Early Alzheimer’s can be treated, says leading OHSU researcher in Portland

The Alzheimer’s Foundation of America is holding a free one-day conference in Portland on Wednesday designed for patients, families and caregivers.

One of the keynote speakers is Oregon Health and Science University’s Kevin Duff, the co-director of the state’s only Alzheimer’s Disease Research Center.

He says early detection recommendations have changed over recent years and with the emergence of new drugs, many early stage patients can experience dramatically improved outcomes — so catching the disease early is critically important.

Duff joins us in studio to discuss the details.

Note: The following transcript was transcribed digitally and validated for accuracy, readability and formatting by an OPB volunteer.

Dave Miller: This is Think Out Loud on OPB. I’m Dave Miller. The Alzheimer’s Foundation of America is hosting a free one-day conference in Portland on Wednesday for patients, families and caregivers. One of the keynote speakers is a co-director of the state’s only Alzheimer’s Disease Research Center. Kevin Duff is a professor of neurology at OHSU. He joins us now to talk about early detection, the emergence of new drugs and more.

It’s great to have you on Think Out Loud.

Kevin Duff: Thank you very much for having me.

Miller: So the talk you’re going to be giving on Wednesday is called, “From Normal Aging to Dementia: How the Brain Changes and Why Early Detection Matters.” I want to start with the first part though. How does a brain normally change as we all get older?

Duff: That’s a great question, and it’s something that we’re continuing to learn more and more about as science advances. But we do notice that as people get older, especially past the age of 65 into the 70s and 80s, that brain cells, the parts of the brain that do the work, start to die off. Those are some normal changes that we expect to see as people get older. However, they happen in relatively small amounts and sort of distributed throughout the brain, which is different than what we expect to see in certain neurological diseases.

Miller: Let’s turn to Alzheimer’s, that particular degenerative disease. What kinds of changes have scientists been able to identify in a brain with Alzheimer’s?

Duff: There’s a few different changes. Some of the earliest changes that we know happen is that there’s an accumulation of an abnormal protein called amyloid, and it builds up throughout the brain but especially in certain parts of the brain. And up until about a dozen years or so ago, the only way that we could really identify these amyloid deposits within the brain was after the person passed away, on autopsy. But again, around 2012 or so, the FDA approved special imaging techniques that could actually see these amyloid deposits in the brain of somebody who’s still alive.

Miller: So just to be clear, then, before about a dozen years ago, Alzheimer’s was diagnosed primarily via symptoms. You have a kind of dementia and it seems likely that we’ll call it Alzheimer’s, but it wasn’t until someone died that folks could look inside the brain and say, “Yeah, we see these amyloid plaques. Now we can definitively say what this person had was Alzheimer’s.”

Duff: Yeah, that’s very true. In fact, up until some of these advanced neuroimaging techniques became available around 2012 or so, we noticed that the way that we would identify somebody who’s having Alzheimer’s disease is by, yes, we do a thorough evaluation neurologically, neuropsychologically, and we rule out all the other things that potentially could cause it. And if we rule everything else out, then usually what we’re left with is Alzheimer’s disease is the cause.

Miller: How early can people actually effectively be tested for, in terms of that one screening you were talking about, at what point in the progression of the disease would a neurologist actually be able to see evidence on that imaging?

Duff: There’s some studies that suggest that the amyloid deposition, the deposits of this amyloid abnormal protein may start even 20 years before the development of a dementing illness.

Miller: Wow. So two decades, potentially, before somebody would even recognize that they’re having symptoms or that their loved ones would, the brain is already starting to change.

Duff: That’s true. We know that these things are happening very early in the course; in fact, well before we start to see symptoms like memory problems or difficulties with day-to-day activities, well before we start to see other changes in the brain.

Some of the later changes that happen in the brain that happen more around the time of diagnosis would be more dramatic reduction in brain cells dying off, of neurons that lead to significant shrinkage within the brain or atrophy in specific parts. Those things tend to happen much later in the course of the disease, but we are now seeing that these amyloid deposits happen much, much sooner.

Miller: To zoom forward to the later part of the progression, the shrinkage of the brain, how would you know that someone’s brain has shrunk?

Duff: Well, we would typically do that with sort of an X-ray of the brain, an MRI. We can do a different type of brain scan that looks at the structure of the brain, and we can measure the size and shape of different regions of the brain.

There’s a couple of different regions that we’re specifically looking at when we’re considering if Alzheimer’s disease might be the cause. There’s some structures in the middle part of the brain, the medial temporal lobe, and that seems to shrink, or those brain cells seem to die off preferentially as somebody’s developing a condition like Alzheimer’s disease.

Miller: Oh, as opposed to what you were saying earlier, where in a “normal aging brain,” the shrinkage is pervasive.

Duff: Yes, it’s all over the brain. We see a subtle, gradual but diffuse shrinkage of the brain. Whereas, as we identify specific types of dementias like Alzheimer’s disease, we’re looking at that atrophy within those medial temporal lobes. But if we were looking at a different type of illness like frontotemporal dementia, there may be brain cells dying off in more of the frontal part of the brain.

