Dr Constantino IadecolaCostantino Iadecola, MD
The amyloid hypothesis has long been believed to be the key to solving the Alzheimer disease puzzle. However, after numerous failed attempts to develop therapies to address amyloid buildup in the brain, some have begun to question the theory.

For Costantino Iadecola, MD, the director and chair of the Feil Family Brain & Mind Research Institute at Weill Cornell Medicine, amyloid is only a single piece of the puzzle. His understanding defines Alzheimer not as a disease, but as a syndrome caused by a number of pathologies at play in the brain.

To tap into some of Iadecola’s insight into the vascular facets, among others, of the condition, and the role that amyloid plays in the development of Alzheimer dementia, he spoke with NeurologyLive in an interview.

NeurologyLive: Should amyloid be our main therapeutic target? How important is its role?

Costantino Iadecola, MD: The amyloid story is an interesting one because the people in which the Alzheimer disease runs in their family, they have mutations in the amyloid precursor protein gene, where the amyloid comes from. They make a lot of it. They make so much of it that the brain cannot get rid of it and that's why it accumulates. These people, in their 30s and 40s, will start to have symptoms. There is a problem of too much amyloid being made. Now, in the in the garden-variety Alzheimer dementia picture, the problem is not overproduction. You make as much amyloid as much as anybody else, is the problem is the brain cannot get rid of it. It's a problem of clearance of amyloid from the brain. About 90% to 95% of the of the people who get Alzheimer have that problem. That's where the vascular piece comes in. About half of the patients who are diagnosed with Alzheimer disease during life, once they go to autopsy, when they the brain is cut up and the pathologies are looked at, they will have vascular disease and amyloid pathology together.

Could anything be done now to help address the impact of Alzheimer disease?

The most common form of dementia is not really Alzheimer disease, but a mixed pathology dementia. People have studied this, and they actually found that there are 5 pathologies that all play a role, in which amyloid and tau are only one piece of the puzzle. So that's what we need to we'll be looking as well. However, the vascular piece is important because it's preventable. That is one thing we can do. We know to make our blood vessels better, and now we can do that by taking certain medications and by diet, exercise. Generally, vascular health measures have reduced the risk of stroke and heart attacks by 20%, 30%, 40%. Probably, if we do that, we can also help the brain get rid of some of this amyloid. Perhaps we may not counteract Alzheimer disease, but we may delay the onset.

All we hope for is to delay the onset. Even 1 year, 2 years, or 3 years will have a tremendous economic impact, a tremendous social impact, on families and caregivers before someone goes into a nursing home. Delaying that point there would be a great success.

Where do you think the next big breakthrough will be in Alzheimer? Will it be an imaging modality or a therapy?

Let's say that I have a magic brain scan that’s going to tell me when the patient is going to get Alzheimer. What am I going to do for him? You’ve got to have both diagnostic tests and the treatment. A treatment without diagnosis is a problem. Are you going to put in in the tap water? A diagnosis without treatment is the same. It's hello, thank you very much, what am I going to do? You need both. We need a biomarker and we need the treatment.

There is some controversy, which I think it to a certain extent is not entirely well placed, about whether amyloid plays a role. The amyloid hypothesis, is that right or wrong? There're five pathologies of what we call Alzheimer disease. It’s not really a disease. It’s a syndrome, which means it's a series of symptoms put together with different mechanistic causes. You have amyloid, you have tau, you have Lewy bodies, you have the hippocampal sclerosis, you have vascular dysfunction—all those things are what cause the so-called Alzheimer syndrome. Now, of course, amyloid is not the whole picture. I'm not surprised that, if you were be able to clear the amyloid by 80%, you're not going to make someone normal if all the tau is still there, and all the blood vessels that don't work are still there. What is also clear, that has emerged over the past the couple of decades, is that you need a multi-pronged approach that combines preventive measures in things you can prevent, like vascular disease, and then treatment approaches that counteract the specific pathogenic factors that underlie those multiple pathologies that we have talked about.

It's not going to be a silver bullet. It's going to be a team effort. Also, at the research level, we're going to have to have a team effort. It's going to be the pathologist working with the immunologist working with the clinical neurologist and imagers and biochemists.

Transcript edited for clarity.