After a Decade, Amyloid PET Scans Receive Broad Insurance Coverage

Clinical care for Alzheimer’s disease is undergoing a sea change. The latest wave? Eleven years after the first amyloid PET tracer was approved by the U.S. Food and Drug Administration, the scans will be broadly covered for Medicare beneficiaries. Previously, the Centers for Medicare and Medicaid Services had offered only “coverage with evidence development,” a program that restricted reimbursement to people participating in an approved clinical study. In addition, beneficiaries were limited to one scan per lifetime.

In an October 13 memo, CMS lifted the CED requirement and one-scan limit. This change allows regional Medicare administrators to make coverage decisions for amyloid PET as they do for other diagnostic tools. The agency noted that its decision was motivated by the approval of plaque-busting immunotherapies, since monitoring progress with these drugs may require multiple scans.

Alzheimer’s researchers hailed the news. “I welcome the CMS decision,” Steven Salloway at Butler Hospital in Providence, Rhode Island, wrote to Alzforum (comment below). “This should provide wider access for amyloid PET in clinical practice, opening the door for treatment with amyloid-lowering antibodies.” Gil Rabinovici at the University of California, San Francisco, led the largest amyloid PET CED study, IDEAS. He called the ruling a win. “This is an important milestone for the field,” he told Alzforum.

Ten years ago, when CMS established the CED requirement, insurers doubted whether the nascent technology was clinically useful (Jan 2013 news; Jul 2013 conference news). Rabinovici and others initiated IDEAS, in partnership with CMS and the Alzheimer’s Association, to try to prove the scans’ worth (Oct 2013 news; Apr 2015 news).

Over five years and more than 11,000 scans, IDEAS researchers found that amyloid PET dramatically affects diagnosis, changing two-thirds of treatment plans (Aug 2017 conference news; Nov 2018 conference news; Apr 2019 news). Nonetheless, the technology had but a tiny effect on health outcomes, dropping hospitalizations by 5 percent and missing the prespecified goal for coverage (Aug 2020 conference news; Rabinovici et al., 2023). 

What, then, changed the equation for CMS? FDA approval of Aduhelm and especially Leqembi (Jun 2021 news; Jan 2023 news; Jul 2023 news). In its decision, CMS noted that during the immunotherapy approval process, many stakeholders requested the agency reconsider its stance.

Rather than issue a National Coverage Determination that would mandate amyloid PET coverage, however, CMS left the issue up to the 12 Medicare Administrative Contractors to decide for their respective regions. Rabinovici noted that this could result in inconsistent coverage across the country. In addition, Medicare Advantage plans, which cover a third of seniors, may choose to reimburse differently than does traditional Medicare. This could worsen health disparities in dementia care.

To help even the playing field, Rabinovici leads a follow-up IDEAS study with a focus on recruiting underrepresented groups. New IDEAS will include at least 2,000 African American and 2,000 Latino or Hispanic participants, and will gather more data on how amyloid PET scans differ in these populations. The original IDEAS study reported lower rates of PET positivity in underrepresented groups than in non-Hispanic whites, but only 12 percent of participants came from these groups (Wilkins et al., 2022). “We think it is so important to gather more real-world data about disparities in dementia care across different minoritized groups,” Rabinovici told Alzforum.

New IDEAS also collects blood samples so scans can be compared with blood-based biomarkers. Many researchers expect blood tests will become the first-line diagnostic in primary care, with follow-up PET scans as necessary.

CMS expressed support for New IDEAS in its decision memo, and Rabinovici said the study will continue. With the lifting of the CED stipulation, scans will be covered as part of routine clinical care, and the study will pick up co-pays, as it did before. New IDEAS is scheduled to complete in 2024.—Madolyn Bowman Rogers

Comments

  1. I welcome the CMS decision to end the CED for PET amyloid imaging and the removal of the limit on amyloid PET to a single lifetime scan. Assuming that local MACs follow suit, this should provide wider access for amyloid PET in clinical practice, opening the door for treatment with amyloid-lowering antibodies that require amyloid confirmation.

    We also welcome the advent of plasma tests that correlate with amyloid PET. The blood tests can be used to prescreen individuals to identify those needing confirmation with PET.

    Follow-up amyloid PET may also be used to monitor response to treatment and to guide clinical practice. Hopefully, these follow-up scans will also be covered by local MACs. Tau PET may also be used in molecular staging of AD and clinical decision making. Though not specifically addressed in this decision, hopefully tau PET will be covered in the future as well.

    View all comments by Stephen Salloway

  2. Amyloid PET imaging offers advantages over CSF analysis for establishing the presence of elevated brain amyloid, and this has implications for routine diagnosis but especially for therapeutics. As we enter the new therapeutic era with lecanemab, the CMS decision to make amyloid PET imaging more accessible is highly welcomed.

