Comprehensive analysis of genetic risk loci uncovers novel candidate genes and pathways in the comorbidity between depression and Alzheimer’s disease

There is growing evidence of a shared pathogenesis between Alzheimer’s disease and depression. Therefore, we aimed to further investigate their shared disease mechanisms. We made use of publicly available brain-specific eQTL data and gene co-expression networks of previously reported genetic loci associated with these highly comorbid disorders. No direct genetic overlap was observed between Alzheimer’s disease and depression in our dataset, but we did detect six shared brain-specific eQTL genes: SRA1, MICA, PCDHA7, PCDHA8, PCDHA10 and PCDHA13. Several pathways were identified as shared between Alzheimer’s disease and depression by conducting clustering pathway analysis on hippocampal co-expressed genes; synaptic signaling and organization, myelination, development, and the immune system. This study highlights trans-synaptic signaling and synaptoimmunology in the hippocampus as main shared pathomechanisms of Alzheimer’s disease and depression.