Long non-coding RNAs (lncRNAs) have been reported to show differential expression in Alzheimer’s disease (AD), albeit with inconsistent results. In addition, only a few studies explored lncRNA expression in human brain samples. In this study, we performed differential gene expression (DGE) analyses on lncRNA expression data (derived from RNA sequencing [RNA-seq]) from a total of n=1,220 samples collected from three different human brain regions. These included 177 individuals drawn from the OPTIMA study (discovery data; n[AD cases] = 95, n[controls] = 82) collected from entorhinal cortex (EC). In addition, we analyzed independent RNA-seq data from the ROSMAP (dorsolateral prefrontal cortex; n[AD cases] = 436, n[controls] = 333]) and BANNER studies (fusiform gyrus; n[AD cases] = 206, n[controls] = 68). In the discovery dataset (EC), we identified 121 significantly differentially expressed lncRNAs after FDR correction. Meta-analysis with ROSMAP and BANNER data resulted in a total of 356 significantly differentially expressed lncRNAs, showing the same direction of effect in all three datasets. Besides replicating many AD-related lncRNAs, we also identified several dozen lncRNAs not previously linked to AD, including Lnc-TNFRSF13B-2, CSRP1-AS1, Lnc-MIB2-1, Lnc-TTC5-2, and GSN-AS1. GO annotation highlighted numerous relevant processes, including neuron development, synapse function, and axon development. To our knowledge, our study comprises the largest RNA-seq-based DGE analysis of the human brain and is the first to utilize EC samples, the site where progressive AD pathology originates. With its large number of novel AD-associated lncRNAs it provides a vastly extended reference for future work on this topic.

The authors have declared no competing interest.

This work was funded by the Deutsche Forschungsgemeinschaft (to L.B., grant ID number 391523883) and the Cure Alzheimer Fund (to L.B., as part of the CIRCUITS-AD project). Additional support was provided by the DFG Research Infrastructure NGS-CC (project 407495230) as part of the Next Generation Sequencing Competence Network (423957469). NGS analyses were carried out at the Competence Centre for Genomic Analysis (Kiel). The use of OPTIMA samples was made possible via the Oxford Brain Bank, supported by Brains for Dementia Research (BDR) (Alzheimer Society and Alzheimer Research UK) and the NIHR Oxford Biomedical Research Centre. C.M.L. was supported by the Heisenberg Program of the DFG (LI 2654/4-1).

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The generation and analysis of RNA-seq data was approved by the Ethics Committee of University of Luebeck under approval number #19-392A.

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All data produced in the present study are available upon reasonable request to the authors.