Although there is a strong association between common mutations of the ApoE gene and the risk of developing late-onset Alzheimer’s disease, researchers have not known what role this gene plays in the disease until now.
Of the three varieties of ApoE – ApoE2, ApoE3 and ApoE4, the team found that in mice, ApoE4 damages the blood vessels that provide nutrients to the brain.

The ApoE gene encodes a protein that helps regulate the levels and distribution of cholesterol and other lipids in the body. Researchers believe that ApoE2 helps protect against cardiovascular disease and Alzheimer’s, ApoE3 is neutral and that ApoE4 confers a higher risk for both conditions.

The study, funded by the National Institutes of Health and published in the journal Nature, was conduced by Berislav Zlokovic, M.D., Ph.D., director of the Center for Neurodegeneration and Regeneration at the Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles.

Dr. Zlokovic explained:

“Understanding the role of ApoE4 in Alzheimer’s disease may be one of the most important avenues to a new therapy. Our study shows that ApoE4 triggers a cascade of events that damages the brain’s vascular system.”

Normally mice only have a single version of ApoE. However, the researchers examined genetically engineered mice, including three lines that produce only human ApoE2, ApoE3 or ApoE4 and one line that lacks the ApoE gene.

They discovered that mice with the ApoE4 version or mice that produced no ApoE at all, had a leaky blood-brain barrier allowing harmful proteins to enter the mice’s brains.

After several weeks, the team discovered that the mice had loss of small blood vessels, loss of connections between brain cells and alterations in brain function.

Roderick Corriveau, Ph.D., a program director of NIH’s National Institute of Neurological Disorders and Stroke (NINDS), which helped fund the study, explained:

“The study demonstrates that damage to the brain’s vascular system may play a key role in Alzheimer’s disease, and highlights growing recognition of potential links between stroke and Alzheimer’s-type dementia. It also suggests that we might be able to decrease the risk of Alzheimer’s disease among ApoE4 carriers by improving their vascular health.”

The team also discovered that unlike ApoE4, ApoE2 and ApoE3 help controlling levels of cyclophilin A (CypA), an inflammatory molecule.

They noted that in blood vessels of mice that produce only ApoE4, CypA levels were about five times higher. The excess CypA led to an activation of the MMP-9 enzyme, which destroys protein components of the blood-brain barrier. Cyclosporine A therapy, an immunosuppressant that blocks CypA, maintained the blood-brain barrier and reduced brain damage. According to earlier studies, the MMP-9 inhibitor had similar beneficial effects, decreasing brain damage after stroke in animal models.

Suzana Petanceska, Ph.D., a program director at NIH’s National Institute on Aging (NIA), which also funded the study, said:

“These findings point to cyclophilin A as a potential new drug target for Alzheimer’s disease.

Many population studies have shown an association between vascular risk factors in mid-life, such as high blood pressure and diabetes, and the risk for Alzheimer’s in late-life. We need more research aimed at deepening our understanding of the mechanisms involved and to test whether treatments that reduce vascular risk factors may be helpful against Alzheimer’s.”

In the United States more than 5 million older adults are affected by Alzheimer’s disease. Beta-amyloid is a hallmark of the disease and is a toxic protein fragment that accumulates in clumps, or plaques, within the brain. Gene mutations that result in increased levels of beta-amyloid are linked with a rare type of Alzheimer’s that occurs between the age of 30 and 60.

According to the researchers, the ApoE4 gene variant is the most strongly associated to late-onset of Alzheimer’s. People who inherit one copy of ApoE4 are three times more likely to develop Alzheimer’s and people who inherit two copies, one from each parent, are 12 times more likely to develop the disease.

The researchers highlight that although beta-amyloid is known to accumulate in and damage blood vessels that cause bleeding into the brain, ApoE4 can destroy the vascular system independently of beta-amyloid. According to Dr. Zlokovic, this damage makes it more challenging to remove beta-amyloid from the brain. Some investigational therapies focus on destroying amyloid plaques, but therapies designed to compensate for ApoE4 might help prevent the plaques from forming, he said.

Written By Grace Rattue