Signatures of disrupted synaptic maintenance in the entorhinal cortex of both pathology‐free APOE4 carriers and aged APOE4 mice: Molecular and cell biology/synaptic disruption

Background The greatest genetic risk factor for late‐onset Alzheimer’s disease (AD) is the possession of the apolipoprotein E4 ( APOE4 ) variant. Yet the mechanism by which APOE4 increases AD susceptibility is unclear. The entorhinal cortex (EC) is one of the first region of the brain to succumb to AD pathology, and previous studies in our lab have revealed unique APOE4 ‐assocated effects on the regulation of important biological processes in the EC of aged APOE4 mice. In this study, we further elucidated APOE4 ‐associated vulnerability in the EC by investigating such alterations in AD pathology‐free brain tissues from human APOE4 carriers. Method Using both confirmed pathology‐free human brain tissue genotyped for APOE status and brain tissue from aged APOE targeted replacement mice, we investigated the effects of APOE4 expression in the EC using a combination of transcriptomic analysis, immunohistochemistry and biochemical assays. Result Differentially expressed genes present in both human and mouse samples revealed APOE4 ‐associated alteration of transcripts in the EC related to both the maintenance and the structural integrity of synapses. Follow up studies have elucidated the ways in which the alterations of these transcripts affects synapse integrity and causes dysregulation of vital biological processes in the EC. Additional studies are currently underway to understand how such pathway dysregulations are related to one another and how they are instrumental in the AD pathology that accumulates early on in the EC. Conclusion Our studies reveal novel insights into the ways in which APOE4 expression may increase AD risk by revealing region‐specific alterations in vital biological processes present in both humans and mice that possess the APOE4 allele. We believe that these results will point to novel ways in which AD can be slowed or prevented, especially among APOE4 carriers.