PROJECT SUMMARY Alzheimer’s disease (AD) is a debilitating form of dementia, and a leading cause of death in the United States. Dominant pathogenesis models postulate that initiating factor are either the aberrant processing of the Alzheimer’s precursor protein (APP), which leads to the accumulation of amyloid peptide toxic species in brain or the expression of an Alzheimer’s disease associated allele, APOE4. In these models, mitochondria respond to the toxicity of amyloid peptides or APOE4 rather than mitochondria driving pathogenesis. Here we explore a novel mitochondrial mechanism initiated by genetic defects in copper delivery mechanisms to the mitochondria (ATP7A, SLC31A1, COX17), the inner mitochondrial membrane mitochondrial citrate transporter SLC25A1 and its interacting protein, NDUFS3. The latter a gene associated to a genetic risk loci in Alzheimer’s disease. We found that the main defect downstream of mutations in these genes that end affecting mitochondria is an upregulation of cholesterol synthesis pathways, cholesterol, and the expression of APOE. These findings have profound implications as they suggest that upregulation of cholesterol and APOE, key risks factor for Alzheimer’s disease, are initiated by a genetic defect affecting mitochondria. Our model challenges the current canonical view that mitochondrial dysfunction is a terminal link in a chain of events ending in synapse dysfunction and Alzheimer’s disease. We envision our mitochondria-driven pathogenesis model as a powerful addition rather than a replacement of the current paradigm of amyloid peptide- or APOE4-driven Alzheimer’s pathogenesis. We posit that the mitochondrion acting as initiator of pathology is an important concept because it argues that disease would unravel in a positive feed-forward circle integrating amyloid peptides, APOE4, cholesterol, and mitochondria. We will test this hypothesis with mouse mutants that impair copper delivery to mitochondria and stablished animal models of Alzheimer’s disease with clinical and genetic validity.