Sex‐specific transcriptome alterations in the cingulate cortex of Lewy body dementia cases

Abstract

AbstractBackgroundLewy body dementia (LBD) is one of the most common causes of dementia and is characterized by the deposition of extracellular amyloid plaques and intracellular accumulation of alpha‐synuclein in the form of Lewy bodies and neurites. Many of these individuals also have concomitant neuropathological changes such as vascular disease, tangles, and TDP‐43. Like in Alzheimer’s disease, APOE4 is the most significant genetic risk factor for the development of LBD. We sought to survey the landscape of transcriptional changes in the cingulate cortex from a large cohort of LBD cases (>400) compared to normal controls of both sexes.MethodWe performed bulk tissue RNAseq and aligned reads to a human reference genome that is informed on the sex chromosome complement of the sample. Differentially expressed genes were determined after genome‐wide correction.ResultWe found a core set of transcriptional changes that were shared between both sexes in pathways related to neuronal functions and inflammation. However, we also identified numerous changes in genetic female samples that were not significantly altered in genetic males, or that were significantly altered but in the opposite direction. Similar male‐specific changes were also found. These alterations were present for genes on both sex chromosomes as well as autosomes. Though cohort sizes were smaller, we also compared this dataset to Alzheimer’s disease and found shared but unique transcriptional alterations.ConclusionOverall, genetic males and females exhibit sex‐shared and sex‐specific gene expression patterns in dementia with Lewy bodies. We are currently assessing splice alterations, running causal gene network analysis, and performing histological validation.