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

description: 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 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.