With another pricey Alzheimer’s disease treatment expected to receive an approval decision soon, the nonprofit Alzheimer’s Association has published the final version of its new diagnostic criteria for the disease. And for the first time, the criteria call on doctors diagnosing the disease to rely on biomarkers — pieces of beta amyloid and tau proteins picked up by lab tests or on brain scans — rather than pen-and-paper tests of memory and thinking.
The idea behind the change, the authors say, is to catch the condition in its earliest and most treatable stages, even before symptoms develop. However, it also means people could be diagnosed with Alzheimer’s based on a blood test alone, even if they don’t have any memory difficulties.
Biology should be the basis of the diagnosis, the authors argue, rather than symptoms. Furthermore, they say, just because a person doesn’t have symptoms doesn’t mean they won’t develop them down the line.
But the criteria have been criticized by outside experts and drug industry watchdog groups who point out that people can have beta amyloid proteins in their brains and blood without ever developing dementia symptoms. They also point out that there’s no research to support the idea that giving a person expensive, risky injected medications before they show symptoms will benefit them in the long run.
Risks and benefits of early diagnosis
In clinical trials, the new drugs – which are antibodies that recognize and grab onto pieces of beta amyloid to remove them from the brain – showed modest benefits.
Beta amyloid peptides are protein pieces that form sticky plaques in the brain. Together with another protein, tau, which makes fibrous tangles that block the communication of nerve cells, they are considered a hallmark of Alzheimer’s disease.
There’s still debate about the role of beta amyloid in the disease, however, and some experts contend that plaques are a consequence of the condition rather than its cause.
In an 18-month study of people who were in the early stages of Alzheimer’s disease, the antibody lecanemab – which the US Food and Drug Administration approved in 2023 – slowed the rate of cognitive decline by 27% compared with a placebo.
Also last year, the experimental drug donanemab appeared to slow the progression of disease by about 35% compared with a placebo. This month, a group of experts that advises the FDA on its drug approval decisions unanimously recommended the approval of donanemab for Alzheimer’s disease.
The drugs come with some risk. As they remove amyloid, they can lead to fluid accumulation, swelling and even microbleeds in the brain, which may lead to hospitalization.
Both trials were in people who had early symptoms of memory decline. Studies that have tested antibodies in patients who had amyloid buildup in their brains but no symptoms have not found a benefit to patients.
“There’s no evidence for it,” said Dr. George Perry, a neurobiologist and editor of the Journal of Alzheimer’s Disease.
Critics say the new criteria could dramatically expand the number of people eligible to take the new drugs and could generate huge profits for drug manufacturers in the process.
“The Alzheimer’s Association should lose all credibility by releasing guidelines labeling perfectly normal people as having Alzheimer’s disease,” said Dr. Adriane Fugh-Berman, director of PharmedOut, a program based at Georgetown University that tracks pharmaceutical marketing tactics.
“If followed, these guidelines will ruin the lives of tens of thousands of people who will be misinformed that they have dementia,” she said. “The only entities that gain from this travesty are the pharmaceutical companies that make drugs for Alzheimer’s and the Alzheimer’s Association, which is preying on fear.”
The Alzheimer’s Association says its criteria is based on the latest developments in Alzheimer’s science. Because Alzheimer’s therapies haven’t been approved for people without symptoms, for now, it recommends against diagnostic testing in people without cognitive impairment, according to the working group that developed the criteria.
“Our goal in sharing them now — even as the field and our knowledge continues to evolve — is to advance diagnosis, treatment and prevention in order to improve individual care and reduce the societal impact of Alzheimer’s,” said Dr. Maria C. Carrillo, the Alzheimer’s Association’s chief science officer and medical affairs lead, and senior author on the new criteria.
Financial conflicts of interest
The new criteria – from the leading patient advocacy organization for Alzheimer’s – were developed by a 20-member working group, many of whom reported financial ties to many of the companies that are marketing new drugs for Alzheimer’s or that have new drugs in development.
A third of the expert panel is directly employed by pharmaceutical companies, while another third has reported some other kind of payment from pharmaceutical or testing companies. Two members of the panel were employees of the Alzheimer’s Association, which also takes funding from pharmaceutical companies. Only a handful of members of the work group declared no relevant conflicts of interest.
“We should not be relying on this paper that was basically developed by industry. It’s just not standard of practice how we think about guidelines,” said Dr. Eric Widera, a geriatrician at the University of California San Francisco who authored a commentary in the Journal of the American Geriatrics Society on the new criteria.
