Experts Challenge New Diagnostic Criteria for Alzheimer’s

A group of international experts is challenging revised diagnostic criteria for Alzheimer’s disease (AD) as laid out by the Alzheimer’s Association (AA) earlier this year.

In a paper published online on November 1 in JAMA Neurology, the International Working Group (IWG), which includes 46 experts from 17 countries, is recommending the diagnosis of AD be limited to individuals with mild cognitive impairment or dementia and not be applied to cognitively normal individuals with AD biomarkers such as amyloid-beta 42/40 or p-tau.

Clinicians should be “very careful” about using the “A” word (Alzheimer’s) for cognitively unimpaired people with AD biomarkers, the paper’s first author Bruno Dubois, MD, professor of neurology, Sorbonne University and Department of Neurology, Pitié-Salpêtrière Hospital, Paris, France, told Medscape Medical News.

Providing an AD diagnosis to those who have a high chance of never developing cognitive impairment can be psychologically harmful, said Dubois.

“It’s not something small like telling someone they have a fever. Just imagine you’re 65 years old and are amyloid positive, and you’re told you have Alzheimer’s disease. It affects the decisions you make for the rest of your life and changes your vision of your future, even though you may never develop the disease,” he added.

Divergent View

The IWG’s perspective on AD contrasts with a recent proposal from the AA. The AA criteria suggest that AD should be regarded solely as a biological entity, which could include cognitively normal individuals with one core AD biomarker.

The IWG notes that its concerns regarding the application of a purely biological definition of AD in clinical practice prompted the group to consider updating its guidelines, potentially offering “an alternative definitional view of AD as a clinical-biological construct for clinical use.”

The group conducted a PubMed search for relevant AD articles, and included references, published between July 2020 and March 2024. The research showed the majority of biomarker-positive, cognitively normal individuals will not become symptomatic during their lifetime.

The risk of a 55-year-old who is amyloid positive developing AD is not that much higher than that for an individual of a similar age who is amyloid negative, Dubois noted. “There’s an 83% chance that person will never develop AD,” he added.

Disclosing a diagnosis of AD to cognitively normal people with only one core AD biomarker represents “the most problematic implication of a purely biological definition of the disease,” the authors noted.

“A biomarker is a marker of pathology, not a biomarker of disease,” said Dubois, adding that a person may have markers for several different brain diseases.

The IWG recommends the following nomenclature: At risk for AD for those with AD biomarkers but low lifetime risk and presymptomatic AD for those with AD biomarkers with a very high lifetime risk of progression such as individuals with autosomal dominant genetic mutations and other distinct biomarker profiles that put them at extremely high lifetime risk of developing the disease.

Dubois emphasized the difference between those showing typical AD symptoms with positive biomarkers who should be considered to have the disease and those with positive biomarkers but no typical AD symptoms who should be considered at risk.

This is an important distinction as it affects research approaches and assessment of risks, he said.

For low-risk asymptomatic individuals, the IWG does not recommend routine diagnostic testing outside of the research setting. “There’s no reason to send a 65-year-old cognitively normal subject off to collect biomarker information,” said Dubois.

He reiterated the importance of clinicians using appropriate and sensitive language surrounding AD when face-to-face with patients. This issue “is not purely semantic; this is real life.”

For these patients in the clinical setting, “we have to be very careful about proposing treatments that may have side effects,” he said.

However, this does not mean asymptomatic at-risk people should not be studied to determine what pharmacological interventions might prevent or delay the onset of clinical disease, he noted.

Presymptomatic individuals who are at a high risk of developing AD “should be the target for clinical trials in the future” to determine best ways to delay the conversion to AD, he said.

The main focus of such research should be to better understand the “biomarker pattern profile” that is associated with a high risk of developing AD, said Dubois.

Plea for Unity

In an accompanying editorial, Ronald C. Petersen, PhD, MD, director, Mayo Clinic Alzheimer’s Disease Research Center and Mayo Clinic Study of Aging, Rochester, Minnesota, and colleagues outline the difference between the IWG and AA positions.

As the IWG uses AD to define those with cognitive impairment and the AA group uses AD to define those with the pathology of the disease, the field is now at a crossroads. “Do we name the disease before clinical symptoms?” they asked.

They note that AA criteria distinguish between a disease and an illness, whereas the IWG does not. “As such, although the primary disagreement between the groups is semantic, the ramifications of the labeling can be significant.”

It’s “incumbent” that the field “come together” on an AD definition, the editorial concluded. “Neither the AA or IWG documents are appropriate to serve as a guide for how to apply biomarkers in a clinical setting. Appropriate-use criteria are needed to form a bridge between biological frameworks and real-world clinical practice so we can all maximally help all of our patients with this disorder.”

Commenting for Medscape Medical News, Reisa Sperling, MD, professor of neurology, Harvard Medical School, and director, Center for Alzheimer Research and Treatment, Brigham and Women’s Hospital and Massachusetts General Hospital in Boston, who is part of the AA work group that published the revised criteria for diagnosis and staging of AD.

She likened AD, which begins in the brain many years before dementia onset, to cardiovascular disease in that it involves multiple processes. She noted the World Health Organization classifies cardiovascular disease as a “disease” prior to clinical manifestations such as stroke and myocardial infarction.

“If someone has Alzheimer’s disease pathology in their brain, they are at risk for dementia or clinical manifestations of the disease — just like vascular disease quantifies the risk of stroke or heart attack, not risk of developing ‘vascular disease’ if the underlying vascular disease is already present,” said Sperling.

A large part of the controversy is related to terminology and the “stigma” of the “A” word in the same way there used to be fear around using the “C” word — cancer, said Sperling.

“Once people began talking about cancer publicly as a potentially treatable disease and began getting screened and diagnosed before symptoms of cancer were manifest, this has had a tremendous impact on public health.”

She clarified that her work group does not recommend screening asymptomatic people with AD biomarkers. “We actually need to prove that treating at the preclinical stage of the disease is able to prevent clinical impairment and dementia,” she said, adding “hopefully, we are getting closer to this.”

Dubois reported no relevant disclosures. Petersen reported receiving personal fees from Roche, Genentech, Eli Lilly and Company, Eisai, and Novo Nordisk outside the submitted work and royalties from Oxford University Press, UpToDate, and Medscape educational activities.