In agreement, cortical neurons differentiated from FAD PS1 mutant (F105C and A246E) iPSCs displayed mitochondrial defects and AD-related phenotypes, both of which were mitigated by APP knockout.<h4>Conclusions</h4>These findings provide critical insights into the bridging role of APP in FAD PS1 mutant-mediated mitochondrial dysfunction, advancing our understanding of the cellular mechanisms underlying AD. Here, PSEN1 is linked to Alzheimer disease.