    For persons being considered for lecanemab therapy, an amyloid PET scan is superior as part of decision-making for treatment compared to a CSF analysis of Aβ/tau ratio for several reasons. First, an amyloid PET result is generally unambiguous whereas the CSF (or plasma) analysis can sometimes be equivocal. Second, the ability to quantitate amyloid burden by PET scan can allow a clinician to:

    a) recognize persons with marginal amyloid elevations (and perhaps question the diagnosis of Alzheimer disease);

    b) appreciate, based on the degree of amyloid elevation, how advanced the process is (as opposed to CSF, where only a binary yes/no answer is available); and

    c) use a baseline amyloid PET scan as the basis for evaluating therapeutic benefits at 12-18 months post therapy with a follow-up scan.

    The latter capability is particularly important for managing lecanemab therapy. In persons in whom lecanemab treatment drove brain amyloid levels to background levels, the possibility of reducing or suspending dosing after 18 months could be a very useful capability. On the other hand, if a follow-up amyloid PET scan failed to show any decline in amyloid burden after 12-18 months, one could deem the therapy for that particular individual as unsuccessful and question the continued value of biweekly infusions. Thus, the Medicare decision will provide genuine value to patients who are being considered for or treated with lecanemab.

    View all comments by David Knopman

  3. It is strange to read this article and the two positive comments from Drs. Salloway and Knopman.

    These highly esteemed scientists and opinion leaders seem to disregard serious shortcomings of the method they recommend, i.e., amyloid PET imaging. These shortcomings, described more than 10 years ago (Feb 2012 community news) anticipated at least two of the unfortunate consequences we face today.

    First, they invalidate the Alzheimer’s diagnostic ATN diagnostic classification, which as of now disregards the outcome of clinical assessment and, according to a proposed revision (Aug 2023 conference news) would also neglect image-based assessment of brain abnormalities. If the revision is implemented, it means the diagnosis of AD will from now on be based solely on "amyloid and tau positivity" (only A and T), where "positivity" may be demonstrated by PET imaging.

    Second, amyloid PET imaging is unsuitable for assessing the efficacy of anti-Alzheimer's therapy. Amyloid PET tracers are non-specific (Moghbel et al., 2012; Kepe et al., 2013) as, in addition to amyloid deposits, they mark inflammation and myelin and myelin damage in the white matter, where there is no amyloid in patients with early Alzheimer's, the target group of recent Alzheimer's RCTs (Høilund-Carlsen et al., 2022; Høilund-Carlsen et al., 2023). 

    Hopefully, these esteemed researchers and the FDA/CMS will become aware of these shortcomings and sound the alarm so that fewer patients are misdiagnosed and subjected to passive anti-AD immunotherapy, as this type of treatment is not only associated with a greatly increased tendency for amyloid-related imaging abnormalities and loss of brain volume (Alves et al., 2023), but probably also increased loss of cerebral function (Høilund-Carlsen et al., 2023). 

    Increased access to amyloid PET will exacerbate the problem, as many amyloid PET positive patients do not have amyloid deposits, and many "amyloid-positive" individuals do not have AD.

    References:

    Alves F, Kalinowski P, Ayton S. Accelerated Brain Volume Loss Caused by Anti-β-Amyloid Drugs: A Systematic Review and Meta-analysis. Neurology. 2023 May 16;100(20):e2114-e2124. Epub 2023 Mar 27 PubMed.

    Høilund-Carlsen PF, Revheim ME, Alavi A, Satyamurthy N, Barrio JR. Amyloid PET: A Questionable Single Primary Surrogate Efficacy Measure on Alzheimer Immunotherapy Trials. J Alzheimers Dis. 2022;90(4):1395-1399. PubMed.

    Høilund-Carlsen PF, Revheim ME, Costa T, Kepp KP, Castellani RJ, Perry G, Alavi A, Barrio JR. FDG-PET versus Amyloid-PET Imaging for Diagnosis and Response Evaluation in Alzheimer's Disease: Benefits and Pitfalls. Diagnostics (Basel). 2023 Jul 3;13(13) PubMed.

    Høilund-Carlsen PF, Revheim ME, Costa T, Alavi A, Kepp KP, Sensi SL, Perry G, Robakis NK, Barrio JR, Vissel B. Passive Alzheimer's immunotherapy: A promising or uncertain option?. Ageing Res Rev. 2023 Sep;90:101996. Epub 2023 Jul 5 PubMed.

    Kepe V, Moghbel MC, Långström B, Zaidi H, Vinters HV, Huang SC, Satyamurthy N, Doudet D, Mishani E, Cohen RM, Høilund-Carlsen PF, Alavi A, Barrio JR. Amyloid-β Positron Emission Tomography Imaging Probes: A Critical Review. J Alzheimers Dis. 2013 May 6; PubMed.

