5-Lipoxygenase (ALOX5) and FLAP (ALOX5AP) gene polymorphisms as factors in vascular pathology and Alzheimer's disease.

We first hypothesized in 2000 that a polymorphism of the human gene encoding the enzyme 5-lipoxygenase (5-LOX) might be associated with Alzheimer's disease. Only a little progress has been made in directly testing our proposal. However, additional important new data lead us to hypothesize that genetic variability not only in the 5-LOX gene, i.e., ALOX5, but also in polymorphism of the five-lipoxygenase activating protein (FLAP) gene, i.e., ALOX5AP, may be associated with Alzheimer's pathology. Studies in mice followed by several extensive clinical studies have identified ALOX5 and ALOX5AP polymorphisms as strong risk factors for atherosclerosis and cerebrovascular pathologies. New data point to a significant aggregation of vascular risk factors and risk of Alzheimer's disease. Preliminary findings in postmortem brain of Alzheimer's patients identified elevated 5-LOX immunostaining in this disease. We suggest that our hypothesis of a link between the ALOX5 and ALOX5AP gene polymorphisms and Alzheimer's disease could be tested in a clinical setting and in animal models, i.e., transgenic mice could be produced by crossing the available 5-LOX-deficient mice with the available transgenic mice models of Alzheimer's disease.