Epidemiological studies have reported that people with solid cancers, such as prostate cancer (PC), are less likely to develop Alzhmeimer's disease (AD) and vice versa. These studies have demonstrated that this inverse association is not wholly explained by survival or diagnosis bias, suggesting an underlying biological cause, with dysfunction in opposing directions, leading to the different pathological presentations observed in cancers and AD. Apolipoprotein E (ApoE) is a multifunctional protein involved with lipoprotein production, amyloid-B regulation and immune responses. It is well reported that the APOE gene is the strongest genetic risk for AD. Research also suggests ApoE interacts with several molecular pathways connected to tumourigenesis such as PI3K/Akt and Wnt signalling. Despite these findings, little is currently understood about the role of ApoE in cancers. This study, therefore, aims to investigate the role of ApoE in PC.

Human PC cell lines LNCaP, PC3, DU145, VCaP, 22Rv1, P4E6 and non-tumorigenic human prostate epithelial cell lines PNT2 and BPH1 were maintained and used for a maximum of ten passages. Expression of APOE mRNA was measured using quantitative real-time PCR and ApoE protein levels were analysed using western blotting with an ApoE antibody at 1:1000. We have induced increased ApoE expression in PC cells using LXR-agonist, RGX-104. To further investigate the inverse correlation between PC and AD, bioinformatic analyses were performed, using open access genome wide association summary statistics and TCGA RNAseq data.

The results suggest APOE mRNA expression is downregulated in both androgen sensitive and castration resistant PC compared to normal prostate epithelial cells. Additionally, PC3 and LNCaP cells displayed the lowest ApoE protein expression amongst those tested. Furthermore, with LNCaP cells, DHT-induced cell proliferation was associated with a reduction in APOE mRNA expression. Preliminary data also suggests increased ApoE expression may reduce growth of PC in LNCaP cells. The bioinformatic analyses suggest a shared causal variant between PC and AD linked to the immune system, with this immune marker positively correlating with ApoE expression, suggesting immune system interaction.

Initial findings suggest that ApoE may play a role in PC tumourigenesis and metastasis, potentially through its interaction with the immune system. These findings may help us better interpret the inverse association between cancer and AD, which could provide better understanding and novel drug targets for both diseases.

Thank you to the Heather Corrie impact fund and University of Bristol for funding this research.