Avoid or Embrace? Practice Effects in Alzheimer's Disease Prevention Trials.

Demonstrating a slowing in the rate of cognitive decline is a common outcome measure in clinical trials in Alzheimer's disease (AD). Selection of cognitive endpoints typically includes modeling candidate outcome measures in the many, richly phenotyped observational cohort studies available. An important part of choosing cognitive endpoints is a consideration of improvements in performance due to repeated cognitive testing (termed "practice effects"). As primary and secondary AD prevention trials are comprised predominantly of cognitively unimpaired participants, practice effects may be substantial and may have considerable impact on detecting cognitive change. The extent to which practice effects in AD prevention trials are similar to those from observational studies and how these potential differences impact trials is unknown. In the current study, we analyzed data from the recently completed DIAN-TU-001 clinical trial (TU) and the associated DIAN-Observational (OBS) study. Results indicated that asymptomatic mutation carriers in the TU exhibited persistent practice effects on several key outcomes spanning the entire trial duration. Critically, these practice related improvements were larger on certain tests in the TU relative to matched participants from the OBS study. Our results suggest that the magnitude of practice effects may not be captured by modeling potential endpoints in observational studies where assessments are typically less frequent and drug expectancy effects are absent. Using alternate instrument forms (represented in our study by computerized tasks) may partly mitigate practice effects in clinical trials but incorporating practice effects as outcomes may also be viable. Thus, investigators must carefully consider practice effects (either by minimizing them or modeling them directly) when designing cognitive endpoint AD prevention trials by utilizing trial data with similar assessment frequencies.

Informations de copyright

Copyright © 2022 Aschenbrenner, Hassenstab, Wang, Li, Xiong, McDade, Clifford, Salloway, Farlow, Yaari, Cheng, Holdridge, Mummery, Masters, Hsiung, Surti, Day, Weintraub, Honig, Galvin, Ringman, Brooks, Fox, Snyder, Suzuki, Shimada, Gräber and Bateman.

Déclaration de conflit d'intérêts

EC, KH, and RY are full-time employees and/or stockholders of Eli Lilly. RB has received funding from Avid Radiopharmaceuticals, Jansse, Hoffman La-Roche/Genentech, Eli LIlly & Co., Eisai, Biogen, AbbVie, and Bristol Meyer Squibbs, has royalties/licenses from C2N Diagnostics, consulting fees from Eisai, Amgen, and Hoffman La-Roche, honoraria from the Korean Dementia Association and the American Neurological Association, and is on the data safety monitoring board or advisory board for Roche/Genentech and Biogen. Unrelated to this article, RB serves as the principal investigator of the DIAN-TU, which is supported by the Alzheimer’s Association, GHR Foundation, an anonymous organization, and the DIAN-TU Pharma Consortium (Active: Eli Lilly and Company/Avid Radiopharmaceuticals, F. Hoffman-La Roche/Genentech, Biogen, Eisai, and Janssen. Previous: Abbvie, Amgen, AstraZeneca, Forum, Mithridion, Novartis, Pfizer, Sanofi, and United Neuroscience). In addition, in-kind support has been received from CogState and Signant Health. G-YH has received research support as a clinical trials site investigator from Anavax, Biogen, Eli Lilly, and Roche, has received research grants from the CIHR, Alzheimer Society of Canada, and NIA/NIH, is supported by the Ralph Fisher Professorship in dementia research from the Alzheimer Society of British Columbia, and has participated in expert advisory committees sponsored by Biogen and Roche. GD’s research is supported by NIH (K23AG064029), the Alzheimer’s Association, and Chan Zuckerberg Initiative, and he serves as a consultant for Parabon Nanolabs Inc., as a Topic Editor (Dementia) for DynaMed (EBSCO), and as the Clinical Director of the Anti-NMDA Receptor Encephalitis Foundation (Inc, Canada; uncompensated) and owns stock in ANI pharmaceuticals. DH, former Department Head of Neurology where the research was conducted, is an inventor on patents for one of the treatments (solanezumab), which has been tested in the DIAN-TU clinical trials. If solanezumab is approved as a treatment for Alzheimer’s disease or Dominantly Inherited Alzheimer’s Disease, Washington University, and will receive part of the net sales of solanezumab from Eli Lilly, which has licensed the patents related to solanezumab from Washington University. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.