For objective 1, we found that insulin resistance-related somatic diseases and traits are linked to brain-based disorders and to cognitive performance. Based on population registry data and large-scale genetic data, we showed that the breadth of this multimorbidity is even larger than anticipated at the start of the PRIME project, additionally including attention deficit/hyperactivity disorder, major depressive disorder, anorexia nervosa, and schizophrenia. Longitudinal data revealed that T2D, insulin-related and inflammation-related markers all associate with cognitive decline.
For objective 2, we performed (epi)genetic analyses and showed that genetic variants related to insulin and immunity are associated with insulin multimorbidity. Furthermore, we generated KCNQ1 knockout induced pluripotent stem cell (iPSC)-based lines to investigate KCNQ1 function in human neurons, showing that knockout of KCNQ1 leads to less neurite outgrowth and differences in immune-related mechanisms, insulin signalling, and mitochondrial function. Employing mouse models, we showed differences in cognition and behaviour in experimental models characterised by alterations in insulin signalling. In the brains of these animals, we found differences in proteins related to the immune system. Lastly, we showed that a mouse model centered around impaired immune activation (also) exhibits both altered insulin signaling and impairments in cognition.
For objective 3, we investigated the role of KCNQ1 across human, cell, and animal data. In the human data, we confirmed the association with T2D, but found no associations with psychiatric disorders or cognition. With the animal work, we found links between KCNQ1 and metabolism and cognition. In the cell models, we showed that KCNQ1 is essential for brain cell growth. We also identified KCNQ1-modulating compounds that could be promising treatments.
For objective 4, we integrated genetic data in a molecular landscaping approach, and linked genetic data to potential immune-related and antidiabetic drug targets. Using animal and cell models we showed that metformin, a drug frequently used in T2D, normalises the biological pathways dysregulated in T2D and improves cognition.
For objective 5, we worked on designing a multimorbidity subtyping algorithm and tested it on different data sets. While we found some predictors, their influence was not as strong and stable as we initially hoped for.
For objective 6, we used the mHealth APP in order to study cognitive performance in real time. Our results indicate that diet and physical activity both can have positive influences on cognition and are promising for preventive strategies.
For objective 7, our results showed that repurposing of insulin signalling-targeted drugs for the treatment of mental phenotypes is effective in human and animal data.
For objective 8, we have conducted a systematic review of existing guidelines and then systematically compiled all clinically relevant findings from PRIME. The insights gained from this were synthesized into a white paper. This document has been made available to guideline committees and policymakers, providing a valuable foundation for future clinical recommendations.
For objective 9, PRIME early career researchers have been trained in different aspects of interdisciplinary knowledge through webinars, masterclasses, a mentoring program, and site visits. In addition, we prepared an e-learning course for clinicians about the co-occurrence of cardiometabolic and mental diseases, which is available online and free of charge.
