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Influence of Different Diagnostic Criteria on Alzheimer Disease Clinical Research
Andrei Bieger1, Wagner S Brum1, Wyllians V Borelli1
1From the Graduate Program in Biological Sciences: Biochemistry (A.B., W.S.B., M.A.D.B., J.P.F.-S., D.O.S., E.R.Z.), Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil; Wallenberg Centre for Molecular and Translational Medicine (M.S.), University of Gothenburg, Sweden; Pharmacology and Therapeutics Graduate Program (W.V.B.), Universidade Federal do Rio Grande do Sul (UFRGS); Memory Center (W.V.B.), Moinhos de Vento Hospital; Department of Anatomy (W.V.B.), Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil; The McGill University Research Centre for Studies in Aging (J.T., A.L.B., T.A.P., S.G., P.R.-N., E.R.Z.), McGill University; Douglas Research Institute (J.T., P.R.-N.), Le Centre Intégré Universitaire de Santé et de Services Sociaux (CIUSSS) de l'Ouest-de-l'Île-de-Montréal, McGill University; Departments of Neurology and Neurosurgery (J.T., S.G., P.R.-N.) and Psychiatry (J.T., S.G., P.R.-N.), McGill University, Montreal, Canada; Graduate Program in Biological Sciences: Pharmacology and Therapeutics (A.G.M., A.F.S.-S., E.R.Z.), Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil; Department of Psychiatry and Neurochemistry (W.S.B., A.L.B., M.S., H.Z., K.B.), Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Sweden; Department of Neurology and Psychiatry (J.P.F.-S., T.A.P.), University of Pittsburgh, PA; Brain Institute of Rio Grande do Sul (J.C.D.C., L.P.S., E.R.Z.), Pontíficia Universidade Católica do Rio Grande do Sul; Department of Biochemistry (D.O.S.), Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil; Neurology Service (R.M.C., A.F.S.-S., M.L.F.C.), Hospital de Clínicas de Porto Alegre; Department of Pharmacology (A.F.S.-S., E.R.Z.), Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil; Department of Neurodegenerative Disease (M.S., H.Z.), Queen Square Institute of Neurology, University College London, United Kingdom; Clinical Neurochemistry Laboratory (H.Z., K.B.), Sahlgrenska University Hospital, Gothenburg, Sweden; UK Dementia Research Institute at University College London (H.Z.), United Kingdom; Hong Kong Center for Neurodegenerative Diseases (H.Z.).
Background And Objectives:
Updates in Alzheimer disease (AD) diagnostic guidelines by the National Institute on Aging-Alzheimer's Association (NIA-AA) and the International Working Group (IWG) over the past 11 years may affect clinical diagnoses. We assessed how these guidelines affect clinical AD diagnosis in a cohort of cognitively unimpaired (CU) and cognitively impaired (CI) individuals.
Methods:
We applied clinical and biomarker data in algorithms to classify individuals from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort according to the following diagnostic guidelines for AD: 2011 NIA-AA, 2016 IWG-2, 2018 NIA-AA, and 2021 IWG-3, assigning the following generic diagnostic labels: (1) not AD (nAD), (2) increased risk of developing AD (irAD), and (3) AD. Diagnostic labels were compared according to their frequency, convergence across guidelines, biomarker profiles, and prognostic value. We also evaluated the diagnostic discordance among the criteria.
Results:
A total of 1,195 individuals (mean age 73.2 ± 7.2 years, mean education 16.1 ± 2.7, 44.0% female) presented different repartitions of diagnostic labels according to the 2011 NIA-AA (nAD = 37.8%, irAD = 23.0%, AD = 39.2%), 2016 IWG-2 (nAD = 37.7%, irAD = 28.7%, AD = 33.6%), 2018 NIA-AA (nAD = 40.7%, irAD = 9.3%, AD = 50.0%), and 2021 IWG-3 (nAD = 51.2%, irAD = 8.4%, AD = 48.3%) frameworks. Discordant diagnoses across all guidelines were found in 512 participants (42.8%) (138 [91.4%] occurring in only β-amyloid [CU 65.4%, CI 34.6%] and 191 [78.6%] in only tau-positive [CU 71.7%, CI 28.3%] individuals). Differences in predicting cognitive impairment between nAD and irAD groups were observed with the 2011 NIA-AA (hazard ratio [HR] 2.21, 95% CI 1.34-3.65, p = 0.002), 2016 IWG-2 (HR 2.81, 95% CI 1.59-4.96, p < 0.000), and 2021 IWG-3 (HR 3.61, 95% CI 2.09-6.23, p < 0.000), but not with 2018 NIA-AA (HR 1.69, 95% CI 0.87-3.28, p = 0.115).
Discussion:
Over 42% of the studied population presented discordant diagnoses when using the different examined AD criteria, mostly in individuals with a single positive biomarker. Except for 2018 NIA-AA, all guidelines identified asymptomatic individuals at risk of cognitive impairment. Our findings highlight important differences between the guidelines, emphasizing the necessity for updated criteria with enhanced staging metrics, considering clinical, research, therapeutic, and trial design aspects.
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