Research diagnostic criteria for Alzheimer’s disease: findings from the LipiDiDiet randomized controlled trial
Authors: Rosenberg Anna , Solomon Alina , Soininen Hilkka , Visser Pieter Jelle , Blennow Kaj , Hartmann Tobias , Kivipelto Miia ,   on behalf of the LipiDiDiet clinical study group, Soininen Hilkka , Hallikainen Ilona , Hallikainen Merja , Helisalmi Seppo , Lappalainen Tarja , Liu Yawu , Paajanen Teemu , Kivipelto Miia , Solomon Alina , Wahlund Lars-Olof , Freund-Levi Yvonne , Hagman Göran , Blennow Kaj , Hartmann Tobias , Fassbender Klaus , Riemenschneider Matthias , Grimm Marcus O. W. , Klees-Rollmann Aline , Luley Maxine , Lyros Epameinondas , Schomburg Robert , Ramelli Daniela , Kennel Jennifer , Frölich Lutz , Hausner Lucrezia , Laske Christoph , Leyhe Thomas , Mychajliw Christian , Koehler Niklas , Schiekofer Stephan , Klünemann Hans , Schröder Johannes , Lütjohann Dieter , Visser Pieter Jelle , Scheltens Philip , van Rossum Ineke , Scheltens Nienke , Bertens Daniela , ten Kate Mara , Barkhof Frederik , Ingala Silvia , Henselmans Johanna M. L. , Roks Gerwin , van Hees Anneke M. J. , van Oudenhoven Floor M. , Hendrix Suzanne B. , Ellison Noel 
Published: March 2021

Abstract
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