Identifying gene expression signatures in individuals with minimal cognitive impairment in the presence of advanced Alzheimer's disease pathology

Abstract

AbstractBackgroundThe pathological hallmarks of Alzheimer’s disease such as amyloid plaques and neurofibrillary tau tangles are usually associated with the primary clinical manifestation of cognitive decline. Recent studies implicate that a subset of “resistant” individuals have high burden of AD pathology, yet do not exhibit dementia (cognitive decline). Here, we compared the publicly available gene expression profiles of these resilient individuals and susceptible individuals (showing both AD pathology and cognitive decline) in dorsolateral prefrontal cortex (DLPFC) brain tissue obtained from individuals enrolled in the Religious Orders Study (ROS) or the Rush Memory and Aging Project (MAP).MethodWe conducted bulk RNA‐Seq analysis on data from the DLPFC of 239 individuals with differing AD pathological findings and clinical consensus diagnosis. This data set is available through the Synapse portal (AMP‐AD consortium). The patients were subdivided into four groups of control, weakly resilient, strongly resilient, and susceptible, according to their degree of pathology (Braak stage) and clinical cognitive diagnosis. The control group included individuals with no cognitive impairment and initial braak stages; 0 and 1. The weakly and strongly resilient groups included individuals with no and mild cognitive impairment with advanced Braak stages respectively, while the susceptible group comprised individuals with AD‐dementia and advanced tauopathy (Braak stage>4). We used DESeq2 between these groups with a multiple factor approach that corrected for sex and age of death.ResultOur findings provide insight into genes that may be attributable to weak or strong resilience in the presence of relatively advanced AD pathology. Some of these candidate genes, such as SERPINA5 and GIPR, have previously been associated AD pathology and other neurodegenerative diseases, but we also identified a set of less well‐characterized genes that may be involved in cognition specific contributions to AD resilience.ConclusionOur study recapitulates genes with known associations with AD pathology, and also identifies new candidate genes and pathways worth pursuing further as potential therapeutic targets to mitigate cognitive decline associated with AD. As ongoing proteomics and snRNA‐seq data is generated, these candidates may be further refined through an integrative approach, yielding new insights into pathways involved in AD pathology‐mediated decline and cognitive resilience.