Altered Heme and Redox Homeostasis Underpin Late-onset Alzheimer's Disease

Early-onset Alzheimer's disease (EOAD) is associated with highly penetrant mutations in genes such as PSEN2, whereas the strongest genetic risk factor for late-onset Alzheimer's disease (LOAD) is the APOE4 allele. Despite intense research efforts, how neuronal dysfunction is initiated in LOAD cases and how the initiating events for EOAD and LOAD differ remain to be clarified. Using biochemical measurements of energy metabolism, heme and redox homeostasis, in combination with RNA-Sequencing analysis, we characterized biochemical and transcriptome differences in neurons differentiated from human EOAD and LOAD iPSC-derived neural stem cells, relative to their respective control neurons. Strikingly, we found that LOAD neurons, not EOAD neurons, are defective in heme and redox homeostasis. The levels of multiple proteins and enzymes involved in heme synthesis, degradation, and oxidative phosphorylation are preferentially decreased in LOAD neurons, not EOAD neurons. Likewise, heme transport is decreased in LOAD neurons. ROS generation is strongly increased in LOAD neurons, not EOAD neurons. Further, many genes involved in heme and redox homeostasis, as well as cellular energy generation, are downregulated in LOAD neurons, not EOAD neurons. Together, these results strongly suggest that altered heme and redox homeostasis in LOAD neurons underlie the initiation of neurological deficits.