At first glance, it might appear that better access to so-called amyloid-PET scans could compensate for some of the racial inequities in Alzheimer’s disease, as Linda Goler Blount called for in a recent First Opinion essay. In theory, such scans should lead to more Black people — who are at higher risk of developing Alzheimer’s — being screened and having greater access to favorable treatment for their disease.
As researchers whose work focuses on PET scanning, including its application to Alzheimer’s disease, we fear that increased access to these scans will result in more misdiagnoses and more people being subjected to a new form of Alzheimer’s treatment that we believe is more harmful than beneficial.
PET stands for positron emission tomography. It’s a type of imaging that can illuminate the metabolic or biochemical functions of tissues and organs and detect disease in its early beginning. Amyloid-PET scanning was designed to detect deposits of a protein known as amyloid in the brain. According to believers of the amyloid hypothesis, this protein causes Alzheimer’s disease and its removal will help people with Alzheimer’s.
But neither the amyloid hypothesis nor the reliability of amyloid-PET scans have been convincingly validated. Multiple publications suggest that the amyloid hypothesis is wrong and that amyloid-PET scanning is a misleading technique that has little diagnostic value and gives but a feeble impression of Alzheimer’s disease. Misinterpreted amyloid PET scans led the FDA to give a hasty approval to the drug aducanumab (marketed by Biogen as Aduhelm), a decision now recognized as being one of the most controversial ones made by the FDA.
Without critical analysis by those reviewing articles and by FDA staffers who don’t have sufficient experience in PET imaging, amyloid-PET scans have been claimed to demonstrate an Aduhelm-induced, dose-dependent reduction in amyloid deposits in the brain. This view was taken for granted by the FDA when it approved Aduhelm solely upon that belief — and with an expectation that this would later cause a delay in cognitive decline — an expectation that, more than a year after the approval, remains to be proven.
We believe there is reason to be vigilant because the damage will be greater with easier access to amyloid-PET scans, a circumstance that may have a substantial impact on the Black community.
The amyloid-PET images used as documentation for Aduhelm’s ability to reduce cerebral amyloid deposits don’t demonstrate any changes in the brain’s narrow outer layer of gray matter, where amyloid deposits are located. Instead, they clearly show changes in the brain’s underlying white matter, where amyloid is not deposited. What this means is that these scans cannot be taken as evidence of amyloid removal, but of a different but unknown process. In our opinion, the white matter changes are most likely an expression of Aduhelm-induced brain damage, or what have been termed amyloid-related imaging abnormalities (ARIAs).
We view the FDA’s approval of Aduhelm, which was granted in defiance of its own expert panel and based solely on questionable amyloid-PET imaging results, to be deeply worrisome and contrary to the agency’s mission to “protect and promote the public health.”
The FDA should not ignore the prevalent, devastating adverse effects of amyloid-related imaging abnormalities, which were a consideration in the decision of the Centers for Medicare and Medicaid Services to cover the cost of Aduhelm only for small subsets of people with early-stage Alzheimer’s who choose to enroll in CMS-approved trials of the drug. Increased access to amyloid-PET scans will bring even more patients into treatment with Aduhelm, which in our view is ineffective at best and may inflict further brain damage on patients at worst.
The economic consequences of using amyloid-PET scans have been examined in the Imaging Dementia — Evidence for Amyloid Scanning (IDEAS) study analyzing data from about 12,000 Medicare beneficiaries with mild cognitive impairment or dementia to show if amyloid-PET scanning curbs health care costs by reducing hospitalizations and emergency room visits. Funded by the Alzheimer’s Association, the American College of Radiology, Avid Radiopharmaceuticals Inc. (a wholly owned subsidiary of Eli Lilly and Company), GE HealthCare, and Life Molecular Imaging (CMS paid for the scans), the study did not achieve its goal: The rates of referral to hospital/emergency departments were 24% among scanned patients versus 25% in comparable patients without a scan.
We recommend that the FDA follow CMS’s restrictive position by pausing the approval of Aduhelm and refraining from processing new applications for similar amyloid-reducing therapies until their beneficial effects, like slowing or stopping cognitive decline, have been fully demonstrated and their adverse effects minimized. Similarly, it needs to be clearly demonstrated that the use of amyloid-PET imaging has any place at all in patients with known or suspected dementia.
The brain damage caused by anti-amyloid treatments may be significant and extensive. That’s why the FDA and/or CMS must demand that sponsors of Aduhelm and other anti-amyloid therapies assess brain function in individuals participating in clinical trials. For this purpose, PET imaging with the well-known and highly reliable PET tracer known as fluorodeoxyglucose (FDG), which has already been approved by both agencies for evaluating brain function, including diagnosing Alzheimer’s disease, should be implemented in anti-amyloid clinical trials to monitor brain function in treated and placebo patients. Any significant decrease in brain function in the Aduhelm-treated group compared to the placebo group should prompt the FDA to revoke approval of Aduhelm.
By potentially increasing access to Aduhelm, greater access to amyloid-PET scanning will be more likely to harm people, including Black people, rather than help them. If amyloid-detecting scans are needed, we recommend FDG-PET scanning, which is more useful for detecting signs of Alzheimer’s disease as well signs of other major diseases, like cancer, atherosclerosis, muscle-joint, and inflammatory disorders.
Poul F. Høilund-Carlsen is a professor of clinical physiology at the University of Southern Denmark in Odense, Denmark. Abass Alavi is a professor of radiology at the University of Pennsylvania’s Perelman School of Medicine in Philadelphia. Jorge R. Barrio is a distinguished emeritus professor at the Davis Geffen UCLA School of Medicine in Los Angeles. The authors declare no conflict of interest related to this essay, which has not received any support from funding agencies or commercial sources.
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