Differential Expression of microRNA in Cerebrospinal Fluid as a Potential Novel Biomarker for Alzheimer’s Disease

Abstract

Background and Objective: The need to find a better reflection of Alzheimer’s disease (AD) pathophysiology led us to investigate differential expression of microRNA (miRNA) in cerebrospinal fluid (CSF) of AD patients compared to matched controls, using a genome-wide data-driven approach.

Methods: From the Amsterdam Dementia Cohort, we selected 19 AD patients with CSF indicative of AD pathophysiology and 19 age and gender-matched controls without CSF evidence of AD (67 ± 6 years old, 20 [53%] female). We measured 754 miRNA in CSF using qRT-PCR (Taqman Array MicroRNA cards A and B, v3.0) according to the Megaplex Taqman protocol. Hierarchical cluster analysis was performed and groups were compared using Linear Models for Microarray Data, a modified t-test. We performed validation analysis using qRT-PCR single assays.

Results: 144 ± 66 miRNA could be detected using Megaplex array analysis (19% ). Mean Ct (average 32.4 ± 0.5) was correlated to age (r = 0.52, p = 0.001). Five miRNA were differentially expressed in CSF of AD patients. None of these could be replicated. After stratification by age, seven miRNA showed differential expression in late-onset AD, of which lower abundance of let-7a was replicated (log10RQ −1.46, p <  0.05). In early-onset AD, twelve miRNA were differentially expressed of which lower abundance of miRNA-532-3p remained borderline significant (log10RQ −1.27, p = 0.05).

Conclusion: Although we could not consistently separate AD patients and controls in the whole group, we have found indications miRNA in CSF are able to reflect aging and perhaps also heterogeneity in AD. Further investigation requires optimizing RNA input, while maintaining strict age matching.