Alzheimer's Disease-Related Mutations in APP Influence Colorectal Tumor Formation in a Sex-Dependent Manner

Cancer and Alzheimer's disease (AD) are major age-associated diseases. Numerous studies have indicated common mechanisms and biological interactions between these conditions. Furthermore, epidemiological data demonstrate negative correlations between several cancers and AD. Despite this, few studies have explored their mutual influence on pathological outcomes. In this study, we utilized a human APP mutant knock-in AD mouse model to investigate how familial mutations influence colorectal cancer development. Using a colitis-associated colorectal cancer model, APP mutations promoted colon tumor formation in male mice but inhibited it in female mice. Correspondingly, inflammatory changes were reduced in the colons of female mice. Transcriptome analysis revealed differential expression, particularly in the enrichment of neuronal marker, steroid hormone, and immune cell signaling pathways. Additionally, distinct macrophage subtypes and neuronal profiles were observed in the colons of male and female APP mutant mice. These findings provide the first elucidation of the sex-dependent effects of APP mutations on colon cancer formation. Overall design: To understand why AOM/DSS treatment resulted in differential phenotypic outcomes in an APP mutant background at the molecular level, we conducted RNA-seq using colon cancer tissues, adjacent normal colon tissues, or normal colon tissues when tumors were not formed