The changing definition of Alzheimer's disease

Widely used criteria for the diagnosis of Alzheimer's disease were established in 1984. These criteria outlined a typical clinical picture, recommended laboratory testing to exclude other causes of dementia, required neuropathological examination for a definitive diagnosis, and categorised individuals without pathological verification as having probable or possible Alzheimer's disease. 1 McKhann G Drachman D Folstein M Katzman R Price D Stadlan EM Clinical diagnosis of Alzheimer's disease: report of the NINCDS–ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology. 1984; 34: 939-944 Crossref PubMed Google Scholar For more than 20 years, Alzheimer's disease remained a probabilistic clinical-pathological syndrome; syndromes are notoriously non-specific and the Alzheimer's disease syndrome was no exception. 2 Knopman DS DeKosky ST Cummings JL et al. Practice parameter: diagnosis of dementia (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2001; 56: 1143-1153 Crossref PubMed Scopus (1318) Google Scholar The gradual appearance of biomarkers (initially non-specific MRI measures of brain atrophy and PET measures of glucose hypometabolism; later CSF and PET measures of amyloid β and pathological tau) resulted in new criteria, proposed by an International Working Group (IWG), for incorporation of biomarkers into the diagnostic assessment. 3 Dubois B Feldman HH Jacova C et al. Research criteria for the diagnosis of Alzheimer's disease: revising the NINCDS–ADRDA criteria. Lancet Neurol. 2007; 6: 734-746 Summary Full Text Full Text PDF PubMed Scopus (3090) Google Scholar , 4 Dubois B Feldman HH Jacova C et al. Advancing research diagnostic criteria for Alzheimer's disease: the IWG-2 criteria. Lancet Neurol. 2014; 13: 614-629 Summary Full Text Full Text PDF PubMed Scopus (1745) Google Scholar Continued evolution of these criteria resulted in the term preclinical dementia, introduced by a US National Institute on Aging–Alzheimer's Association (NIA–AA) workgroup and the IWG. 5 Dubois B Hampel H Feldman HH et al. Preclinical Alzheimer's disease: definition, natural history, and diagnostic criteria. Alzheimers Dement. 2016; 12: 292-323 Summary Full Text Full Text PDF PubMed Scopus (696) Google Scholar , 6 Sperling RA Aisen PS Beckett LA et al. Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on Aging–Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011; 7: 280-292 Summary Full Text Full Text PDF PubMed Scopus (3999) Google Scholar This term was meant to describe individuals with no symptoms but who expressed biomarkers indicating the presence of amyloid β and tau pathology, with the goal of identifying those in the very earliest stages of Alzheimer's disease who might benefit from therapeutic trials and, eventually, therapy. This description of asymptomatic individuals was controversial enough, but in 2018, the NIA–AA group introduced a research framework in which people with biomarkers indicating pathological accumulation of amyloid β and tau were categorised as having Alzheimer's disease (no longer modified by the term preclinical or probable), regardless of the presence of symptoms. 7 Jack Jr, CR Bennett DA Blennow K et al. NIA–AA Research Framework: toward a biological definition of Alzheimer's disease. Alzheimers Dement. 2018; 14: 535-562 Summary Full Text Full Text PDF PubMed Scopus (2228) Google Scholar Removing clinical criteria eliminated the syndromic aspect of Alzheimer's disease and its inherent non-specificity. However, this shift to an entirely biological or biomarker-based entity also raised questions and objections. In The Lancet Neurology, Bruno Dubois and colleagues from the IWG 8 Dubois B Villain N Frisoni G et al. Clinical diagnosis of Alzheimer's disease: recommendations of the International Working Group. Lancet Neurol. 2021; (publishing online April 29.)https://doi.org/10.1016/S1474-4422(21)00066-1 Summary Full Text Full Text PDF PubMed Scopus (10) Google Scholar critique the shortcomings of this approach, and propose updated criteria for the use of biomarkers in a clinical setting. Clinical diagnosis of Alzheimer's disease: recommendations of the International Working GroupIn 2018, the US National Institute on Aging and the Alzheimer's Association proposed a purely biological definition of Alzheimer's disease that relies on biomarkers. Although the intended use of this framework was for research purposes, it has engendered debate and challenges regarding its use in everyday clinical practice. For instance, cognitively unimpaired individuals can have biomarker evidence of both amyloid β and tau pathology but will often not develop clinical manifestations in their lifetime. Full-Text PDF