Alzheimer Disease as a Clinical-Biological Construct—An International Working Group Recommendation
Authors: Dubois Bruno , Villain Nicolas , Schneider Lon , Fox Nick , Campbell Noll , Galasko Douglas , Kivipelto Miia , Jessen Frank , Hanseeuw Bernard , Boada Mercè , Barkhof Frederik , Nordberg Agneta , Froelich Lutz , Waldemar Gunhild , Frederiksen Kristian Steen , Padovani Alessandro , Planche Vincent , Rowe Christopher , Bejanin Alexandre , Ibanez Agustin , Cappa Stefano , Caramelli Paulo , Nitrini Ricardo , Allegri Ricardo , Slachevsky Andrea , de Souza Leonardo Cruz , Bozoki Andrea , Widera Eric , Blennow Kaj , Ritchie Craig , Agronin Marc , Lopera Francisco , Delano-Wood Lisa , Bombois Stéphanie , Levy Richard , Thambisetty Madhav , Georges Jean , Jones David T. , Lavretsky Helen , Schott Jonathan , Gatchel Jennifer , Swantek Sandra , Newhouse Paul , Feldman Howard H. , Frisoni Giovanni B. 
Published: November 2024

Importance

Since 2018, a movement has emerged to define Alzheimer disease (AD) as a purely biological entity based on biomarker findings. The recent revision of the Alzheimer’s Association (AA) criteria for AD furthers this direction. However, concerns about a purely biological definition of AD being applied clinically, the understanding of AD by society at large, and the translation of blood-based biomarkers into clinical practice prompt these International Working Group (IWG) updated recommendations.

Objective

To consider the revised AA criteria and to offer an alternative definitional view of AD as a clinical-biological construct for clinical use. The recommendations of the 2021 IWG diagnostic criteria are updated for further elaborating at-risk and presymptomatic states.

Evidence Review

PubMed was searched for articles published between July 1, 2020, and March 1, 2024, using the terms “biomarker” OR “amyloid” OR “tau” OR “neurodegeneration” OR “preclinical” OR “CSF” OR “PET” OR “plasma” AND “Alzheimer’s disease.” The references of relevant articles were also searched.

Findings

In the new AA diagnostic criteria, AD can be defined clinically as encompassing cognitively normal people having a core 1 AD biomarker. However, recent literature shows that the majority of biomarker-positive cognitively normal individuals will not become symptomatic along a proximate timeline. In the clinical setting, disclosing a diagnosis of AD to cognitively normal people with only core 1 AD biomarkers represents the most problematic implication of a purely biological definition of the disease.

Conclusions and Relevance

The ultimate aim of the field was to foster effective AD treatments, including preventing symptoms and dementia. The approach of diagnosing AD without a clinical and biological construct would be unwarranted and potentially concerning without a clear knowledge of when or whether symptoms will ever develop. It is recommended that those who are amyloid-positive only and, more generally, most biomarker-positive cognitively normal individuals, should not be labeled as having AD. Rather, they should be considered as being at risk for AD. The expansion of presymptomatic AD is viewed as a better diagnostic construct for those with a specific pattern of biomarkers, indicating that they are proximate to the expression of symptoms in the near future.