An atlas of cortical circular RNA expression in Alzheimer disease brains demonstrates clinical and pathological associations

We generated parietal cortex RNA-seq data from individuals with and without Alzheimer disease (AD; n(control) = 13; n(AD) = 83) from the Knight-ADRC. Using this and an independent (MSBB) AD RNA-seq dataset, we quantified cortical circular RNA (circRNA) expression in the context of AD. We identified significant associations between circRNA expression and AD diagnosis, clinical dementia severity, and neuropathological severity. We demonstrated that a majority of circRNA AD-associations are independent from changes in cognate linear mRNA expression or brain cell-type proportions. We provided evidence for circRNA expression changes occurring early in pre-symptomatic AD, and in autosomal dominant AD. We also observed AD-associated circRNAs co-expressing with known AD genes. Finally, we identified potential microRNA binding sites in AD-associated circRNAs for microRNAs predicted to target AD genes. Together, these results highlight the importance of analyzing non-linear RNAs and support future studies exploring the potential roles of circRNAs in AD pathogenesis.