Ceramide Links Alzheimer’s Disease to Decreased Cancer Risk: A Lipid Behind the Enigma of Inverse Comorbidity

For decades, epidemiologic studies have consistently reported an inverse comorbidity between Alzheimer’s disease (AD) and cancer: Individuals with AD are less likely to develop cancer and vice versa. The biological basis of this paradox has remained largely unresolved. A study by Kassir and colleagues in this issue of Cancer Research provides a compelling mechanistic insight into this paradox by demonstrating that amyloid precursor protein and its cleavage product Aβ40, known for their pathologic accumulation in the AD brain, also accumulate in peripheral T cells where they suppress mitochondrial ceramide production and lethal autophagy. This preservation of mitochondrial function enhances the antitumor immunity of T cells. Previous work has established that ceramide can promote neurodegeneration in the brain. The suppression of ceramide generation by amyloid precursor protein and Aβ40 in the periphery, thereby preserving mitochondrial integrity and supporting anticancer immunity, further establishes ceramide as a context-dependent regulator of cell fate and a key factor in the inverse AD–cancer relationship. See related article by Kassir et al., p. 3791