5-Lipoxygenase gene polymorphism and onset of Alzheimer's disease

Recently, inflammatory pathways have been recognized as possible pathophysiological mechanisms of aging-associated neurodegenerations, and slowing of the progression of Alzheimer's disease can be achieved with anti-inflammatory drugs. The formation of endogenous inflammatory lipid mediators, leukotrienes, is initiated by 5-lipoxygenase (5-LOX), which is also expressed in neurons. We recently reported that aging is associated with a significant increase in neuronal 5-LOX gene expression and with increased, 5-LOX inhibitor-sensitive, vulnerability of neurons to degeneration. On the basis of these findings we have proposed that the 5-LOX pathway may influence the progression of aging-associated diseases, such as Alzheimer's. In humans, mutations of the promoter of the 5-LOX gene occur in a normal population with a frequency of about 25%. These mutations result in a decreased expression of the 5-LOX gene. Thus, it is hypothesized here that the onset of Alzheimer's disease will be delayed in subjects who display a mutation in the 5-LOX gene promoter, and that consequently the frequency of occurrence of the three known 5-LOX mutated alleles will be greater in subjects with onset of Alzheimer's at a very old age than in subjects with an earlier onset.