Performance of Validated MicroRNA Biomarkers for Alzheimer’s Disease in Mild Cognitive Impairment

Article type: Research Article

Authors: Sandau, Ursula S.^{a; 1} | Wiedrick, Jack T.^{b; 1} | Smith, Sierra J.^a | McFarland, Trevor J.^a | Lusardi, Theresa A.^c | Lind, Babett^d | Harrington, Christina A.^e | Lapidus, Jodi A.^{b; f} | Galasko, Douglas R.^g | Quinn, Joseph F.^{h; i} | Saugstad, Julie A.^{a; *}

Affiliations: [a] Department of Anesthesiology & Perioperative Medicine, Oregon Health & Science University, Portland, OR, USA | [b] Biostatistics & Design Program, Oregon Health & Science University, Portland, OR, USA | [c] Knight Cancer Institute Cancer Early Detection Advanced Research Center, Oregon Health & Science University, Portland, OR, USA | [d] Department of Neurology, Layton Aging and Alzheimer’s Center, Oregon Health & Science University, Portland, OR, USA | [e] Integrated Genomics Laboratory, Oregon Health & Science University, Portland, OR, USA | [f] Oregon Health & Science University– Portland State University School of Public Health, Portland, OR, USA | [g] Department of Neurosciences, University of California San Diego, La Jolla, CA, USA | [h] Parkinson Center and Movement Disorders Program, School of Medicine, Oregon Health & Science University, Portland, OR, USA | [i] Portland VAMC Parkinson’s Disease Research, Education, and Clinical Center, Portland, OR, USA

Correspondence: [*] Correspondence to: Dr. Julie A. Saugstad, Department of Anesthesiology & Perioperative Medicine, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, L459 Portland, OR 97239-3098, USA. Tel.: +1 503 494 4926; Fax: +1 503 494 3092; E-mail: [email protected].

Note: [1] These authors contributed equally to this work.

Abstract: Background:Cerebrospinal fluid (CSF) microRNA (miRNA) biomarkers of Alzheimer’s disease (AD) have been identified, but have not been evaluated in prodromal AD, including mild cognitive impairment (MCI). Objective:To assess whether a set of validated AD miRNA biomarkers in CSF are also sensitive to early-stage pathology as exemplified by MCI diagnosis. Methods:We measured the expression of 17 miRNA biomarkers for AD in CSF samples from AD, MCI, and cognitively normal controls (NC). We then examined classification performance of the miRNAs individually and in combination. For each miRNA, we assessed median expression in each diagnostic group and classified markers as trending linearly, nonlinearly, or lacking any trend across the three groups. For trending miRNAs, we assessed multimarker classification performance alone and in combination with apolipoprotein E ɛ4 allele (APOE ɛ4) genotype and amyloid-β42 to total tau ratio (Aβ42:T-Tau). We identified predicted targets of trending miRNAs using pathway analysis. Results:Five miRNAs showed a linear trend of decreasing median expression across the ordered diagnoses (control to MCI to AD). The trending miRNAs jointly predicted AD with area under the curve (AUC) of 0.770, and MCI with AUC of 0.705. Aβ42:T-Tau alone predicted MCI with AUC of 0.758 and the AUC improved to 0.813 (p = 0.051) after adding the trending miRNAs. Multivariate correlation of the five trending miRNAs with Aβ42:T-Tau was weak. Conclusion:Selected miRNAs combined with Aβ42:T-Tau improved classification performance (relative to protein biomarkers alone) for MCI, despite a weak correlation with Aβ42:T-Tau. Together these data suggest that that these miRNAs carry novel information relevant to AD, even at the MCI stage. Preliminary target prediction analysis suggests novel roles for these biomarkers.

Keywords: Alzheimer’s disease, amyloid, APOE ɛ4, biomarkers, cerebrospinal fluid, microRNA, mild cognitive impairment, tau proteins

DOI: 10.3233/JAD-200396

Journal: Journal of Alzheimer's Disease, vol. 78, no. 1, pp. 245-263, 2020