Should Biomarkers (and Pharma) Drive Alzheimer’s Diagnosis?

Many Alzheimer’s experts were dismayed — but not surprised — when the Alzheimer’s Association stated that the disease could be diagnosed on the basis of pathology using biomarkers, rather than symptoms.

The June 2024“Revised Criteria for Diagnosis and Staging of Alzheimer’s Disease” evolved from a 2018 “research framework” paper that proposed a move toward a biological definition. The authors of the revised criteria paper described it as a “bridge between research and clinical care,” and “general principles to inform diagnosis and staging.”

However, an International Working Group (IWG) of 45 scientists critiqued the revised diagnostic criteria in a recent paper in JAMA Neurology. Alzheimer’s disease (AD)should continue to be defined by a constellation of symptoms in addition to pathology, they wrote, and most biomarker-positive cognitively normal individuals “should not be labeled as having AD”, rather, they should be considered “at risk”.

Experts critical of the new diagnostic criteria said there is insufficient evidence that biology is destiny. Others suggested the authors were influenced by industry ties to push for earlier diagnosis — even in individuals with no cognitive impairment.

“The problem with the Alzheimer’s group is they were very co-opted,” said Peter J. Whitehouse, MD, PhD, a professor of neurology at Case Western Reserve University in Cleveland. The Alzheimer’s Association is “irresponsible” in promoting the idea that biomarkers can diagnose AD, Whitehouse told Medscape Medical News.

Biomarkers aren’t reliable and a “positive” test might scare people into thinking that there’s nothing they can do to improve their brain health, he said. There’s also the expense to the healthcare system if thousands of the worried well seek amyloid imaging or other diagnostics, he added.

The IWG’s proposal to label people “at risk” is better, said Whitehouse. “It allows people to say, ‘Well, okay, what can I do to reduce my risk?’”

Does Pathology Equal AD?

The diagnostic criteria state that “an abnormal Core 1 biomarker is sufficient to establish a diagnosis of AD.” Those biomarkers include amyloid PET, approved cerebrospinal fluid biomarkers, and plasma biomarkers (such as phosphorylated tau 217). “Unimpaired individuals with abnormal biomarker test results are at risk for symptoms due to AD,” the criteria authors wrote. “They are not at risk for a disease they already have.”

The IWG disagreed. The core 1 biomarkers “are individually insufficient to account for the many mechanisms and interactions underlying the disease process,” they countered.

Eric Widera, MD, professor of medicine at the University of California San Francisco, and a member of the IWG called the revised criteria “bad medicine.” Someone who never develops cognitive impairment but has positive biomarkers would be labeled as having AD for the rest of their life, he said, among other issues, that could jeopardize insurance coverage and employment, Widera told Medscape Medical News.

“We’re not there, from an evidence perspective, to say, yes, those people have this disease,” he said. No trials point to how many people with positive biomarkers will develop dementia. There is especially scant evidence for people of color or those with lower socioeconomic status because drug and risk trials have mostly enrolled higher-income White patients, he explained.

Diagnosing biomarker-positive, cognitively-unimpaired people with AD may be a disservice, he said. “We don’t even know if that’s the right patient population to really encourage things like exercise and good health maintenance because it may be the people without amyloid are the people that we should really be focusing on,” he said, noting that “it may be too late once you have amyloid.”

While “amyloid and tau are definitely associated with the pathology of Alzheimer’s disease, there are lots of other things that are going on that could also be contributing to that person’s condition,” said Elyse Couch, PhD, assistant professor of Health Services, Policy, and Practice at School of Public Health, Brown University, Providence, Rhode Island. Couch noted that there’s heterogeneity in the clinical profiles of dementia.

“I’m not fully supportive of the idea of labeling people as having a stage I Alzheimer’s disease when they have no symptoms,” she said, adding, “the evidence doesn’t really support this just yet.”

“To me, the big driving force of this is the amyloid therapies,” Couch told Medscape Medical News.

Some of the experts Medscape Medical News spoke with said their concerns about pushing for a biology-based diagnosis were marginally allayed by new clinical practice guidelines published by the Alzheimer’s Association in December. The guidelines aimed at specialists and primary care, call for a thorough neuro-cognitive evaluation and de-emphasize a biomarker-first protocol.

Those guidelines make it clear that “primary care providers should not be sending out these diagnostic tests,” said Widera, who applauded the approach.

The Alzheimer’s Association is preparing clinical practice guidelines for later this year or early 2026 that will spell out how to apply the diagnostic criteria, Maria Carrillo, PhD, chief science officer and medical affairs lead, told Medscape Medical News.

They will state that biomarker tests should not be employed in individuals who have no symptoms, said Carrillo, adding, “that is not something that a clinician should be willing to provide.”

https://img.medscapestatic.com/vim/live/professional_assets/medscape/images/thumbnail_library/2020%20Carrillo%20Credit_Alz_Association.png>>

Caption: Maria Carrillo, PhD

But experts said the biomarker construct is out there, despite the Alzheimer’s Association trying to walk it back.

