Link Found Between Vascular Disease and Alzheimer’s Disease

The gene FMNL2 may affect risk of both cerebrovascular disease and Alzheimer’s, according to a new study. Mutations in this gene appear to prevent the efficient clearance of toxic proteins that lead to Alzheimer’s disease (AD). This finding could suggest a way to prevent AD in people with hypertension, diabetes, obesity, or heart disease.

The study was led by researchers at Columbia University’s Vagelos College of Physicians and Surgeons.

It has long been known that people with hypertension, diabetes, high cholesterol, or obesity have a higher likelihood of developing Alzheimer’s disease (AD).

“Not only do we have a gene, but we have a potential mechanism,” says Richard Mayeux, MD, senior author of the paper and chair of neurology at Columbia and New York-Presbyterian/Columbia University Irving Medical Center. “People have been trying to figure this out for a couple of decades, and I think we have our foot in the door now. We feel there must be other genes involved and that we’ve just scratched the surface.”

Mayeux and his colleagues found FMNL2 during a genome-wide hunt to uncover genes associated with both vascular risk factors and Alzheimer’s disease. The search involved five groups of patients representing different ethnic groups.

Although FMNL2, stood out during the analysis, its specific role was unclear. Caghan Kizil, PhD, a visiting associate professor, then addressed the question using zebrafish as a model organism for AD.

“We had this gene, FMNL2, that was lying at the interface between Alzheimer’s disease in the brain and cerebrovascular risk factors,” says Kizil. “So, we had an idea that FMNL2 might operate in the blood-brain barrier, where brain cells meet the vasculature.”

The blood-brain barrier is a semi-permeable, highly controlled border between capillaries and brain tissue that serves as a defense against disease-causing pathogens and toxins in the blood. Astrocytes, a specialized type of brain cell, form a protective sheath around the blood vessel. This sheath needs to loosen for the clearance of amyloid—the aggregates of proteins that accumulate in the brain and lead to AD.

The zebrafish model confirmed the presence of FMNL2 in the astrocyte sheath, which retracted its grip on the blood vessel once toxic proteins were injected into the brain, presumably to allow for clearance. When Kizil and his colleagues blocked the function of FMNL2, this retraction did not occur, preventing clearance of amyloid from the brain. The same process was then confirmed using transgenic mice with Alzheimer’s.

This process may also occur in the human brain. The researchers studied postmortem human brains and found increased expression of FMNL2 in people with AD, along with breach of the blood-brain barrier and retraction of the astrocytes.

Based on these findings, the researchers propose that FMNL2 opens the blood-brain-barrier by controlling its astrocytes, and that this promotes the clearance of extracellular aggregates from the brain. Cerebrovascular disease, by interacting with FMNL2, reduces amyloid clearance in the brain.

The team is currently in the process of investigating other genes that could be involved in the interplay between AD and cerebrovascular disease, which, along with FMNL2, could provide future approaches for drug development.