APOE4 impairs oxidative phosphorylation and cholesterol metabolism in Alzheimer’s Disease

Alzheimer’s disease (AD) is strongly associated with mitochondrial dysfunction, especially in the presence of the APOE4 allele. Here I review recent research on the connection between APOE4 and impairment of mitochondrial oxidative phosphorylation (OXPHOS). In APOE4 carriers, decreased basal respiration rates suggest reduced mitochondrial respiration, and studies have reported downregulation of mitochondrial proteins critical for OXPHOS function. Furthermore, cytotoxic APOE4 fragments in neurons inhibit OXPHOS by decreasing mitochondrial membrane potential. In addition, APOE4-induced cholesterol accumulation in astrocytes and oligodendrocytes correlates with mitochondrial OXPHOS impairment. Lastly, I highlight the potential of statins, which are known to lower cholesterol levels, as a therapeutic treatment. Given the crucial role of mitochondrial dysfunction in AD pathology, a better understanding of how APOE4 affects mitochondrial OXPHOS would aid in the development of new strategies to slow down AD progression.