At the 2023 CTAD conference in Boston, scientists discussed updates to the definition of Alzheimer’s disease in light of new technology and treatments, and in turn the way the disease is diagnosed. These updates might make it easier for people to get the right diagnosis and treatment sooner.
Driven by advances in new biomarker detection technologies and the approval of Leqembi — a disease-modifying therapy — scientists are updating the definition of Alzheimer’s disease, which was last published in 2018. At the 16th Annual Clinical Trials in Alzheimer’s Disease (CTAD), the working group led by Dr. Clifford R. Jack Jr., a professor at the Mayo Clinic, discussed updates to a first draft presented early this year. It invites a future of expanded access to earlier diagnosis, some say. Among others, it has stirred up controversy and allegations of conflicts of interest.
Jack told Being Patient that the main changes include updating the diagnosis criteria and biomarkers classification. This is especially important as some companies have made unproven direct-to-consumer blood tests for Alzheimer’s biomarkers widely available to the public.
“In the general population of cognitively normal people, there is no reason to do biomarker testing,” Jack said. “The results from the biomarker test would not provide any medically actionable information. There is no approved disease-modifying treatment for people at this point who are asymptomatic.”
In the text of the updated guidelines, Jack and other scientists advise against these tests — and are having additional meetings to figure out “how hard to come down” on these tests and that any biomarker testing should be done under the direct supervision of a doctor.
Not all biomarkers and diagnostics are equal
Various diagnostic tests for Alzheimer’s are designed to pick up on a specific biomarker or set of biomarkers — like the presence of a certain protein in the brain.
If one of these biomarkers catches Alzheimer’s disease cases 99 percent of the time, but still catches a lot of false positives, is it still useful?
And — how many false positives are too many?
Currently, there’s no guidance or recommendations for researchers, clinicians, and diagnostic companies. Benchmark criteria provided by these guidelines can help scientists guide the development and search for new, useful biomarkers for Alzheimer’s disease.
“Just because a test is being offered or marketed by a company does not mean that it necessarily has good diagnostic performance or that it’s any good,” Jack said. “In our document, we have outlined minimum performance criteria that we believe any biomarker [from cerebrospinal fluid, plasma, or blood] needs to meet in order to be considered suitable for diagnostic purposes.”
One definition for research, one definition for the clinic
According to the new guidelines, an individual who is otherwise cognitively healthy but has high levels of Alzheimer’s biomarkers may be considered to have presymptomatic Alzheimer’s disease — but only in a research setting so scientists can learn precisely what these biomarkers mean for healthy individuals.
Jack emphasized several times in his interview that healthy individuals should not be getting biomarker testing done outside of this setting.
“We make a clear distinction in the document between what is scientifically possible for research purposes, versus what is recommended or what is appropriate for clinical care,” he said.
During the live panel, some neurologists in the audience emphasized the importance of making these definitions and recommendations usable by healthcare staff like nurses and physician’s assistants, who might interact with patients more often than neurologists.
“I think that’s really part of where that next step of taking the definition and trends within the literature and translating that into usable clinical practice guidelines across the entire care provider spectrum,” said Heather Snyder, vice president of medical and scientific relations at the Alzheimer’s Association and one of the panelists at the event.
Controversy over the new Alzheimer’s diagnostic guidelines
Several prominent researchers are not on board with the new diagnostic guidelines. And in 2011 and 2018, the Alzheimer’s Association and the NIA were both included in the title of new Alzheimer’s diagnostic guidelines. However, the National Institutes of Health asked to remove the NIA from the joint title for these new guidelines.
“The NIA representatives will continue to contribute in their advisory role. We welcome their involvement, as well as their ongoing support of the advancement of Alzheimer’s research and care,” Niles Frantz, the director of news media engagement for the Alzheimer’s Association told Being Patient.
A diagnostic caveat
One glaring issue, experts say, is that the new guidelines focus solely on biomarkers, rather than on the clinical disease itself. This is could be a problem, because the biomarkers don’t always mean Alzheimer’s — and Alzheimer’s doesn’t always come with these biomarkers: Some 30 percent of older individuals with high levels of amyloid and tau never actually develop Alzheimer’s or other forms of dementia.
“Industry and industry-funded advocacy groups have set their sights on streamlining the diagnosis process to maximize the number of people eligible for presymptomatic treatment,” wrote Dr. Adriane Fugh-Berman in an essay for Hastings Bioethics Forum.
“But if individuals with increased levels of a biomarker never experience cognitive impairment, then what, exactly, is being diagnosed or treated?”
Even the tools used for years to detect amyloid biomarkers in the brain aren’t perfect according to some experts. “Many amyloid PET positive patients do not have amyloid deposits, and many ‘amyloid-positive’ individuals do not have Alzheimer’s disease,” Poul Flemming Hoilund-Carlsen, a clinical researcher and professor at the University of Southern Denmark, wrote on Alzforum.
Potential conflicts of interest
Critics of the new diagnostic guidelines also point to the long list of financial conflicts of interest between the individuals working to redefine Alzheimer’s disease and companies developing diagnostic tests and treatments based on these biomarkers.
Former Food and Drug Administration regulator Billy Dunn, who greenlit the controversial approval of Aduhelm — who had off-the-books meetings and what investigators deemed an inappropriate relationship with the drugmaker Biogen and retired in a hurry when then news came out— is now an advisor for these new diagnostic guidelines.
UPDATED 27 Oct. 2023, 10:14 a.m. ET: This story was updated with more context around the controversy.
UPDATED 4 November, 2023, 10:38 A.M.: This story was updated to provide more context for the NIH decision to remove NIA from the criteria. At the time of publication, the NIH had not commented. Since, they provided comment that because NIA served in an advisory role, “NIA” would be “removed from the formal title of the criteria.” This reasoning is explained herein.