Exploring the relationship between Alzheimer's disease and colorectal/breast cancers using SEER database, Mendelian randomization, and transcriptomic data.

[BACKGROUND] Alzheimer's disease (AD) and cancer are among the most prevalent age-related diseases. Despite previous research into their potential relationship, the nature of their association remains poorly understood. This study aims to examine the clinical characteristics of AD and various cancers using data from the Surveillance, Epidemiology, and End Results (SEER) database, investigate the causal relationship between AD and cancers through Mendelian randomization (MR) analysis, and identify potential shared underlying mechanisms through transcriptomic profiling.

[METHODS] Clinical data from AD patients were retrieved from the Surveillance, Epidemiology, and End Results (SEER) database, and survival analysis was conducted using Kaplan-Meier curves. For the two-sample Mendelian randomization (MR) analysis, data were obtained from genome-wide association study (GWAS) databases. Multiple MR approaches, including inverse-variance weighted, MR-Egger, and weighted median methods, were applied, along with assessments of heterogeneity and sensitivity to ensure the robustness and reliability of the results. Transcriptomic data for AD, colorectal cancer (CRC), and breast cancer (BC) were downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified through differential expression analysis, followed by functional enrichment analysis using Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis.

[RESULTS] A total of 42,768 cancer patients who died from AD were included from the SEER database. Survival analysis revealed a more favorable prognosis (p < 0.01) in patients younger than 65 years. Asian or Pacific Islander patients exhibited better survival outcomes compared with White patients. Regarding tumor sites, patients with uterine corpus cancer had the best prognosis, while lung cancer patients had the poorest outcomes. Patients who received surgery, radiotherapy, or chemotherapy showed significantly improved survival compared to those who received no cancer treatment. Higher household income and being married were also associated with better prognosis, although no significant difference was observed by gender. MR analysis demonstrated a significant positive causal relationship between AD and CRC, and a weak inverse relationship between AD and BC, suggesting that increased genetic susceptibility to AD is associated with elevated CRC risk and reduced BC risk. Intersection analysis of DEGs revealed that shared DEGs between AD and BC were enriched in GO terms related to amino acid transport regulation, organic acid transport regulation, positive regulation of vesicle docking, and myo-inositol transmembrane import. Shared DEGs between AD and CRC were enriched in presynaptic actin cytoskeleton organization, proteasome ubiquitin-independent protein catabolic process, negative regulation of cellular amide metabolic process, and adenylate cyclase binding. KEGG enrichment analysis indicated that AD and BC may share the synaptic vesicle cycle pathway.

[CONCLUSION] Our study reveals significant subgroup heterogeneity among cancer patients who died from AD. MR analysis demonstrates that AD increases the risk of CRC while showing weak evidence for a decreased risk of BC. These associations may be mediated by mechanisms involving amino acid transport regulation, myo-inositol transmembrane import, and synaptic vesicle cycling. These findings offer new perspectives on the AD-cancer relationship and may guide future investigations into shared mechanisms.