Researchers are making headway in explaining why people who carry the ApoE4 genetic variant, the largest genetic risk factor for Alzheimer’s, are more likely to suffer from damaged blood-brain barriers.
It was never clear to researchers whether the ApoE4 gene was responsible for the early malfunction of the blood-brain barrier, a protective barrier shielding the brain from toxins or pathogens, or whether it worked together with the proteins beta-amyloid and tau.
Now, scientists have found that the genetic variant may stimulate certain proteins in an inflammatory pathway, driving the blood-brain barrier to break down, regardless of the levels beta-amyloid and tau present in the brain.
Scientists have also pinpointed how ApoE4 may trigger the accumulation of beta-amyloid proteins along blood vessels — influencing a condition known as cerebral amyloid angiopathy.
“Researchers have overlooked vascular dysfunctions,” said Axel Montagne, Associate Professor of Research Physiology & Neuroscience at University of Southern California. “But in recent years — with the advancement of new imaging tools and discovery of other biomarkers — researchers realize that vascular functions are tightly linked to Alzheimer’s.”
Nearly half of dementia cases are triggered, in part, by vascular disease which reduces blood supply to neurons in the brain. And lowering your risk of heart disease and stroke can help prevent dementia. As the saying goes: What’s good for the heart is good for the brain.
The blood-brain barrier is crucial as its endothelial cells are wedged closely together, forming the inner linings of the blood vessels and allowing only certain molecules and gases to flow into brain tissue. Meanwhile, Montagne said cells like pericytes and astrocytes wrap along the surface of the blood vessels, upholding integrity of the blood-brain barrier.
In one of the recent studies, published in Nature, scientists examined the blood-brain barriers of participants who were either cognitively normal or displayed early symptoms of Alzheimer’s. The participants, aged 45 and older, underwent a battery of blood and cerebrospinal fluid tests, brain scans and imaging for the harmful proteins.
After accounting for variables such as lifestyle, demographics, and the presence of beta-amyloid and tau, the researchers found that carriers of ApoE4 with cognitive impairment had greater damage in their blood-brain barriers than ApoE3 carriers with cognitive impairment.
In fact, even healthy participants who carried the ApoE4 genetic variant had greater blood-brain barrier dysfunctions compared to healthy participants without ApoE4.
“People who have ApoE4 genes that are expressed in pericytes will have a cascade of molecular events that will release two proteins — cyclophilin A and MMP9 for matrix metalloproteinase-9,” Montagne said, who is an author of the study.
“Those two molecules will destroy the tight junctions between endothelial cells … You will see a physical gap between endothelial cells that will [become] a breach for blood to leak inside the brain.”
The team’s findings bolster growing evidence that vascular dysfunctions are linked with Alzheimer’s. Higher blood pressure — especially at an earlier age — increases risk of dementia later on. More than 90 percent of people with Alzheimer’s have cerebral amyloid angiopathy.
While researchers have known that ApoE4 is the strongest risk factor for the condition, the cellular and molecular links were unclear.
In a study published Monday, researchers sought to answer the question by developing lab models of the human blood-brain barrier.
“It turned out that the pericytes from the ApoE4 cells drastically increased their expression level of ApoE,” said Li-Huei Tsai, Picower Professor of Neuroscience and Director of the Picower Institute For Learning and Memory at MIT.
The scientists then identified a pathway that elevated ApoE expression, triggering more beta-amyloid to accumulate.
“The reason why knowing the pathway is important is because we already have FDA-approved small molecules that can inhibit this pathway,” Tsai said.
One of the FDA-approved drugs that the team tested is currently used to prevent organs from shrinking after transplants. And Tsai pointed to an intriguing finding from past studies: “There are known publications following those individuals who received organ transplant under medication with this drug,” Tsai said. “These people turned out to have a much reduced incident of developing dementia.”
Meanwhile, the researchers found that the drug reduced the levels of ApoE proteins and the buildup of beta-amyloid after administering it in mice and blood-brain barrier models.
A better understanding of the relationship between ApoE4 and the breakdown of a person’s blood-brain barrier is critical to scientists’ ability to identify and engineer ways to prevent, mitigate, and cure that damage. Clinical trials to heal the blood-brain barrier are already underway.
Montagne and his team are testing various medications to treat impaired barriers in animal studies. Researchers are also conducting a clinical trial on a drug for stroke patients to heal their blood-brain barriers. And a clinical trial of ultrasound treatment is underway to disrupt the blood-brain barrier in the regions of the brain affected by Alzheimer’s, such as the hippocampus.