Translational investigation of apathy and affective symptom hub genes in Alzheimer’s disease

Abstract

AbstractBackgroundApproximately 90% of Alzheimer’s disease (AD) patients experience at least one neuropsychiatric symptom (NPS) over the course of disease progression. However, little is known about the neural mechanisms underlying NPS in AD, leaving treatment options for these symptoms underdeveloped. Here we use a translational approach to refine hub gene candidacy for the two most common NPS domains in AD (i.e., apathy, affective) and identify targets for investigation of causal relationships between genes and behavior.MethodWeighted gene co‐expression network analysis (WGCNA) was performed on RNA‐sequencing data from human postmortem anterior cingulate cortex of 60 individuals with AD and antemortem clinical evaluations of NPS. Human and mouse protein‐protein interaction networks (PPIs) were constructed from WGCNA modules that significantly correlated with NPS domains. Expression levels of potential hub genes discovered in humans were measured in the prefrontal cortex (PFC) of 16‐month‐old wild type (WT) and 5xFAD mice by RT‐qPCR and correlated with composite z‐scores for representative apathy‐ and affective‐like behaviors.ResultWGCNA revealed that a microglial phagocytic pathway and complement cascade module was uniquely correlated with apathy. PPI analyses refined the list of 43 WGCNA potential apathy hub genes to 21 candidate hub genes suitable for translational investigation. Further, human and mouse PPI analyses identified TYROBP as the highest‐ranking apathy hub gene. Expression levels of Tyrobp were significantly higher in the PFC of 5xFAD mice than in WT controls and positively correlated with apathy z‐scores. Only two genes retained affective domain hub gene candidacy (Tgfb1 and Nfkbia) in mice. Whereas Tgfb1 expression was elevated in the 5xFAD PFC, Nfkbia was not differentially expressed. Z‐scores for affective‐like behavior did not significantly correlate with either Tgfb1 or Nfkbia expression levels.ConclusionOur results suggest that the complement system is uniquely implicated in cases of AD with apathy; Tyrobp is a strong candidate gene for the regulation of that relationship. 5xFAD mice are an appropriate model for future investigation of Tyrobp‐complement‐apathy mechanisms in AD. Further study is needed to evaluate Tgfb1 and Nfkbia as possible regulators of affective behavior in models that exhibit other AD pathology(s) (e.g., tau) alone or in conjunction with pathologic amyloid‐beta.