Alzheimer’s Diagnosis Takes More Than Biomarkers, Working Group Says

A definition of Alzheimer’s disease — one that requires objective cognitive deficits in addition to brain amyloid for Alzheimer’s to be diagnosed — was proposed by the International Working Group (IWG).

The proposal was presented at the Clinical Trials on Alzheimer’s Disease (CTAD) annual meeting in Madrid and published simultaneously in JAMA Neurology.

It’s an extension of earlier positions by the IWG that for clinical use, cognitive symptoms must be present and a definition of Alzheimer’s rooted only in biomarkers is not enough.

“Alzheimer’s disease should be defined as a clinical-biological entity where a diagnosis is made in consideration of a clinical disorder supported by positive amyloid and tau biomarkers,” said Howard Feldman, MD, of the University of California San Diego in La Jolla, who presented the IWG recommendations at CTAD.

This definition allows Alzheimer’s to be diagnosed at an early prodromal stage once mild but definite clinical features are evident, he noted.

This viewpoint varies significantly from criteria published by the Alzheimer’s Association (AA) workgroup earlier this year, Feldman told MedPage Today.

The AA criteria defined Alzheimer’s disease as a process that can be detected by abnormal biomarkers even when patients do not have cognitive symptoms. Defining diseases biologically is standard in cancer, heart disease, and diabetes, the AA workgroup noted.

A purely biological definition of Alzheimer’s that diagnoses cognitively normal adults with one positive core biomarker as having Alzheimer’s disease could lead to false positives and people living with a label of Alzheimer’s disease even if they never have cognitive symptoms, Feldman maintained.

“The problem with the AA criteria is that they consider, in clinical settings, to make and to disclose the diagnosis of Alzheimer’s disease in cognitively normal people who are biomarker-positive — the majority of whom will never develop the disease clinically,” IWG leading member Bruno Dubois, MD, MSc, of the Sorbonne University in Paris, told MedPage Today.

The IWG included 46 Alzheimer’s experts from 17 countries who reviewed available evidence about biomarkers and diagnosing Alzheimer’s disease from July 2020 to March 2024. Their goal was to evaluate the AA criteria and offer a different defining perspective of Alzheimer’s for clinical use.

Based on their review, the IWG proposed:

• Cognitively impaired people with specific clinical phenotypes and positive biomarkers would be classified as having Alzheimer’s disease
• Cognitively normal individuals with positive amyloid-related biomarkers only would be classified as “asymptomatic at risk of Alzheimer’s disease,” reflecting that these people have an increased lifetime risk of developing symptomatic disease
• People with autosomal dominant genetic mutations, Down syndrome, or other distinct biomarker profiles associated with an almost deterministic and very high lifetime risk of Alzheimer’s progression would be classified as having “presymptomatic Alzheimer’s disease”

The AA group defined Alzheimer’s by positive biomarkers, but it also advised against testing cognitively unimpaired individuals outside of research studies, noted Ronald Petersen, MD, PhD, of the Mayo Clinic in Rochester, Minnesota, and co-authors in a JAMA Neurology editorial.

The AA group argued that “the application of biomarker-defined Alzheimer’s disease to asymptomatic persons is a research construct,” Petersen and colleagues wrote. However, it’s reasonable to expect that many cognitively unimpaired people will soon have access to affordable Alzheimer’s biomarker tests, the editorialists pointed out.

The IWG group argued that “labeling asymptomatic persons with Alzheimer’s disease will do irrevocable harm to persons who may never become symptomatic,” they added.

The importance of an incorrect diagnosis is well characterized by the IWG group, but lessons from other diseases like cancer may offer important guidance, the editorialists suggested: “The assumption that irrevocable damage would ensue if asymptomatic individuals receive a biomarker diagnosis of Alzheimer’s disease may have elements of paternalism similar to avoiding the word ‘cancer’ in the past.”

The conceptual approach proposed by the IWG is to maintain the essential clinical-pathological concept of Alzheimer’s, Feldman noted.

“We separate asymptomatic at-risk individuals from those who already have the disease,” he stated. “Predictive accuracy, cutoff points, and utility across diverse populations are still needed. Rather than applying a diagnostic label of Alzheimer’s disease, we advocate for this being a state of risk.”

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