Research diagnostic criteria for Alzheimer’s disease: findings from the LipiDiDiet randomized controlled trial

Anna Rosenberg*, Alina Solomon, Hilkka Soininen, Pieter Jelle Visser, Kaj Blennow, Tobias Hartmann, Miia Kivipelto, on behalf of the LipiDiDiet clinical study group, Ilona Hallikainen, Merja Hallikainen, Seppo Helisalmi, Tarja Lappalainen, Yawu Liu, Teemu Paajanen, Lars-Olof Wahlund, Yvonne Freund-Levi, G. ran Hagman, Klaus Fassbender, Matthias Riemenschneider, Marcus O. W. GrimmAline Klees-Rollmann, Maxine Luley, Epameinondas Lyros, Robert Schomburg, Daniela Ramelli, Jennifer Kennel, Lutz Frölich, Lucrezia Hausner, Christoph Laske, Thomas Leyhe, Christian Mychajliw, Niklas Koehler, Stephan Schiekofer, Hans Klünemann, Johannes Schröder, Dieter Lütjohann, Philip Scheltens, Ineke van Rossum, Nienke Scheltens, Daniela Bertens, Mara ten Kate, Frederik Barkhof, Silvia Ingala, Johanna M. L. Henselmans, Gerwin Roks, Anneke M. J. van Hees, Floor M. van Oudenhoven, Suzanne B. Hendrix, Noel Ellison

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


Background: To explore the utility of the International Working Group (IWG)-1 criteria in recruitment for Alzheimer’s disease (AD) clinical trials, we applied the more recently proposed research diagnostic criteria to individuals enrolled in a randomized controlled prevention trial (RCT) and assessed their disease progression. Methods: The multinational LipiDiDiet RCT targeted 311 individuals with IWG-1 defined prodromal AD. Based on centrally analyzed baseline biomarkers, participants were classified according to the IWG-2 and National Institute on Aging–Alzheimer’s Association (NIA-AA) 2011 and 2018 criteria. Linear mixed models were used to investigate the 2-year change in cognitive and functional performance (Neuropsychological Test Battery NTB Z scores, Clinical Dementia Rating-Sum of Boxes CDR-SB) (criteria × time interactions; baseline score, randomization group, sex, Mini-Mental State Examination (MMSE), and age also included in the models). Cox models adjusted for randomization group, MMSE, sex, age, and study site were used to investigate the risk of progression to dementia over 2 years. Results: In total, 88%, 86%, and 69% of participants had abnormal cerebrospinal fluid (CSF) β-amyloid, total tau, and phosphorylated tau, respectively; 64% had an A+T+N+ profile (CSF available for N = 107). Cognitive-functional decline appeared to be more pronounced in the IWG-2 prodromal AD, NIA-AA 2011 high and intermediate AD likelihood, and NIA-AA 2018 AD groups, but few significant differences were observed between the groups within each set of criteria. Hazard ratio (95% CI) for dementia was 4.6 (1.6–13.7) for IWG-2 prodromal AD (reference group no prodromal AD), 7.4 (1.0–54.7) for NIA-AA 2011 high AD likelihood (reference group suspected non-AD pathology SNAP), and 9.4 (1.2–72.7) for NIA-AA 2018 AD (reference group non-Alzheimer’s pathologic change). Compared with the NIA-AA 2011 high AD likelihood group (abnormal β-amyloid and neuronal injury markers), disease progression was similar in the intermediate AD likelihood group (medial temporal lobe atrophy; no CSF available). Conclusions: Despite being less restrictive than the other criteria, the IWG-1 criteria reliably identified individuals with AD pathology. More pragmatic and easily applicable selection criteria might be preferred due to feasibility in certain situations, e.g., in multidomain prevention trials that do not specifically target β-amyloid/tau pathologies. Trial registration: Netherlands Trial Register, NL1620. Registered on 9 March 2009.
Original languageEnglish
Article number64
JournalAlzheimer's Research and Therapy
Issue number1
Publication statusPublished - 1 Dec 2021

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