Exploring the co-morbid relationship between Alzheimer's disease and lung cancer in the 5xFAD transgenic mouse model.

Abstract

Background: Alzheimer's disease (AD) and lung cancer are leading causes of mortality among the older population. Epidemiological evidence suggests an antagonistic relationship between them, whereby patients with AD exhibit a reduced risk of developing cancer and vice versa. However, the precise mechanism by which AD antagonizes lung cancer progression warrants further elucidation.

Methods: To this end, we established a co-morbidity model using 5xFAD transgenic mice induced with the carcinogen urethane. We visualized and quantified surface lung tumor colonies, assessed pathological parameters associated with lung cancer and AD using histopathological analysis, and employed single-cell sequencing and molecular pathological analyses to explore the mechanisms by which AD confers resistance to lung cancer.

Results: Our findings revealed a significant reduction in lung tumor incidence in the AD group compared with that in the wild-type (WT) group. The results indicated a close association between AD-induced inhibition of lung tumor progression and iron homeostasis imbalance and increased oxidative stress. Moreover, greater CD8⁺ T cytotoxic lymphocyte and effector natural killer cell infiltration in the lung tumor tissues of AD mice and enhanced CD8⁺ T cytotoxic lymphocyte-mediated killing of target cells may be the primary factors contributing to the inhibition of lung tumor growth in the presence of AD.

Conclusion: This study identified essential mechanisms through which AD suppresses lung tumorigenesis, thereby providing targets for potential therapeutic interventions in these diseases.