Does depression in Alzheimer's disease show evidence of differential gene expression in neurons or microglia compared to Alzheimer's disease without depression?

Abstract

Background: Depression in Alzheimer's disease (AD) is common, distressing, difficult to treat and inadequately understood.

Objective: We compared gene expression in neurons and microglia from AD patients +/- depression, stratified according to depression polygenic risk score (PRS-D) and looked for differential pathway regulation.

Methods: We identified AD patients with (n = 95) or without depression (n = 25) whose brains had been donated to a UK brain bank. Exclusion criteria included other disorders known to affect cognition, previous major psychiatric disorder and a neuropathological diagnosis of a non-AD dementia. Depression was defined as a clinical depression diagnosis or Geriatric Depression Scale/Center for Epidemiologic Studies Depression Scale >7. PRS-D was calculated using LDpred2. In the AD + depression group, only the top (n = 29) and bottom tertile (n = 30) of PRS-D were analyzed by microarray. Tissue from superior frontal gyrus (SFG) and anterior insula (AIns) was sorted into neuronal and microglial fractions, and gene expression measured using a ClariomS Pico microarray.

Results: After quality control, microarray data were available for AIns microglia (n = 51), AIns neurons (n = 59), SFG microglia (n = 60) and SFG neurons (n = 63). No individual genes had a p < 0.05, adjusted for false discovery rate. Gene set enrichment analysis identified significantly upregulated and downregulated pathways in both brain regions and cell types. More pathways were differentially expressed in microglia than in neurons. Many of these pathways related to infection or inflammation but also included olfactory transduction and Parkinson's disease.

Conclusions: In conclusion we have identified pathways that may contribute to the development of depression in AD. A majority were identified predominantly in microglia.