The reviewed data suggest that the downregulation of GPR109A, caused by genetic (e.g., in schizophrenia) [16] and/or environmental factors (e.g., obesity in AD) [35], disinhibits cPLA2, an enzyme that triggers the degradation of myelin and, consequently, contributes to cognitive impairment in schizophrenia and aging-associated MCI and AD (Figure 1). This evidence concerns the gene HCAR2 and obesity due to melanocortin 4 receptor deficiency.