Advances in stem cell engineering, omics technologies and data sciences offer a unique scope for deciphering the myriad ways molecular circuits dysfunction in pathologies of the brain. Recently, we have developed and explored iPSC-derived neurons from familial Alzheimer’s disease patients using a systems-level, multi-omics approach, identifying disease-related endotypes, which are commonly dysregulated in patient-derived neurons and patient brain tissue alike. By integrating RNA-Seq, ATAC-Seq, and ChIP-Seq approaches, we determined that the defining disease-causing mechanism of AD is de-differentiation of neurons, driven primarily through the REST-mediated repression of neuronal lineage specification gene programs and the activation of cell cycle reentry and non-specific germ layer precursor gene programs concomitant with modifications in chromatin accessibility. Strikingly, our reanalysis of previously-generated AD-patient brain tissue showed similar enrichment of neuronal repression and de-differentiation mechanisms. Surprisingly, our earlier work on glioblastoma also showed de-differentiation and initiation of some of the shared diseased endotypes as common features. We postulate that de-differentiation and reprogramming are hallmark mechanisms of numerous pathologies, arguably genetically evolved to serve as protection mechanisms.