Posterior cingulate cortex reveals an expression profile of resilience in cognitively intact elders Christy M. Kelley, 1,2, * Stephen D. Ginsberg, 3,4,5,6 Winnie S. Liang, 7 Scott E. Counts 8,9 and Elliott J. Mufson 1,2 * Current affiliations: The Institute for Future Health, Scottsdale, AZ 85257, USA and Arizona State University, Tempe, AZ 85281, USA The posterior cingulate cortex, a key hub of the default mode network, underlies autobiographical memory retrieval and displays hypometabolic changes early in Alzheimer disease. To obtain an unbiased understanding of the molecular pathobiology of the aged posterior cingulate cortex, we performed RNA sequencing (RNA-seq) on tissue obtained from 26 participants of the Rush Religious Orders Study (11 males/15 females; aged 76–96 years) with a pre-mortem clinical diagnosis of no cognitive impairment and post-mortem neurofibrillary tangle Braak Stages I/II, III, and IV. Transcriptomic data were gathered using next-generation se- quencing of RNA extracted from posterior cingulate cortex generating an average of 60 million paired reads per subject. Normalized expression of RNA-seq data was calculated using a global gene annotation and a microRNA profile. Differential expres- sion (DESeq2, edgeR) using Braak staging as the comparison structure isolated genes for dimensional scaling, associative network building and functional clustering. Curated genes were correlated with the Mini-Mental State Examination and semantic, working and episodic memory, visuospatial ability, and a composite Global Cognitive Score. Regulatory mechanisms were determined by co-expression networks with microRNAs and an overlap of transcription factor binding sites. Analysis revealed 750 genes and 12 microRNAs significantly differentially expressed between Braak Stages I/II and III/IV and an associated six groups of transcription factor binding sites. Inputting significantly different gene/network data into a functional annotation clustering model revealed ele- vated presynaptic, postsynaptic and ATP-related expression in Braak Stages III and IV compared with Stages I/II, suggesting these pathways are integral for cognitive resilience seen in unimpaired elderly subjects. Principal component analysis and Kruskal– Wallis testing did not associate Braak stage with cognitive function. However, Spearman correlations between genes and cognitive test scores followed by network analysis revealed upregulation of classes of synaptic genes positively associated with performance on the visuospatial perceptual orientation domain. Upregulation of key synaptic genes suggests a role for these transcripts and asso- ciated synaptic pathways in cognitive resilience seen in elders despite Alzheimer disease pathology and dementia. 1 Department of Translational Neuroscience, Barrow Neurological Institute, St. Joseph’s Hospital and Medical Center, Phoenix, AZ 85013, USA 2 Department of Neurology, Barrow Neurological Institute, St. Joseph’s Hospital and Medical Center, Phoenix, AZ 85013, USA 3 Center for Dementia Research, Nathan Kline Institute, Orangeburg, NY 10962, USA 4 Department of Psychiatry, New York University Grossman School of Medicine, New York, NY 10016, USA 5 Department of Neuroscience & Physiology, New York University Grossman School of Medicine, New York, NY 10016, USA 6 NYU Neuroscience Institute, New York University Grossman School of Medicine, New York, NY 10016, USA 7 Translational Genomics Research Institute, Phoenix, AZ 85004, USA 8 Department of Translational Neuroscience, Michigan State University College of Human Medicine, Grand Rapids, MI 49503, USA 9 Department of Family Medicine, Michigan State University College of Human Medicine, Grand Rapids, MI 49503, USA Received February 26, 2022. Revised May 12, 2022. Accepted June 17, 2022. Advance access publication June 21, 2022 © The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. B BR AIN COMMUNICATIONS AIN COMMUNICATIONS https://doi.org/10.1093/braincomms/fcac162 BRAIN COMMUNICATIONS 2022: Page 1 of 18 | 1 Downloaded from https://academic.oup.com/braincomms/article/4/4/fcac162/6612699 by guest on 24 December 2023