIA.