A Precision Medicine Model for Targeted NSAID Therapy in Alzheimer’s Disease

Article type: Research Article

Authors: O’Bryant, Sid E. ^{a; *} | Zhang, Fan^b | Johnson, Leigh A. ^a | Hall, James^a | Edwards, Melissa^c | Grammas, Paula^d | Oh, Esther^{e; f} | Lyketsos, Constantine G. ^f | Rissman, Robert A. ^{g; h}

Affiliations: [a] Department of Pharmacology & Neuroscience; Institute for Healthy Aging, University of North Texas Health Science Center, Fort Worth, TX, USA | [b] Vermont Genetics Network, University of Vermont, VT, USA | [c] University of Texas MD Anderson Cancer Center, TX, USA | [d] George & Anne Ryan Institute for Neuroscience, University of Rhode Island, RI, USA | [e] Department of Medicine, Johns Hopkins University, Baltimore, MD, USA | [f] Department of Psychiatry, Johns Hopkins University, Baltimore, MD, USA | [g] Department of Neurosciences, UCSD School of Medicine, La Jolla, CA, USA | [h] VA San Diego Healthcare System, San Diego, CA, USA

Correspondence: [*] Correspondence to: Sid E. O’Bryant, PhD, University of North Texas Health Science Center, Department of Pharmacology & Neuroscience, 3500 Camp Bowie Blvd, Fort Worth, TX 76107, USA. Tel.: +1 817 735 2961; Fax: +1 817 735 0628; E-mail: Sid.OBryant@unthsc.edu.

Abstract: Background: To date, the therapeutic paradigm for Alzheimer’s disease (AD) has focused on a single intervention for all patients. However, a large literature in oncology supports the therapeutic benefits of a precision medicine approach to therapy. Here we test a precision-medicine approach to AD therapy. Objective:To determine if a baseline, blood-based proteomic companion diagnostic predicts response to NSAID therapy. Methods:Proteomic assays of plasma from a multicenter, randomized, double-blind, placebo-controlled, parallel group trial, with 1-year exposure to rofecoxib (25 mg once daily), naproxen (220 mg twice-daily) or placebo. Results: 474 participants with mild-to-moderate AD were screened with 351 enrolled into the trial. Using support vector machine (SVM) analyses, 89% of the subjects randomized to either NSAID treatment arms were correctly classified using a general NSAID companion diagnostic. Drug-specific companion diagnostics yielded 98% theragnostic accuracy in the rofecoxib arm and 97% accuracy in the naproxen arm. Conclusion:Inflammatory-based companion diagnostics have significant potential to identify select patients with AD who have a high likelihood of responding to NSAID therapy. This work provides empirical support for a precision medicine model approach to treating AD.

Keywords: Alzheimer’s disease, bioinformatics, biomarkers, clinical trial, inflammation, precision medicine, proteomics

DOI: 10.3233/JAD-180619

Journal: Journal of Alzheimer's Disease, vol. 66, no. 1, pp. 97-104, 2018