Do You Have Alzheimer’s? New Diagnostic Criteria Might Change the Answer

A new definition of Alzheimer’s has been published — and it’s drawing a lot of criticism. According to this set of new diagnostic criteria published in the journal Alzheimer’s and Dementia, a patient doesn’t need to have symptoms in order to have an Alzheimer’s diagnosis.  It can be diagnosed by its biomarkers alone. 

These biomarkers — which measure protein build-up in the brain — can be detected by amyloid PET scan, cerebrospinal fluid collected via lumbar puncture, or vetted biomarker blood tests. The working group wants doctors to consider anyone with beta-amyloid in the brain, according to any of these tests — even if they have no symptoms and may never have them — to be considered as a candidate for expensive new early-stage Alzheimer’s drugs, like Leqembi and Kisunla. 

The working group is largely made up of U.S. and European Alzheimer’s experts, about one third of whom are directly employed by companies that make the diagnostic tools and drugs, another third that have received some form of payment from these companies, as well as two people who work or have worked in the past on regulatory committees that approve new Alzheimer’s drugs. That’s not sitting well with a lot of outside experts.

“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 — but if individuals with increased levels of a biomarker never experience cognitive impairment, then what, exactly, is being diagnosed or treated?,” wrote Dr. Adriane Fugh-Berman in an essay for Hastings Bioethics Forum.

“These guidelines potentially will redefine millions of people of having a new disease, Alzheimer’s disease, even if they have absolutely no symptoms, just based on a single test that they have amyloid at some specific level,” Dr. Eric Widera, a geriatrician and professor of medicine at UCSF, told Being Patient.

A new definition of Alzheimer’s disease — no symptoms required

Again, the working group, headed by Dr. Clifford R. Jack Jr. at the Mayo Clinic, believes anyone who is positive for these biomarkers has Alzheimer’s disease. 

According to the diagnostic criteria, certain accurate blood tests can be used to diagnose Alzheimer’s. But one big problem critics see is that it is too early to integrate most of these new Alzheimer’s biomarker blood tests into clinical practice. 

At this year’s AAIC, researchers presented evidence that Precivity’s AD2 blood test was 90 percent accurate at diagnosing the disease based on biomarkers: Testing the population still means many people will receive a false negative or a false positive result, changing the course of their life.

“It is crucial to emphasize that a biomarker for Alzheimer disease pathology, however accurate, should not serve as a standalone diagnostic test for Alzheimer disease but must be interpreted in a clinical context,” Dr. Sebastian Palmqvist, a professor at Lund University in Sweden, who led the study, told Being Patient.

There aren’t any laws or regulations in the U.S. or elsewhere that prevent companies from offering these blood tests to the public, and these companies don’t always make it easy for doctors or patients to understand the accuracy or limitations. Until very recently, the FDA didn’t even require the makers of these tests to prove they were effective before going to market. While future tests will need to receive FDA approval, the new regulation doesn’t apply to the tests already on the market. 

“I think we need to be very careful about saying blood’s going to replace cerebrospinal fluid [tests], and I think it shouldn’t,” Nicholas Ashton, senior director of the Banner Research Blood-Based Biomarker Program, told Being Patient. “If you can collect the CSF, you get much more information [about the pathology].”

Because these pre-symptoms diagnostics are not yet reliable or established, some experts, including Widera, think it is an impractical suggestion to expand the Alzheimer’s definition to asymptomatic individuals. Widera also took issue with the fact that the new guidelines don’t address whether or not asymptomatic individuals shouldn’t be tested for Alzheimer’s until midway through the document, making it feel like an afterthought.

“Why is that hidden deep inside these guidelines, why isn’t it right there at the start?” Widera told Being Patient. “If they had a diverse set of individuals that were not just heavily focused on pharma and industry and FDA, they would have thought this through.”

Conflicts of interest

A number of experts have raised the issue of ethical conflicts among the authors of the new criteria.

The working group lacks diversity, with members only from the U.S. and a few European countries, but no one from Asia, South America, Africa, nor Australia. (Jack said they are seeking input from more researchers and clinicians in these regions for future versions of these recommendations.) Meanwhile, authors include employees of the FDA and the chief scientific officer of the Alzheimer’s Association.

The National Institute on Aging was also included in the titles of these guidelines In 2011 and 2018. However, the National Institutes of Health asked to remove the NIA from the joint title. 

It’s fair to have pharmaceutical companies on board to figure out a research framework for developing new treatments for diseases like Alzheimer’s, Widera said, but he does not think it’s appropriate that they have a say in how the disease is diagnosed. 

“Are we OK as a society by having pharma, device, [and] diagnostic companies defining who does and who does not have a disease?” he said. “A third of the members who are on these guidelines committees, the guideline committee, are directly employed by industry. The Alzheimer’s Association, who takes in millions of dollars from industry, I would also argue, should not be part of that disease, because they have a conflict of interest.”

He’s not alone in these concerns: Last year, the American Geriatrics Society called the panel members’ financial ties to industry “wholly inappropriate.”

Last year, the American Geriatrics Society called the panel members’ financial ties to industry “wholly inappropriate.”

Jack told CNN he had no conflict of interest and that he “personally wrote about 99 percent of the text in the final document.”

One glaring red flag is the inclusion among the authors of both the former and current directors of the Office of Neuroscience at the FDA, Billy Dunn and Theresa Burrachio. (Regulators that decide on whether new drugs are approved in other countries were not included as authors.) Dunn has a track record of greenlighting expensive drugs against recommendations from independent advisory committees. He led the agency through its controversial approval of Aduhelm, an anti-amyloid drug which has since been withdrawn from the market by its manufacturer. Dunn had off-the-books meetings and what investigators deemed an inappropriate relationship with the drugmaker Biogen and retired in a hurry when news came out. During his FDA tenure, Dunn also pushed for the accelerated approval of Amylyx Pharmaceuticals drug Relvyrio, an expensive drug to treat amyotrophic lateral sclerosis, against the recommendations of an advisory committee. The drug was withdrawn from the market after failing a Phase 3 clinical trial. 

Jack justified the idea of diagnosing asymptomatic individuals with Alzheimer’s by drawing examples from other diseases, such as cancer or HIV.

“No one in infectious disease would claim that HIV infection without symptoms is not a real disease,” he said. “No one in oncology would claim that cancer without symptoms is not a real disease.”

But it may be more complicated than that. Critics have drawn comparisons to pharmaceutical-company funded campaigns promoting awareness for low testosterone and prediabetes, where treatment might cause more harm than good. And although today, researchers recommend against diagnosing Alzheimer’s without symptoms, critics raise concerns that this may change when new drugs hit the market. This raises the question for someone without any symptoms of a disease — someone who might never develop said symptoms — could treatment for a disease that may never cause symptoms do more harm than good?