Does Vessel Dysfunction Drive Alzheimer's Disease?

by Crystal Phend for MedPage Today:

Traditionally, there was neurodegenerative dementia and there was vascular dementia. But it might not be so simple, as research is fleshing out a role of the vasculature in both.

Costantino Iadecola, MD, and the team he directs at the Cornell Brain and Mind Research Institute in New York City have been delving into the mechanisms linking Alzheimer's disease and vascular dysfunction through mouse models and basic science. Iadecola spoke with MedPage Today for an overview of those discoveries and what it means for clinical practice.

What follows is an edited version of that conversation.

What has changed in our understanding of dementia?

"Dementia was thought to be either on a vascular basis, like vascular dementia, or Alzheimer's disease, which was called neurodegenerative dementia. The two diseases were thought to be completely distinct, until in the '90s or so epidemiological data started to show that people with Alzheimer's disease also had vascular risk factors, so hypertension and diabetes and obesity, each can double the risk of Alzheimer's disease. That led to the idea that perhaps Alzheimer's is not such a pure neurodegenerative disease and vascular risk factors may play a role."

"The famous Nun Study showed that people who had a little bit of Alzheimer's pathology at autopsy that normally would not be sufficient to cause dementia, if these people also had small ischemic lesions in basal ganglia, which by themselves wouldn't do anything bad, the dementia would be much, much worse. So that spurred a series of investigations, including basic science studies that I have been involved in, in which it was shown that amyloid beta has profound vascular effects. So it looks like you have a double whammy in which amyloid on one hand destroys neurons and makes them dysfunctional at first in time also affects blood vessels, leading to ischemia essentially. So the two things together make it much worse."

How does the amyloid that we're familiar with forming damaging plaques in the brain have an impact on blood vessels?

"Our studies suggest that a-beta -- not necessarily amyloid (amyloid is the stuff made by many a-beta molecules) -- even soluble a-beta is able to bind to receptors on the wall of cerebral blood vessels called CD-36, which is an innate immunity receptor. And this receptor is linked to a free-radical-producing enzyme called NADPH oxidase. When it is activated, a-beta leads to a surge of free radicals, and these free radicals then damage DNA in endothelial vascular cells. It leads to activation of... a DNA repair enzyme that then leads to... a lot of calcium getting into cells and essentially poisons the cells so endothelial cells cannot work well anymore."

"There are two forms of amyloid. One is parenchymal amyloid, the so-called neuritic plaques that you're most familiar with, and there is also vascular amyloid, or cerebral amyloid angiopathy (CAA).

"In the case of CAA, the amyloid travels to the blood vessel and sets itself around the blood vessel, forming a circle around it. And that's the worst possible thing, CAA. The amyloid that accumulates around the blood vessels is made by a-beta 1240, whereas the plaques are made mostly by a-beta 1242. The reason for that is a-beta 1242 is very sticky, so it sticks to the tissue and forms aggregates much easier."

Is there any practical implication for practice?

"In Alzheimer's patients, before they become demented, there is already dysfunction of the blood vessels in the brain. For example, patients before they develop Alzheimer's disease they have alteration of the blood brain barrier, which is another aspect of vascular function. So all this data matches what we find in the laboratory, the mouse work suggesting that one of the first things that a-beta does is really alter blood vessel function, while it also alters neuronal function -- nobody is arguing with that. But it's a double hit. There are two things going on."

"All these data together suggest that while we try to figure out how to treat Alzheimer's with medicines, we should really make an effort to curtail the vascular risk factors because they can have a beneficial effect on the progression of the disease."

Source: http://bit.ly/1M0MaGV