The idea that study of rare genetic variants can highlight biological mechanisms of relevance is not new, indeed is widely accepted and acknowledged as providing valuable insights, as, e.g., the single-gene risk factors for dementia (APP, PSEN1, and 2), and the role of copy-number variants and de novo mutations of high penetrance in schizophrenia and autism spectrum disorder.58–60 The t(1;11) translocation, similarly, provides a clear-cut and useful biological model for major psychiatric disorder. This evidence concerns the gene APP and dementia.