ARTICLE IN BRIEF
Scientists reported that the APOE4 transgenic animals subjected to cerebral hypoperfusion performed worse on behavioral tests compared to animals with two copies of the human version of APOE3. It is the first time that scientists have mounted evidence for the link between APOE4 and the white matter lesions common in vascular dementia, as well as Alzheimer's disease.
Scientists have been trying to figure out how the apolipoprotein E4 (APOE4) allele increases a person's risk for late-onset Alzheimer's disease (AD) since the seminal discovery in 1993. Recent data suggest that APOE4 also increases the risk of dementia caused by vascular factors.
Now, a team of scientists at Weill Cornell Medicine contend they have the answer, at least in animals: The human variant reduces the number of small cerebral blood vessels, and the blood vessels that remain are not as responsive to the demands on the brain. The result is that the brains of the animals are more vulnerable to damage.
In the current study, the scientists reported that the APOE4 transgenic animals subjected to cerebral hypoperfusion performed worse on behavioral tests compared to animals with two copies of the human version of APOE3.
It is the first time that scientists have mounted evidence for the link between APOE4 and the white matter lesions common in vascular dementia, as well as Alzheimer's disease. The study was published in the September 19 issue of Nature Communications.
There have been a lot of ideas why APOE4 confers its risk, but the imaging technology was not good enough to peer deep into the brain's tangle of blood vessels and the white matter's long nerve fibers to provide a high-resolution image, the study authors noted.
“The field will now understand more about how APOE4 links to both vascular dementia and AD,” said senior study author Costantino Iadecola, MD, the Anne Parrish Titzell professor of neurology and director and chair of the Feil Family Brain and Mind Research Institute. “The next step is to see if we can identify a particular cell type targeted by APOE4 that leads to these vascular changes.”
STUDY METHODS, FINDINGS
Two factors led the scientists to design the study: They had access to a 3-photon microscopy that offered a clear view of blood vessels and white matter tracks. There is growing evidence that people who are APOE4 positive have a higher incidence of white matter lesions, typical of small vessel disease. At the same time, there are also white matter lesions in people with AD. They thought that maybe APOE4 promotes white matter disease, and it was time to test their idea.
The researchers used knock-in mice that express the human APOE4 allele, and another transgenic model that expresses the APOE3 variant. The first thing they discovered was that blood flow in the APOE4 animals was reduced by 14 to 19 percent in the caudate nucleus and the somatosensory cortex compared to normal mice. (These areas are hard hit in vascular dementia.) This reduced blood flow was related to about 20 percent fewer small blood vessels. By contrast, the APOE3 mice had the same blood flow as the normal mice.
Normally, neural activity leads to an increase in blood flow. They observed that blood flow did not increase as much as it did in the APOE3 animals when they were exposed to a whisker stimulus.
Next, they wanted to know what would happen if they starved the brain of oxygen. They put coils around the carotid arteries and compared the blood flow in both groups of animals. Again, the APOE4 animals had a greater reduction in blood flow.
The APOE4 mice became more cognitively impaired. But why? They used the 3-photon microscopy to look at the white matter in the corpus callosum and found that the APOE4 mice had more white matter damage.
“It suggests that insufficient blood flow was exacerbated in these mice and the white matter was more susceptible to damage,” Dr. Iadecola said.
The researchers observed that reduced blood flow led to hypoxia, which led to white matter damage and cognitive impairment. “The pattern of brain damage looks like the pathology seen in human vascular dementia and in Alzheimer's,” said Dr. Iadecola.
Autopsy studies have shown that about 50 percent of AD cases have a combination of vascular and neurodegenerative pathology. “We now show that there is a vascular component of APOE4 that damages blood vessels,” Dr. Iadecola said.
The investigators still don't know how this happens. “Creating this state we saw that the APOE4 animals were more susceptible to white matter lesions, and that could explain the vascular dementia,” said Dr. Iadecola.
The scientists are now testing whether boosting APOE3 or APOE2 in animal models could reverse or stop white matter damage. (Scientists are using a viral vector to deliver the gene to the brain.)
“It would be great if we could modulate APOE status,” said Dr. Iadecola. “APOE does a lot of important things and we need to figure out how to replace it without causing problems. If we can attribute these changes to a particular cell we may be able to target that cell.”
The scientists are also testing a few other hypotheses: Among them, they think it is possible that the endothelial cells are not working properly in the APOE4 animals and such dysfunction could play a role. Furthermore, there are immune cells located around the blood vessels and it could be that these cells are involved in this process. They have preliminary evidence that APOE4 triggers certain immune cells in the brain to release superoxide and other highly reactive species. These potentially damaging molecules inhibit blood vessel development, and inhibit the ability of the vessels to increase blood flow as needed, said Dr. Iadecola.
“There is definitely a major role for APOE4 in cerebral amyloid angiopathy,” said Samuel E. Gandy, MD, PhD, professor of neurology and of psychiatry, Mount Sinai chair in Alzheimer's disease research, and director of the Mount Sinai Center for Cognitive Health and NFL Neurological Care. “The situation in humans is well described: APOE4 carriers begin depositing amyloid early (in the mid-40s) and they have substantially more cerebral amyloid angiopathy than do non-carriers.”
“The APOE protein in cerebral amyloid angiopathy probably comes from interstitial vascular smooth muscle cells. It is likely that the combination of amyloidosis and vessel wall degeneration aggravate each other,” Dr. Gandy explained.
“But a huge mystery lies in understanding how cerebrovascular atherosclerosis increases the risk for AD. Whatever underlies the link between atherosclerosis and AD will probably also explain why so many of the risk-reduction factors for AD (low cholesterol, low body mass, low blood sugar, controlled blood pressure, lots of exercise) are identical to what we know as good factors for heart health.”
“This is a great paper that shows a profound circulatory issue that can cause white matter and neuronal changes,” said Berislav Zlokovic, MD, PhD, director of the Center for Neurodegeneration and Regeneration at the Zilkha Neurogenetics Institute at the Keck School of Medicine at the University of Southern California in Los Angeles. “These white matter changes could be an early biomarker. On high-resolution scans, we can see a loss of structural connectedness and this could be caused by the effects of APOE4 on blood vessels.”
Dr. Zlokovic and his colleagues published earlier animal studies showing that the E4 allele directly damages blood vessels that feed the brain. They reported that the blood-brain barrier becomes leaky and toxic substances can get in the brain and damage brain cells. This process did not happen in animals with the E2 or E3 alleles.
“We should study white matter changes more carefully,” he added. “This finding helps move the field in a new direction that could ultimately help patients.”