    Moghbel MC, Saboury B, Basu S, Metzler SD, Torigian DA, Långström B, Alavi A. Amyloid-β imaging with PET in Alzheimer's disease: is it feasible with current radiotracers and technologies?. Eur J Nucl Med Mol Imaging. 2012 Feb;39(2):202-8. PubMed.

    View all comments by Poul Flemming Hoilund-Carlsen
    • User Profile Image Kasper Kepp
      Technical University of Denmark
    • Posted:

    The concept of using biomarkers to monitor disease is so appealing that it sometimes leads us to forget essential scientific critical thinking.

    This move follows a long process that increasingly equates dementia of the Alzheimer's type to the presence of amyloid, most notably seen in the accelerated approval of drugs by FDA using reduced amyloid PET tracer uptake as a surrogate of clinical efficacy.

    Many people have dementia without amyloid and many are healthy and do not convert to AD from MCI with amyloid. A subset of those with amyloid later convert to AD clinically; these, together with dementia patients without amyloid, are those we need to worry about in order to help at high specificity, avoid misuse of resources, and preserve scientific understanding in the field.

    I am surprised so many scientists accept a costly initiative without pointing out the primary limitations, for example, not considering the actual specificity of the method and the problem of false positives, which is probably the first thing anyone would think about when applying a test of this type broadly.

    To some researchers all this suggests that amyloid is not the main *pathogenesis* even though it obviously plays a large role in the *pathology.* In science, many false positives, and studies showing that amyloid is increased by everything from oxidative stress to sleep variations, should at least give us pause to think more about this.

    Regarding the problem of false positives, see e.g.:

    "The pooled sensitivity and specificity were 0.84 and 0.62, respectively, for predicting the conversion of MCI to AD," in Ruan and Sun, 2022; "for every 100 PIB scans one person with a negative scan would progress and 28 with a positive scan would not actually progress to Alzheimer’s dementia" in Zhang et al., 2014. 

    For a review covering these and other issues, see Kepp et al., 2023. 

    References:

    Ruan D, Sun L. Amyloid-β PET in Alzheimer's disease: A systematic review and Bayesian meta-analysis. Brain Behav. 2023 Jan;13(1):e2850. Epub 2022 Dec 27 PubMed.

    Kepp KP, Robakis NK, Høilund-Carlsen PF, Sensi SL, Vissel B. The amyloid cascade hypothesis: an updated critical review. Brain. 2023 Oct 3;146(10):3969-3990. PubMed.

    View all comments by Kasper Kepp

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References

News Citations

  1. Not So Fast: Amyloid PET Needs More Data Before Insurance Pays
  2. Coverage Denial For Amyloid Scans Riles Alzheimer’s Community
  3. Alzheimer’s Community Mobilizes to Show Benefits of Amyloid Scans
  4. $100M IDEAS: CMS Blesses Study to Evaluate Amyloid Scans in Clinical Practice
  5. In Clinical Use, Amyloid Scans Change Two-Thirds of Treatment Plans
  6. Amyloid PET Aids Diagnosis. But Could CSF Do Just as Well?
  7. Results from IDEAS Study Published
  8. IDEAS Finds Small Drop in Hospitalizations, Missing Goal
  9. Aducanumab Approved to Treat Alzheimer’s Disease
  10. U.S. FDA Gives Green Light to Leqembi, aka Lecanemab
  11. FDA Grants Traditional Approval to Leqembi

Therapeutics Citations

  1. Aduhelm
  2. Leqembi

Paper Citations

  1. Rabinovici GD, Carrillo MC, Apgar C, Gareen IF, Gutman R, Hanna L, Hillner BE, March A, Romanoff J, Siegel BA, Smith K, Song Y, Weber C, Whitmer RA, Gatsonis C. Amyloid Positron Emission Tomography and Subsequent Health Care Use Among Medicare Beneficiaries With Mild Cognitive Impairment or Dementia. JAMA Neurol. 2023 Nov 1;80(11):1166-1173. PubMed.
  2. Wilkins CH, Windon CC, Dilworth-Anderson P, Romanoff J, Gatsonis C, Hanna L, Apgar C, Gareen IF, Hill CV, Hillner BE, March A, Siegel BA, Whitmer RA, Carrillo MC, Rabinovici GD. Racial and Ethnic Differences in Amyloid PET Positivity in Individuals With Mild Cognitive Impairment or Dementia: A Secondary Analysis of the Imaging Dementia-Evidence for Amyloid Scanning (IDEAS) Cohort Study. JAMA Neurol. 2022 Oct 3;79(11):1139-47. PubMed.

External Citations

  1. memo
  2. New IDEAS

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