In a paper published online in JAMA Neurology, the International Working Group (IWG), which includes 46 experts from 17 countries, is recommending that the diagnosis of Alzheimer’s disease be limited to individuals with mild cognitive impairment or dementia and not be applied to cognitively normal individuals with Alzheimer’s disease 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 Alzheimer’s disease biomarkers, said the paper’s first author Bruno Dubois, MD, professor of neurology, Sorbonne University and Department of Neurology, Pitié-Salpêtrière Hospital, Paris, France.
Providing an Alzheimer’s disease 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 Alzheimer’s disease contrasts with a recent proposal from the Alzheimer’s Association. The Alzheimer’s Association criteria suggest that Alzheimer’s disease should be regarded solely as a biological entity, which could include cognitively normal individuals with one core Alzheimer’s disease biomarker.
The IWG noted that its concerns regarding the application of a purely biological definition of Alzheimer’s disease in clinical practice prompted the group to consider updating its guidelines, potentially offering “an alternative definitional view of Alzheimer’s disease as a clinical-biological construct for clinical use.”
The group conducted a PubMed search for relevant Alzheimer’s disease 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 Alzheimer’s disease 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 Alzheimer’s disease.”
Disclosing a diagnosis of Alzheimer’s disease to cognitively normal people with only one core Alzheimer’s disease 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 Alzheimer’s disease for those with Alzheimer’s disease biomarkers but low lifetime risk and presymptomatic Alzheimer’s disease for those with Alzheimer’s disease biomarkers with a very high lifetime risk for 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 Alzheimer’s disease symptoms with positive biomarkers who should be considered to have the disease and those with positive biomarkers but no typical Alzheimer’s disease 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 Alzheimer’s disease 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 Alzheimer’s disease “should be the target for clinical trials in the future” to determine best ways to delay the conversion to Alzheimer’s disease, 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 Alzheimer’s disease, said Dubois.