The revised criteria essentially said, “you can diagnose asymptomatic Alzheimer’s disease, but we don’t recommend that you do it,” said Couch, calling that a “confusing” message.

Explosion of AD in the Cognitively Normal?

The IWG is concerned that the revised criteria would fuel “an explosion of cognitively normal persons who are labeled as having AD on a purely biological definition of the disease.”

Carrillo disagreed, told Medscape Medical News, “I sincerely doubt there will be a wave of clinicians wanting to diagnose people without symptoms. I just don’t think that that is likely”.

However, there may be patient interest. “It is reasonable to expect that many cognitively unimpaired individuals are going to start having access to a growing number of affordable AD biomarker tests,” wrote Ronald Peterson, MD, PhD, in an editorial accompanying the IWG paper.

One of the most-viewed papers on JAMA this year evaluated a blood test for AD. The authors of that paper said interest was driven by the availability of anti-amyloid therapies.

“Initiation of treatment requires biomarker-positive test results for Alzheimer’s disease, leading to increased need for biomarker testing,” wrote Sebastian Palmqvist, MD, PhD and colleagues.

Widera said it was just a matter of time, noting that Eli Lilly, which makes the anti-amyloid therapy donanemab (Kisunla), is encouraging people to seek out biomarker testing through their website, more than normal aging.

Individuals are prompted to talk to their physicians to “help determine if testing is the right next step for you.” If you sign up for emails, you might get one that reads, “the earlier you test for buildup of amyloid plaques with your doctor, the more options you may have.”

People “are being pushed by these drug ads to check their amyloid levels,” said Widera.

Being told to ask a doctor “sounds like it’s the right thing to do, but sometimes doctors are not familiar with the ins and outs of these tests, and it’s easy for them to just go ahead and write a prescription,” said Whitehouse.

Carrillo said there “will always be physicians who are going to be willing to take direct pay for a diagnostic off-label,” but that most people won’t be able to pay for tests out-of-pocket. She noted that insurers limit who can receive anti-amyloid therapies.

Author Conflicts and National Institute on Aging (NIA)

However, Widera, said that the push toward the anti-amyloid medications — which also include lecanemab (Leqembi, Biogen and Eisai) — is “baked into” the diagnostic criteria, in part because of the authors’ ties to industry.

Of the 20 authors, five were drug company employees. Three others received consulting fees from Eli Lilly, Biogen, and Eisai, among other drug makers active in the AD field. One author is a shareholder in Vivid Genomics, a company developing precision genomics for dementia diagnosis. Another has a patent planned, issued or pending on “Methods of diagnosing AD with phosphorylation changes.”

Coauthor Billy Dunn, MD, is a consultant for Cerveau Technologies, a company investigating AD-related PET imaging agents, and a board member at drug maker Prothena. Dunn joined Prothena shortly after he retired from his position as head of the US Food and Drug Administration’s Office of Neuroscience where he oversaw the controversial approval of Biogen and Eisai’s anti-amyloid therapy aducanumab. That drug was later discontinued by Biogen.

Early drafts of the revised criteria and related papers were billed as joint Alzheimer’s Association–NIA criteria and employees of the NIA were among the authors. However, the final 2024 publication does not include NIA in the title and only acknowledges two employees as “contributing committee members.” 

An NIA spokesperson told Medscape Medical News, the change “was prompted by the NIH [National Institutes of Health] Office of the Director, which reminded NIA that this situation was noncompliant with the Use of NIH Names and Logo policy.” The agency subsequently “asked the Alzheimer’s Association to remove our name from the title,” said the spokesperson.

The agency is continuing to collaborate with the Alzheimer’s Association, the spokesperson said.

Carrillo would not comment on the NIA action. But she defended industry participation as “not necessarily a bad thing”. She said that many guidelines involve experts with potential conflicts.

“The trick is managing those conflicts,” Carrillo added, insisting that it was possible to “create guardrails.”

Both Widera and Couch said the Alzheimer’s Association diagnostic criteria had not followed accepted processes.

Couch, who has been involved in guidelines writing, agreed that conflicts are common. But she said the AD group had not been transparent in divulging how it managed the conflicts. For instance, the paper could have spelled out whether some authors recused themselves from certain recommendations, she said.

The revised criteria are not billed as guidelines, but rather as “objective criteria for diagnosis and staging AD.”

For his part, Whitehouse believed the development of the diagnostic criteria was tainted because of the authors’ alliances with industry.

“Alzheimer’s is not a clear diagnostic entity,” he said. “It’s very fuzzy — despite what Lilly says — as to where normal aging begins and Alzheimer’s starts or ends”.

Widera and Whitehouse reported no relevant financial relationships. Couch disclosed that she has a research fellowship with the Alzheimer’s Association.

Alicia Ault is a Saint Petersburg, Florida-based freelance journalist whose work has appeared in many health and science publications, including Smithsonian.com. You can find her on X @aliciaault and on Bluesky @aliciaault.bsky.social.