Examining the genetic relationship between Alzheimer’s disease, schizophrenia and their shared risk factors using genomic structural equation modelling

Epidemiological studies have demonstrated an association between dementia and schizophrenia. There is a significant symptom overlap between the two disorders-psychosis is seen in 50% of patients with Alzheimer's disease and cognitive impairment is a key feature of schizophrenia. Whether these overlapping clinical presentations reflect shared aetiology is unclear. Therefore, we aimed to model the genetic correlation between Alzheimer's disease, schizophrenia and their shared risk factors using genomic structural equation modelling to identify potentially overlapping biological pathways between these traits. We measured genetic correlation between Alzheimer's disease, schizophrenia and 13 shared risk factors, including body fat percentage, less education, alcohol intake, insomnia, loneliness, less social/leisure activity, major depression, mean arterial pressure, smoking, socioeconomic deprivation, low-density lipoprotein cholesterol, eye problems and type 2 diabetes mellitus. Schizophrenia and Alzheimer's disease were not significantly genetically correlated but were both significantly associated with loneliness. Colocalization suggested that the association between loneliness and Alzheimer's disease was predominantly driven by a shared causal variant on Chromosome 11. Factor analysis of shared risk factors produced four latent factors representing clusters of shared genetics between socioeconomic traits, psychiatric traits, cardiometabolic traits and smoking-related traits. Both Alzheimer's disease and schizophrenia were significantly associated with the socioeconomic latent factor. Although there is little direct genetic overlap between schizophrenia and Alzheimer's disease, loneliness may play an important role in the association between these two disorders. In addition, the shared genetics between socioeconomic traits may affect susceptibility to both Alzheimer's disease and schizophrenia to a greater extent than trait-specific pathways.