Widera says it’s a familiar playbook for the pharmaceutical industry: expanding the market for a drug by first expanding the population diagnosed with the disease that it treats. “This is diagnostic creep,” he said.
He cites examples such as the “Is it low T?” awareness campaign, launched by Abbott Labs, which made a testosterone replacement product as well as a more sensitive test for the hormone.
Biogen similarly created the “It’s Time We Know” campaign in 2021 to spread awareness of mild cognitive impairment after its Alzheimer’s drug Aduhelm won a controversial FDA approval the same year. Aduhelm has since been taken off the market.
Widera estimates that as many as 1 in 10 normally functioning 50-year-olds would test positive for beta amyloid under the new criteria. Currently, about 6 million Americans are living with Alzheimer’s, but estimates suggest roughly 40 million would test positive for beta amyloid.
“Publications such as this are a necessary component of a strategy aimed at selling as many monoclonal antibodies as possible,” said Dr. Karl Herrup, a professor of neurobiology at the University of Pittsburgh School of Medicine.
Defending the need for industry input
Dr. Clifford Jack, who studies brain imaging at the Mayo Clinic, led the development of the new guidelines and says he is proud of what the committee accomplished.
“I personally wrote about 99% of the text in the final document. And I have no conflict of interest at all,” he said.
The change in the guidelines was spurred, the authors say, by the availability of the first drugs to slow the progress of the disease as well as new blood tests for amyloid and tau proteins. Those tests are available to doctors and patients through the specialty labs that make them, but they have not been approved by the FDA, which requires rigorous proof that a test doesn’t give too many false negative or false positive results before it gives a green light for widespread use.
In a comment on the new criteria, published Friday in the journal Nature Medicine, members of the work group said it was composed of members from industry, clinical medicine and academia as well as the FDA and the federal National Institute on Aging, to incorporate a diversity of viewpoints.
“We want these criteria to reflect the best available current scientific knowledge, and some of that knowledge is contained in industry, who are the ones who are actually running these trials,” Jack said.
“I can honestly say that I did not see any attempt at any point by a committee member to insert any kind of commercial interest into these guidelines,” he said.
The first draft of the criteria, which were first presented at the Alzheimer’s Association International Conference in 2023, noted that they were being developed as a collaboration between the Alzheimer’s Association and the National Institute on Aging.
But the new criteria received criticism, and the institute removed its name from the title after it was asked to do so by administration within the wider National Institutes of Health. The collaboration violated an NIH policy not to endorse private entities, products or services, according to an email from the National Institute on Aging.
“NIA continues to serve on the working group and looks forward to continuing its collaborative efforts with the Alzheimer’s Association and other involved workgroup organizations,” the agency said in a statement.
Since the draft criteria were released, the Alzheimer’s Association has clarified that these are not meant to serve as detailed diagnostic guidelines for clinicians. Instead, the criteria are meant to be a “bridge” between research and the doctor’s office.
New guidelines in the works
The association said it plans to convene a new workgroup, with different members, to develop “nuts-and-bolts” guidelines for Alzheimer’s diagnosis for doctors. It’s not clear how much those guidelines will be based on the diagnostic criteria.
“It’s going to have to be very concrete, and it probably will include recommendations that describe specific commercial products,” Jack said.
The Alzheimer’s Association is committed to the development of trustworthy clinical practice guidelines “and other types of evidence-based guidance informing clinical decision-making at the individual, health system, and population levels,” spokesperson Niles Franz said.
“A core criterion for trustworthy guidelines, as defined by the National Academy of Medicine, involves collaboration between an organizing body and panels of clinical and subject-matter experts who are minimally conflicted both intellectually and financially,” Franz said in a statement.
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“To that end, the Association recently established rules for collecting [conflict of interest] disclosures from guideline panel nominees, criteria for evaluating these forms and selecting panel members, and process for managing existing and new conflicts during and after guideline development,” he said.
Franz said the association hopes to have the new clinical guidelines ready for publication by 2025.
In the meantime, Widera and others say the decision to take one of the new amyloid-clearing drugs is highly personal and one that should be made in close collaboration with a physician.
“There is, I would say, probably more controversy around these guidelines than there are about the drugs themselves,” Widera said.
Widera says he hopes that in the next round of guidelines, the Alzheimer’s Association will consider the risks involved.
“If you’re going to broaden the definition of what a disease is, you should also say what is the risk and harm of doing so,” he said.