Exploring small non-coding RNAs as blood-based biomarkers to predict Alzheimer’s disease

Alzheimer’s disease (AD) diagnosis relies on clinical symptoms complemented with biological biomarkers, the Amyloid Tau Neurodegeneration (ATN) framework. Small non-coding RNA (sncRNA) in the blood have emerged as potential predictors of AD. We identified sncRNA signatures specific to ATN and AD, and evaluated both their contribution to improving AD conversion prediction beyond ATN alone. This nested case–control study was conducted within the ACE cohort and included MCI patients matched by sex. Patients free of type 2 diabetes underwent cerebrospinal fluid (CSF) and plasma collection and were followed-up for a median of 2.45-years. Plasma sncRNAs were profiled using small RNA-sequencing. Conditional logistic and Cox regression analyses with elastic net penalties were performed to identify sncRNA signatures for A+(T|N)+ and AD. Weighted scores were computed using cross-validation, and the association of these scores with AD risk was assessed using multivariable Cox regression models. Gene ontology (GO) and Kyoto encyclopaedia of genes and genomes (KEGG) enrichment analysis of the identified signatures were performed. The study sample consisted of 192 patients, including 96 A+(T|N)+ and 96 A-T-N- patients. We constructed a classification model based on a 6-miRNAs signature for ATN. The model could classify MCI patients into A-T-N- and A+(T|N)+ groups with an area under the curve of 0.7335 (95% CI, 0.7327 to 0.7342). However, the addition of the model to conventional risk factors did not improve the prediction of AD beyond the conventional model plus ATN status (C-statistic: 0.805 [95% CI, 0.758 to 0.852] compared to 0.829 [95% CI, 0.786, 0.872]). The AD-related 15-sncRNAs signature exhibited better predictive performance than the conventional model plus ATN status (C-statistic: 0.849 [95% CI, 0.808 to 0.890]). When ATN was included in this model, the prediction further improved to 0.875 (95% CI, 0.840 to 0.910). The miRNA-target interaction network and functional analysis, including GO and KEGG pathway enrichment analysis, suggested that the miRNAs in both signatures are involved in neuronal pathways associated with AD. The AD-related sncRNA signature holds promise in predicting AD conversion, providing insights into early AD development and potential targets for prevention.