Alzheimer’s disease, lung cancer, and brain cancer—all devastating, all leading public health challenges—have been thought to harbor connections at the molecular level, connections that could explain curious co-morbidities. Specifically, in cases of Alzheimer’s disease, the risk of developing lung cancer is decreased, and the risk of developing glioblastoma, a kind of brain tumor, is increased.

Once-hidden connections between Alzheimer’s disease, lung cancer, and glioblastoma are coming to light now that tissue samples from patients with these diseases are yielding more and more clues about gene expression. For example, in a study conducted by scientists based at the Spanish National Cancer Research Centre (CNIO), transcriptomic gene expression data was found to support the existence of molecular substrates that could at least partially account for the inverse co-morbidity between Alzheimer’s disease and lung cancer, and the direct co-morbidity between Alzheimer’s disease and glioblastoma.

Details appeared June 30 in the journal Scientific Reports, in an article entitled “A Molecular Hypothesis to Explain Direct and Inverse Co-Morbidities between Alzheimer’s Disease, Glioblastoma and Lung Cancer.” This article describes how the CNIO scientists undertook a “systemic meta-analysis of transcriptomic gene expression data” to compare the deregulated genes in each disease to each other. The scientists, the article noted, took care to use lung and brain control samples to detect basal tissue-associated gene expression, and thereby rule out confounding data.

“A functional analysis of the sets of deregulated genes points to the immune system, up-regulated in both Alzheimer’s disease and glioblastoma, as a potential link between these two diseases,” wrote the article’s author. “Mitochondrial metabolism is regulated oppositely in Alzheimer’s disease and lung cancer, indicating that it may be involved in the inverse co-morbidity between these diseases.”

The authors of the current paper emphasized that they intended to explain previously published findings that overexpressed genes in central nervous system diseases (Alzheimer's disease, Parkinson's disease, and schizophrenia) were underexpressed in cancer (lung, colon, and prostate), and vice versa. Understanding the molecular bases of these processes, the authors suggested, could provide valuable information regarding the study of the causes of each disease and the possible design of new therapeutic strategies (drug repositioning).

“The analysis of glioblastoma, which has a direct co-morbidity link with Alzheimer's and that, in addition, originates in the same organ, has allowed us to better understand the molecular co-morbidity between Alzheimer's disease and cancer, and eliminate tissue-dependent bias,” remarked Jon Sánchez-Valle, a researcher at CNIO’s Barcelona Supercomputing Center and the lead author of the paper.

The CNIO team analyzed more than 1000 samples from patients to identify 198 genes whose function is altered significantly in the three cases. Of these, 112 had a similar pattern in Alzheimer's disease and glioblastoma and the opposite pattern in lung cancer.

By comparing the biological processes altered through the deregulation of these genes, the CNIO scientists confirmed that mitochondrial dysfunction plays a key role in the development of Alzheimer's and could also lead to an increased risk of brain tumors in patients with Alzheimer's, through the emergence of chronic inflammation in the brain. The decrease in the energy supply and the generation of reactive oxygen species (ROS) due to alterations in the mitochondrial function would, in turn, be related to the protection against lung cancer in patients with Alzheimer's.

“These results,” wrote the authors of the current study, “could help to suggest drug repurposing and drug combination strategies in the future. Initial relevant examples could include combinations of proteasome and chaperone inhibitors, anti-oxidants and oxidative phosphorylation or TCA cycle [tricarboxylic acid or Krebs cycle] inhibitors for LC [lung cancer] treatment.”