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

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BackgroundDepression in Alzheimer's disease (AD) is common, distressing, difficult to treat and inadequately understood.ObjectiveWe 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.MethodsWe 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.ResultsAfter 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 ConclusionsIn conclusion we have identified pathways that may contribute to the development of depression in AD. A majority were identified predominantly in microglia.

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