Research out of Johns Hopkins University shows why our memory falters as we grow older. Pathways to the brain’s hippocampus degrade — by as much as 20 percent — as we age. I spoke recently with Michael Yassa, an assistant professor of psychological and brain sciences and lead author on the paper in PNAS, about the work — and how it could eventually help Alzheimer’s disease patients.
How did you conduct this research?
[These pathways are] how bits of the brain communicate with each other. If you have input coming in through your eyes or ears, it gets filtered through those pathways before it gets to the part of your brain that stores memories. Early on, we tried to look for evidence of this specific pathway that leads into the hippocampus because people haven’t been able to get an anatomical way to look at it [in humans]. It’s very small and tucked among other fibers going in different directions.
We tried to find a way to use technology called diffusion imaging. We were able to use a high spatial resolution to look at things in far more detail. Once we do that, we can see evidence of this pathway if we restrict our field of view to a specific direction. We know from anatomical studies in the rodent and some primates exactly where this should be. Using a bit of fancy math, we’re able to get a signature of that pathway. We were able to quantify this — basically use a measurement scheme to see what degree to which this pathway is intact in young individuals and older individuals. We found that, as you get older, there is a clear degradation in this pathway.
How significant is the degradation?
It’s hard to have absolutes. It’s not like it’s completely gone. These were 60- to 80-year-olds we tested. These are folks that are completely healthy. It’s along the lines of a 10 to 20 percent degradation. That degradation was enough to cause memory deficits.
We evaluated their memory performance based on a task geared toward the function of the hippocampus. This is a task that engages your ability to tell similar experiences from each other — what you had for breakfast today versus yesterday. You want to call on the right experience. When you have an impairment in that pathway, you have a deficit in the ability of the hippocampus to take new experiences and store them in your brain. Instead, it seems to be susceptible to older, similar memories you’ve stored before. That leads to confusion.
And this expands on previous research because this hasn’t been examined in humans before?
Absolutely. We have not had a way to do this in people’s brains as they’re alive and hanging out in the scanner. That was the real breakthrough for us. The original data on this was published in a PNAS paper last year.
The innovative thing for this paper is that we were able to link path integrity to the function of that hippocampus. We can vary the hippocampal input and see what it does as a function of that input. We changed how similar experiences are. The hippocampus is supposed to do something very predictable there. It’s supposed to take things that are similar and make them dissimilar, so we can store them separately without overwriting anything. Its ability to do that as you got older was impaired. We could see evidence of that in fMRI, a way to look at where blood flow is going in the brain when you’re doing a memory task. If we did this kind of task while you’re in the scanner, the hippocampus lights up. The extent to which it lights up predicts how well you do on a memory task outside the scanner. We found a real link between this pathway and the hippocampal ability to do its job. Both were linked to how people perform on memory in everyday life.
The next step is clinical trials in early Alzheimer’s patients?
We’ve tried to isolate things we think are related to memory loss and aging. Memory loss is a hallmark of Alzheimer’s. It’s much more dramatic in Alzheimer’s disease. It’s no surprise that the same region in the brain we’re interested in for aging — the hippocampus — seems to deteriorate first in the course of Alzheimer’s disease. We tried to come up with a set of conditions in the hippocampus that might predict memory loss.
We’ll look at Alzheimer’s patients to see if we can do treatment trials to reverse some of those deficits. When I say reverse, I mean it a bit tongue-in-cheek. If you have a pathway that’s degrading, it’s hard to say a drug is going to reverse it. We’d hope for slowing it down and maybe halting it completely. With Alzheimer’s disease, that whole part of the brain essentially disappears. How can we halt it to the regular level it’s supposed to deteriorate at when you’re aging normally?
The goal of this work has been to develop a treatment?
A goal of the work we do with aging is focusing on how we can use this. There are a lot of commonalities between aging and Alzheimer’s. Alzheimer’s is a dramatic version of some of those deficits. But at the level of the hippocampus, we’re finding a lot is similar. Some of my earlier work found a condition where a small part of the hippocampus was almost too active. We found a more dramatic version of that [in people with] mild cognitive impairment, an early stage of Alzheimer’s. One of our logics was: If we can bring down hyperactivity, maybe we can rescue memory deficits. In the rat, that works. We’re looking at that in the human as well.
How far away is a possible treatment?
My prediction, as an Alzheimer’s researcher, would be that we’re going to have something truly remarkable in the field — maybe not from us in our lab — within the next five to 10 years. That’s something I think a lot of people agree on because we have a much better understanding now of what’s going on in Alzheimer’s disease. Things are moving much more rapidly than in the past. I think we’ll be able to see something remarkable about Alzheimer’s causes and treatments within the next decade.
Is work in the field moving faster because of technology?
That’s a huge part of it. And the ability to work across sites and across institutions, which was not feasible in the past because people all had different protocols for scanning and behavioral testing. We have large endeavors funded by the National Institutes of Health that fund multiple institutions to do joint projects with many thousands of patients. That’s the kind of work — where you can combine data sets across many sites –that’s going to revolutionize the way we think about therapy.
Photo: Michael Yassa