Inverse correlation between Alzheimer's disease and cancer from the perspective of hypoxia.

Sporadic Alzheimer's disease and cancer remain epidemiologically inversely related, and exploring the reverse pathogenesis is important for our understanding of both. Cognitive dysfunctions in Alzheimer's disease (AD) might result from the depletion of adaptive reserves in the brain. Energy storage in the brain is limited and is dynamically regulated by neurovascular and neurometabolic coupling. The research on neurodegenerative diseases has been dominated by the neurocentric view that neuronal defects cause the diseases. However, the proposal of the 2-hit vascular hypothesis in AD led us to focus on alterations in the vasculature, especially hypoperfusion. Chronic hypoxia is a feature shared by AD and cancer. It is interesting how contradicting chronic hypoxia's effects on both cancer and AD are. In this article, we discuss the potential links between the 2 diseases' etiology, from comparable upstream circumstances to diametrically opposed downstream effects. We suggest opposing potential mechanisms, including upregulation and downregulation of hypoxia-inducible factor-1α, the Warburg and reverse-Warburg effects, lactate-mediated intracellular acidic and alkaline conditions, and VDAC1-mediated apoptosis and antiapoptosis, and search for regulators that may be identified as the crossroads between cancer and AD.