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Which MCI Patients Should be Included in Prodromal Alzheimer Disease Clinical Trials?

Grill, Joshua D., PhD*,†,‡; Nuño, Michelle M., MSc*,§; Gillen, Daniel L., PhD*,§ for the Alzheimer’s Disease Neuroimaging Initiative

Alzheimer Disease & Associated Disorders: April-June 2019 - Volume 33 - Issue 2 - p 104–112
doi: 10.1097/WAD.0000000000000303
Original Articles
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Background: Prodromal Alzheimer disease (AD) clinical trials enroll patients with mild cognitive impairment (MCI) meeting biomarker criteria, but specific enrollment criteria vary among trials.

Methods: We used data from AD Neuroimaging Initiative (ADNI) MCI participants to assess AD biomarker eligibility, variation in trial outcome measures, and statistical power.

Results: Most (65%) participants meet eligibility criteria based on low cerebrospinal fluid amyloid beta (Aβ). Relative to trials enrolling exclusively based on low cerebrospinal fluid Aβ, trials including participants with a high ratio of phosphorylated tau to Aβ would include an additional 15% of participants. Fewer (34% to 62%) participants met criteria for Aβ and tau. Differences in clinical and demographic characteristics of modeled trial samples were minimal. Those with low Aβ and high tau showed the greatest change over time on outcome measures.

Conclusions: Eligibility rates for prodromal trials vary depending on the specific biomarker criteria, though differences in demographics and the variation associated with outcome measures are minimal. Broadening inclusion criteria beyond amyloid alone may facilitate recruitment but include patients showing slower progression over time. Biomarker criteria selection should be informed by the goal of enrolling individuals most likely to utilize and benefit from the intervention under investigation in a particular setting.

*Institute for Memory Impairments and Neurological Disorders

Department of Psychiatry and Human Behavior

Department of Neurobiology and Behavior

§Department of Statistics, University of California, Irvine, Irvine, CA

Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf.

J.D.G., M.M.N., and D.L.G.: designed and performed the study. J.D.G.: drafted the manuscript. All authors contributed in an editorial capacity to the writing of the manuscript and approved the final version.

J.D.G. and D.L.G. were supported by NIA AG016573, 1R21AG056931, AG059407, and UC Cures Alzheimer’s BRD-16-501350. J.D.G. is currently supported by UL1 TR000153. M.M.N. supported by the National Science Foundation Graduate Research Fellowship (grant No. DGE-1321846).

Any opinions, findings, and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of the National Science Foundation.

Data collection and sharing for this project was funded by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012).

ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co. Inc.; Meso Scale Diagnostics LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health http://(www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California.

J.D.G.: received research funding from Biogen Idec, Eli Lilly & Company, Genentech, the Alzheimer’s Disease Cooperative Study, and the Alzheimer’s Therapeutic Research Institute. He has consulted for CogniCiti. The remaining authors declare no conflicts of interest.

Reprints: Joshua D. Grill, PhD, University of California Irvine, 3204 Biological Sciences III, Irvine, CA 92697-4545 (e-mail: jgrill@uci.edu).

Received November 16, 2018

Accepted February 19, 2019

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