APOE4 ACCELERATES NEURODEGENERATION AND EXACERBATES ALZHEIMER’S DISEASE RELATED PATHOLOGY IN CEREBRAL ORGANOIDS

Abstract

APOE4 is the strongest genetic risk factor for late-onset Alzheimer's disease (AD) compared to the common APOE3 allele. The cerebral organoids derived from human induced pluripotent stem cells (iPSCs) have been shown to be a novel model system closely resembling the physiological condition of human brains. To understand how human apoE isoforms differentially impact neuron viability and AD-related pathologies, we developed iPSC lines with different APOE genotypes from individuals with either normal cognition or sporadic AD and further into cerebral organoids. We found that cerebral organoids from AD patients with APOE ε4/4 genotype showed accelerated differentiation pattern and had enhanced neuronal apoptosis in the ventricular zone-like area at day 90 when compared to those from normal controls or AD with the APOE ε3/3 genotype. Cerebral organoids from AD patients also had increased AD-related pathologies including the levels of Aβ40, Aβ42, and phosphorylation tau. More interestingly, we found that apoE4 exacerbates tau pathology in a disease status-independent manner. Transcriptomic analysis by RNA-sequencing revealed an enrichment of apoptosis pathway in cerebral organoids from AD patients with the APOE ε4/4 genotype. Together, our results using the cerebral organoids suggest that apoE4 accelerates neurodegeneration in addition to impacting AD-related pathology in a human-relevant model system. Both the cerebral organoid model system and the information on apoE4-relevant disease pathways should help the development of new therapeutics for AD.