The dual presence of a gene, ApoE4, has been known to increase risk of Alzheimer’s disease nearly tenfold — a significant wrinkle in disease research that scientists have been hard-pressed to explain since its discovery. Whereas previous attempts to understand the ties between ApoE4 and Alzheimer’s disease have been mostly futile, a new study conducted by scientific experts from Rochester University and the University of Southern California may have finally ironed-out the details.
"We are beginning to understand much more about how ApoE4 may be contributing to Alzheimer's disease," said Robert Bell, PhD, from Rochester University and lead author of the study.
Bell’s study, financed by the Alzheimer’s Association and The Jeffrey Epstein VI Foundation among others, found that ApoE4 has the capacity to release an excess amount of protein cyclophilin A into the cardiovascular system, which incites inflammation in conditions such as atherosclerosis. Researchers also deemed the accumulation of protein cyclophilin A within pericyte cells helping to maintain the blood-brain barrier — a happenstance that reduces blood to the brain, thus allowing toxic substances to pervade — as more likely when ApoE4 is present.
"In the presence of ApoE4, increased cyclophilin A causes a breakdown of cells lining the blood vessels in the brain in the same way as found in cardiovascular disease or abdominal aneurysm. This establishes a new vascular target to fight Alzheimer's disease," Bell said.
Mice carrying the ApoE4 gene were surveyed by researchers and found to have five times as much cyclophilin A in their pericyte cells; the presence of cyclophilin A also instigated an increase in the inflammatory molecule NF Kappa B, which served to raise levels of matrix metalloproteinases molecules (MMP), resulting at last in the mice’s blood vessels dying. Those mice with ApoE4 present did not have as complete of a blood flow through the brain compared to their uninhibited counterparts and therein, injurious substances like thrombin, fibrin and hemosiderin were invited to enter the brain tissue. When researchers removed ApoE4 from test subjects’ systems via the use of cyclosporine A as an inhibitor, the brain damage was inverted — blood flow reverted to normalcy and toxin levels were reduced by 80 percent.
Up to this point, amyloid beta protein has been the primary malefactor in the brains of patients diagnosed with Alzheimer’s disease. The new study promotes the theory of a strong vascular origin as well, a facet important for physicians and medical professionals to consider when treating those with the disease. "Our study has shown major neuronal injury resulting from vascular defects that are not related to amyloid beta," said Berislav Zlokovic, MD, PhD, an adjunct professor at Rochester and director of the Center for Neurodegeneration and Regeneration and professor. “It's very important to investigate other leads, perhaps where amyloid beta isn't as centrally involved," he added.
Jeffrey Epstein, namesake and leader of The Jeffrey Epstein VI Foundation — an organization involved in the study’s funding — noted the importance of genetic research to the prevention of and possible cure for Alzheimer’s disease: "This cyclophilin A, genetic link is crucial," he said. "It will allow scientists to chemically inhibit vascular disease in conjunction with genetic therapy. But it will also help scientists concentrate on other protein inducing genes as possible offenders."