Rethinking Neurodegeneration: The Hidden Role of Blood Vessels in Alzheimer's Disease

So let's just kind of start with stepping back and historically looking at some of the Alzheimer's research that has been, you know, kind of in the past.

And they've Maybe I've got this wrong, but they've treated blood vessels as secondary damage to what was going on inside the brain.

But your work suggests that maybe this is not necessarily true, that some of that vascular dysfunction may be intertwined with some of the tau pathologies itself.

Can you talk about that? And are we witnessing something that is very different in how we think about neurodegeneration?

Yeah, that's exactly right.

And that's a great place to start because you're right.

Historically, if we go back even to some of the earliest writings about Alzheimer's disease, you know, a hundred years or so ago, they were describing vascular changes in Alzheimer's disease, but it was kind of set to the side because the thing that jumps out to you when you look at pathology in an Alzheimer's disease brain is amyloid beta plaques and tau-containing neuroferbular retangles.

And, you know, there's been a lot of work over the years looking at vascular function and how it changes in disease.

So there have been some really excellent longitudinal studies where people have looked at cohorts of 5,000 individuals and track them over up to seven years or more.

And they can see that cerebral perfusion changes.

is reduced just at baseline in people who are at a higher risk of developing Alzheimer's disease later in life.

And I think it's been estimated even that 50 to 80% of all Alzheimer's disease cases that come to autopsy end up having vascular abnormalities in some shape or form or another in addition to plaques and tangles.

And so there really is just this tight link between vascular function and just risk of developing Alzheimer's disease.

But I think largely the field has kind of ascribed that to, you know, it's just worse to have two diseases than one.

So if you're at risk for cardiovascular disease, that's going to put you at risk for a whole host of other disorders.

And one of those is Alzheimer's.

And so largely, you know, the focus hasn't been so much on, you know, reversing vascular pathology.

It's been in reversing amyloids.

Our best amyloid, our best therapeutics currently are targeting amyloid beta plaques, and they're really good at clearing plaques in the brain.

But they don't necessarily reverse some of these vascular changes.

And so what our work did, and we published this, I think, a couple years ago down in Acton Neuropathologica, is we were looking at tissues in a new way.

So instead of looking at traditional thin tissue sections, we We were looking at very thick sections.

So when I say thick, I mean not particularly thick.

So these are about a millimeter.

So if you take a centimeter, we're looking at a tenth of a centimeter, essentially thick piece of tissue.