Abstract
Objective To evaluate the safety and efficacy of low-dose naproxen for prevention of progression in presymptomatic Alzheimer disease (AD) among cognitively intact persons at risk.
Methods Investigation of Naproxen Treatment Effects in Pre-symptomatic Alzheimer's Disease (INTREPAD), a 2-year double-masked pharmaco-prevention trial, enrolled 195 AD family history–positive elderly (mean age 63 years) participants screened carefully to exclude cognitive disorder (NCT-02702817). These were randomized 1:1 to naproxen sodium 220 mg twice daily or placebo. Multimodal imaging, neurosensory, cognitive, and (in ∼50%) CSF biomarker evaluations were performed at baseline, 3, 12, and 24 months. A modified intent-to-treat analysis considered 160 participants who remained on-treatment through their first follow-up examination. The primary outcome was rate of change in a multimodal composite presymptomatic Alzheimer Progression Score (APS).
Results Naproxen-treated individuals showed a clear excess of adverse events. Among treatment groups combined, the APS increased by 0.102 points/year (SE 0.014; p < 10−12), but rate of change showed little difference by treatment assignment (0.019 points/year). The treatment-related rate ratio of 1.16 (95% confidence interval 0.64–1.96) suggested that naproxen does not reduce the rate of APS progression by more than 36%. Secondary analyses revealed no notable treatment effects on individual CSF, cognitive, or neurosensory biomarker indicators of progressive presymptomatic AD.
Conclusions In cognitively intact individuals at risk, sustained treatment with naproxen sodium 220 mg twice daily increases frequency of adverse health effects but does not reduce apparent progression of presymptomatic AD.
Classification of evidence This study provides Class I evidence that, for people who are cognitively intact, low-dose naproxen does not significantly reduce progression of a composite indicator of presymptomatic AD.
Glossary
- AD=
- Alzheimer disease;
- AE=
- adverse event;
- APS=
- Alzheimer Progression Score;
- CI=
- confidence interval;
- INTREPAD=
- Investigation of Naproxen Treatment Effects in Pre-symptomatic Alzheimer's Disease;
- ITT=
- intent-to-treat;
- LP=
- lumbar puncture;
- MCI=
- mild cognitive impairment;
- mITT=
- modified intent-to-treat;
- MoCA=
- Montreal Cognitive Assessment;
- NSAID=
- nonsteroidal anti-inflammatory drug;
- p-tau=
- phosphorylated tau;
- PREVENT-AD=
- Pre-symptomatic Evaluation of Novel or Experimental Treatments for Alzheimer's Disease;
- RBANS=
- Repeatable Battery for Assessment of Neuropsychological Status;
- SAE=
- serious adverse event;
- t-tau=
- total tau;
- UPSIT=
- University of Pennsylvania Smell Identification Test
Footnotes
↵* These authors contributed equally to this work.
↵† These authors contributed equally to the direction and supervision of this work.
Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
Data used in preparation of this article were obtained from the program of 49 PRe-symptomatic EValuation of Novel or Experimental Treatments for 50 Alzheimer's Disease (PREVENT-AD) at the Centre for Studies on Prevention of 51 Alzheimer's Disease (StoP-AD), Douglas Mental Health University Institute 52 Research Center Archive 53 4.0 (June 27, 2017). The authors and coinvestigators thank all the members of the PREVENT-AD Research Group who made contributions to the study.
The Article Processing Charge was funded by the Fonds de Recherche du Québec-Santé.
Editorial, page 829
Patient Page, page e2181
- Received June 1, 2018.
- Accepted in final form January 7, 2019.
- Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
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