Diagnostic Drama: Clinicians Argue Dueling Definitions of Alzheimer’s

An international group of researchers is challenging the controversial new definition of Alzheimer’s proposed by a group of researchers convened by the Alzheimer’s Association. The diagnostic criteria set out by the Alzheimer’s Association redefined the disease as purely biological: Anyone with high levels of beta-amyloid in the brain, even those without any cognitive symptoms, would have the disease. 

Nicolas Villain, a neurologist at Sorbonne University in Paris and a critic of this proposal, co-leads clinical the International Working Group. Representatives from Alzheimer’s Europe and more than 40 researchers from 17 countries published diagnostic criteria challenging the Alzheimer’s Association. The IWG views the disease as a combination of both clinical symptoms and biological changes in the brain. 

Aside from a small minority of patients with genetic forms of Alzheimer’s, the IWG criteria call people with amyloid but no symptoms “at risk” of Alzheimer’s rather than presymptomatic.

“Changing to a biological definition erases the gravity of disease,” Villain told Being Patient. “Three quarters of individuals with a biological definition don’t have symptoms, and more than half will never develop symptoms.”

Expanding the definition of Alzheimer’s to include people who are amyloid positive but have no cognitive symptoms quadruples the number of people who have the disease.  And while the Alzheimer’s Association guidelines don’t advocate for testing asymptomatic individuals, Villain believes it lays the ground for misunderstandings and inappropriate diagnoses.

Who decides on a definition? 

The IWG guidance was developed by 46 researchers across 17 countries. In contrast, the Alzheimer’s Association was written by 17 authors across five countries. 

The vast majority of researchers developing both sets of guidelines received funding or worked with pharmaceutical companies. However, no researchers who signed off on the IWG guidelines were directly employed by pharmaceutical companies at the time of publication. Five of the authors of the Alzheimer’s Association guidelines were, however. As a result, last year, the American Geriatrics Society called the panel members’ financial ties to the pharmaceutical industry “wholly inappropriate.” 

None of the authors of the IWG guidelines are in charge of approving new drugs in the U.S. or elsewhere. Two of the authors of the Alzheimer’s Association guidelines are current or former FDA executives in charge of greenlighting drugs for brain diseases. 

One of them is former FDA exec Billy Dunn has a track record of greenlighting expensive drugs against recommendations from independent advisory committees. He led the agency through its controversial accelerated approval of Aduhelm, an anti-amyloid drug that 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. 

Eliezer Masliah, who worked at the U.S. government’s National Institute of Health, is listed as a contributing committee member on the Alzheimer’s Association guidelines. A Science investigation found that Masliah engaged in research misconduct over more than two decades. The NIH has since released a statement saying Masliah engaged in research misconduct. 

Villain said the IWG reached out to work with Clifford Jack, who led the Alzheimer’s Association working group, on the 2024 guidelines, but he “politely declined.” 

Do these definitions affect patient care?

Most people who test positive for Alzheimer’s biomarkers will never develop symptoms of the disease. The IWG puts the risk of a 55-year-old who tests positive for biomarkers of beta-amyloid at a 17 percent chance of developing symptoms over their lifetime. 

With that in mind, Villain is concerned that biomarker tests may be misused, giving patients an inappropriate and worrying Alzheimer’s diagnosis. Some reporting claims that doctors will ditch cognitive tests altogether under the biological definition. Many experts feel this is jumping the gun.

Some — including Dr. Suzanne Schindler, a clinical neurologist and dementia specialist at Washington University School of Medicine, who wasn’t involved in authoring either set of guidelines — argue these concerns aren’t currently affecting patients.

No one is rushing to test asymptomatic individuals: Specialty clinics have limited capacity and biomarker tests are still expensive. Even most people with memory problems don’t receive biomarker testing. Their memory problems may be caused by other conditions like sleep apnea, other medications, or menopause. 

“In our clinical practice, these distinctions really do not impact patient care at this point in time,” Schindler told Being Patient. 

While Schindler understands the concerns outlined by the IWG, she said that “waiting until someone has really severe pathology to be able to call it Alzheimer’s disease also doesn’t seem quite right.”

Right now, appropriate use recommendations for blood tests advise against testing asymptomatic individuals. 

“I do think that the major issue right now is clinicians who can order these blood tests may not understand exactly what they mean or how to use and interpret them,” Schindler said. “I think that the risk of clinicians who are inexperienced using these tests and appropriately ordering them and interpreting them incorrectly is the same regardless of how you define Alzheimer disease.” 

In the U.S., these blood tests are expensive, not covered by Medicare, and impractical to roll out to a large population. 

“I actually don’t know any clinicians, period, that are doing biomarker testing in cognitively unimpaired individuals,” Schindler said. “Even in our large memory clinic, where we do a lot of biomarker testing, we’re still only doing biomarker testing in about 15 percent of our patients.” 

However, companies may once again try to offer direct-to-consumer testing for Alzheimer’s biomarkers. 

In 2023, Quest Diagnostics unleashed an inaccurate direct-to-consumer Alzheimer’s blood test that anyone over 18 could order. Dr. David Weisman, a neurologist at Abington Neurological Associate, told Being Patient described the test as “an absolute catastrophe.” After near-universal backlash from clinicians, the company stopped offering the test directly to patients.

Critics have also drawn comparisons between the expansion of the disease definition imposed by the AA guidelines to pharmaceutical-company-funded campaigns promoting awareness for low testosterone and prediabetes, conditions that don’t always lead to the development of disease where treatment may cause more harm than good. 

Villain and his colleagues write that the biomarkers-only definition of Alzheimer’s opens the door to approving drugs for cognitively healthy individuals based on their ability to lower the levels of beta-amyloid without waiting to see whether they slow cognitive decline. Prominent Alzheimer’s researchers recently published a paper arguing just that. 

Does it matter which definition of Alzheimer’s your doctor believes? In the not-so-distant future, it could change the way we think about Alzheimer’s disease and how regulators approve new anti-amyloid treatments. Meanwhile, Villain hopes to reconcile these differences and reach a consensus with the Alzheimer’s Association working group.