International experts propose revised Alzheimer's disease definitions

Today, Prof. Howard Feldman presented revised diagnostic criteria for Alzheimer's disease at the Clinical Trials on Alzheimer's Disease (CTAD) Conference in Madrid on behalf of the International Working Group (IWG).

The IWG, led by Professor Bruno Dubois and Dr. Nicolas Villain (Hôpital universitaire Pitié-Salpêtrière-Sorbonne Université, Paris, France), Professor Howard Feldman (University of California, San Diego, USA) and Professor Giovanni Frisoni (Hôpitaux universitaires de Genève, Geneva, Switzerland) and comprised of 46 International experts from 17 countries, including a representative of Alzheimer Europe, reviewed the available evidence on the role and influence of biomarkers on the diagnosis and definition of Alzheimer's disease.

The IWG proposed a number of important recommendations which were published today in parallel to this presentation in the Journal of the American Medical Association – Neurology (JAMA Neurology):

• Alzheimer's disease should be defined as a clinical-biological entity where diagnosis is made in consideration of both a clinical disorder and the support of positive amyloid and tau biomarkers.
• This definition supports a diagnosis of Alzheimer's disease at an early prodromal stage once mild but definite clinical features are in place.
• For people who are cognitively normal with positive amyloid related biomarkers only, the IWG proposes the term "Asymptomatic at risk of Alzheimer's disease", since these individuals have an increased lifetime risk of developing symptomatic Alzheimer's disease.
• The IWG also proposes the category of "Presymptomatic Alzheimer's disease" for those people with autosomal dominant genetic mutations, with Down syndrome and with other distinct biomarker profiles that put them at extremely high lifetime risk of expressing the clinical disorder (f.ex. combining amyloid positivity with tau accumulations in the neocortical regions).

When presenting these recommendations, Professor Feldman highlighted: "The recommendations of the IWG that are published today advocate for the diagnosis of Alzheimer's disease as being one that is established clinically with support from biomarkers which reflect disease pathology. We consider that on their own these biomarkers reflect varying levels of risk of developing disease in people without clinical symptoms."

In its recommendations, the IWG also takes a position on the recently published "Revised criteria for diagnosis and staging of Alzheimer's disease" of the Alzheimer's Association Workgroup. The IWG highlights that a purely biological definition of Alzheimer's disease, which extends a diagnosis of Alzheimer's disease to cognitively normal people with one core biomarker, could lead to false positives and people potentially living with a label of Alzheimer's disease without ever developing any symptoms (patients-in-waiting) with large societal ramifications. Dr Nicolas Villain commented: "As our understanding of Alzheimer's disease evolves, the advancements in biomarkers are allowing for earlier diagnosis, even before symptoms appear. However, it's crucial to emphasise that our main focus should be on the potential future risks of cognitive decline associated with these biomarkers, rather than just the biological changes themselves."

These recommendations are the collaborative effort of 46 international experts who emphasise that diagnosing Alzheimer's disease should primarily rely on clinical evaluation supported by biomarkers. Importantly, we are distinguishing between two groups: those who show typical Alzheimer's symptoms and have positive biomarkers are diagnosed with the disease, while those who have positive biomarkers but no typical Alzheimer's symptoms are considered at risk. This distinction is crucial as it paves the way for more targeted research, risk assessment, and the development of personalised treatments for those at risk."

Professor Bruno Dubois

The IWG also stressed the importance of continued research on asymptomatic people at risk of AD to better understand and measure individual risks. Professor Frisoni commented: "Further developing brain health services for the prevention of dementia could lead to better evaluation of risk, communication of risk and risk reduction strategies targeting modifiable risk factors."

Jean Georges, the Executive Director of Alzheimer Europe and one of the co-authors welcomed the recommendations: "The IWG recommendations are in line with Alzheimer Europe's current position against routine biomarker testing for diagnostic purposes in individuals without any cognitive symptoms. Labelling people who test positive for amyloid as having preclinical Alzheimer's disease may have significant negative psychological consequences. Instead, we would recommend disclosing an individual's risk, ensuring that appropriate support, counselling and tailored risk reduction plans are provided to help them process and manage this information."