Dubois B, Villain N, Schneider L, Fox N, Campbell N, Galasko D, Kivipelto M, Jessen F, Hanseeuw B, Boada M, Barkhof F, Nordberg A, Froelich L, Waldemar G, Frederiksen KS, Padovani A, Planche V, Rowe C, Bejanin A, Ibanez A, Cappa S, Caramelli P, Nitrini R, Allegri R, Slachevsky A, de Souza LC, Bozoki A, Widera E, Blennow K, Ritchie C, Agronin M, Lopera F, Delano-Wood L, Bombois S, Levy R, Thambisetty M, Georges J, Jones DT, Lavretsky H, Schott J, Gatchel J, Swantek S, Newhouse P, Feldman HH, Frisoni GB. Alzheimer Disease as a Clinical-Biological Construct-An International Working Group Recommendation. JAMA Neurol. 2024 Nov 1; Epub 2024 Nov 1 PubMed.
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VU University Medical Center
Vrije Universiteit Amsterdam
VU University Medical Center
The IWG criteria are put forward as strongly contrasting the Alzheimer Association (AA) Revised Criteria. We feel that this contrast is made larger than it actually is. Similar to the IWG, the AA Revised criteria recommend diagnosis of AD only in the symptomatic stages, and advise against AD diagnosis in presymptomatic individuals.
As such, we feel that whilst the diagnosis of preclinical AD is put forward as a major point of divergence between the two recommendations, similarities are in fact larger. Both groups define AD biologically as a driving theoretical construct, and underscore the long preclinical phase of biological changes due to AD before symptoms become apparent. The recognition of the long preclinical phase is paramount to tackle the disease before irreversible damage has occurred.
The AA criteria are not meant as clinical guidelines on how to use the biomarkers in clinical practice. Considering the work that has to be done to move to clinical guidelines, for plasma biomarkers the AA has started a working group, including authors of both IWG and AA criteria, to perform a meta-analysis of available literature and define a draft clinical guidance on use of plasma biomarkers in symptomatic individuals.
One of the arguments behind the IWG recommendations to be careful with the use of biomarkers in cognitively unimpaired individuals is that many people with amyloid positivity at postmortem did not experience cognitive decline during their lives. However, there is limited literature to support this statement, because there are few studies that compared in vivo clinical and biomarker results with tissue autopsy results obtained after only a short time lag. In addition, postmortem studies often suffer from survival bias. Importantly, there are very few postmortem AD studies in individuals at their ages where biomarkers have their strongest relevance, i.e., individuals younger than 75. Cognitively healthy individuals in such postmortem studies where people did die relatively young, before clinical dementia has started: another bias. This is an issue we cannot easily resolve due to the long time lag between build-up of pathology and clinical symptoms in AD. This warrants new study designs, large enough to evaluate sources of bias, and relying on approved in vivo methods for detection of AD pathology, i.e., amyloid and tau PET, and CSF analysis.
Given that preclinical AD may have a disease course of at least 20 years and that the first amyloid PET tracer came to the market only 20 years ago, it is evident that it is not yet possible to reliably answer the question how many individuals remain asymptomatic in the face of AD pathology. New longitudinal studies with biomarker measurements at baseline and sufficient duration of follow-up are needed to determine how many amyloid positive individuals remain cognitively unimpaired in the long run.
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