Validation of MicroRNA Biomarkers for Alzheimer’s Disease in Human Cerebrospinal Fluid

Article type: Research Article

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

Affiliations: [a] Biostatistics & Design Program, Oregon Health & Science University, Portland, OR, USA | [b] Department of Anesthesiology & Perioperative Medicine, Oregon Health & Science University, Portland, OR, USA | [c] Cancer Early Detection Advanced Research Center, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA | [d] Integrated Genomics Laboratory, Oregon Health & Science University, Portland, OR, USA | [e] Department of Neurology, Layton Aging and Alzheimer’s Center, 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, CA, USA | [h] Portland Veterans Affairs Medical 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: saugstad@ohsu.edu.

Abstract: We previously discovered microRNAs (miRNAs) in cerebrospinal fluid (CSF) that differentiate Alzheimer’s disease (AD) patients from Controls. Here we examined the performance of 37 candidate AD miRNA biomarkers in a new and independent cohort of CSF from 47 AD patients and 71 Controls on custom TaqMan arrays. We employed a consensus ranking approach to provide an overall priority score for each miRNA, then used multimarker models to assess the relative contributions of the top-ranking miRNAs to differentiate AD from Controls. We assessed classification performance of the top-ranking miRNAs when combined with apolipoprotein E4 (APOE4) genotype status or CSF amyloid-β42 (Aβ42):total tau (T-tau) measures. We also assessed whether miRNAs that ranked higher as AD markers correlate with Mini-Mental State Examination (MMSE) scores. We show that of 37 miRNAs brought forth from the discovery study, 26 miRNAs remained viable as candidate biomarkers for AD in the validation study. We found that combinations of 6–7 miRNAs work better to identify AD than subsets of fewer miRNAs. Of 26 miRNAs that contribute most to the multimarker models, 14 have higher potential than the others to predict AD. Addition of these 14 miRNAs to APOE4 status or CSF Aβ42:T-tau measures significantly improved classification performance for AD. We further show that individual miRNAs that ranked higher as AD markers correlate more strongly with changes in MMSE scores. Our studies validate that a set of CSF miRNAs serve as biomarkers for AD, and support their advancement toward development as biomarkers in the clinical setting.

Keywords: Alzheimer’s disease, amyloid-β₄₂ , apolipoprotein E, biomarkers, cerebrospinal fluid, microRNA, Mini-Mental State Examination, total tau

DOI: 10.3233/JAD-180539

Journal: Journal of Alzheimer's Disease, vol. 67, no. 3, pp. 875-891, 2019