Miller: But would you only know the specificity of the shrinking region if you did an X-ray, say, now, and then one, two or 10 years from now?

Duff: I think that’s a great point, in that if we just looked at one individual who came into our office and they’re saying, “I’m starting to have memory problems,” and we do one of those MRI’s of the brain, we’ll be comparing that individual to their age-match peers – other people who hopefully are normal, who also have had that brain scan. And the patient that we’re seeing, their brain scan may look … always have been a little bit low or small, so maybe we can’t tell that much in that initial visit unless the changes are dramatic. But as you mentioned, yeah, it is probably most useful if there are serial assessments following that person over time to see what types of changes are occurring.

Miller: So then this gets to big questions about who should be getting these tests and when, because one of the things that is really staying with me so far in our conversation is that these amyloid plaques, they could show up maybe 20 years before symptoms. And that leads me to think, “Oh, maybe the answer is that everybody, when they turn 40, they should start getting scanned.” But I’m not sure that that makes sense, population-wide in terms of costs, false positives or scaring people unnecessarily. So how do you think about the question of who should be tested, first of all? And then we can talk about when.

Duff: Those are great questions. All those are exactly the reasons that we don’t have mass screenings of MRIs on everybody once they turn the age of 40. What we do want to look for are some risk factors. Somebody who has a strong family history of Alzheimer’s disease or other neurological conditions, that may put them more to the forefront of getting screened earlier.

Miller: And when you say earlier, do you mean potentially pre-memory loss, pre-concerns from them or their loved ones about cognitive decline?

Duff: It definitely could be, and again, I think it would depend on the degree of severity of those risk factors.

Miller: OK, so the first one is family history.

Duff: Family history.

Miller: What about genetic tests, which is maybe related to but separate from a family history? How helpful are our genetic tests right now?

Duff: Right now, we don’t have a lot of great genetic tests that have a one-to-one relationship, that if you are positive on this genetic test that you’re definitely going to develop Alzheimer’s disease. Some of the ones that we have are more about risk.

For example, there’s a genetic risk called the APOE gene test that people could get through any of a number of commercial vendors. And whether an individual has one or two copies of a specific type of gene, the E4 gene, that increases their risk of developing Alzheimer’s disease but it definitely doesn’t guarantee it.

Even if somebody had two copies of that genetic marker, it doesn’t mean that they will definitely go on to develop the disease. Our genetic tests are still lagging behind where we are with some of our more diagnostic screening measures.

Miller: OK, you started with family history. What are the other risk factors that would lead you or other clinicians to say, “You know, I actually really do think you should get tested?”

Duff: Some of it would be starting to notice early changes in one’s thinking abilities. The ones that typically show up the earliest are challenges with short-term memory. So, not being able to remember conversation that one had, or not being able to remember a list of grocery items that you’re going to get at the store, or not being able to remember a book that you just read. If those things are starting to happen more and more, and they’re starting to interfere with that person’s day-to-day life, and maybe most importantly that they’re a change from how that person was in the past, those start to be more concerning.

For example, some patients come into my office and I ask them, “Do you have any difficulty remembering people’s names?” And they say, “Yes,” but then they laugh and they say, “But I’ve never been good with names.” For that person, that’s not really a change in their function. But if I had another patient who said, “No, I used to be very good at remembering people’s names, and now I’m struggling with that more and more,” that second person is much higher at risk.

Miller: What’s the upside to an early diagnosis?

Duff: Up until probably about 15 years ago, there was not a lot of upside besides being aware of what’s going on. Sometimes people need a label or a reason for their struggles with memory or behavior, or struggles with day-to-day activities. So there was some value in understanding what’s causing these problems, but we didn’t have a lot of effective treatments. In fact, many of our treatments up until about 15 years ago were much more symptomatic in basis and not really designed to treat the underlying cause of the illness.

But over the past several years, we’ve had a number of different drugs that have come on the market, have been approved by the Food and Drug Administration, that do seem like they’re effective in reducing those amyloid deposits within the brain. So for the first time in my career working in this field we do have actual treatments that may be effective in aspects of the illness.

Miller: What are the medications, the current state-of-the-art medications effective for? What can they do and what can’t they do?

Duff: That’s a great point because they are not the panacea just yet that I think everybody was hoping for. So again, as I mentioned, we do know that one of the markers of Alzheimer’s disease is having one of these brain scans that looks for amyloids and we see these deposits within the brain.

Miller: Could I stop you right there? Because the phrase that I remember learning in the past and I’ve been using, that I just realized you’re not using – you’re talking about amyloid deposits, I’ve heard about amyloid plaques. Is this a meaningful distinction and am I using incorrect language?

Duff: No, no, you’re using it correctly. What we see is that this amyloid starts to accumulate and as it sticks together and accumulates, accumulates, eventually they turn into plaques, but then we look at it more globally throughout the brain as deposits. So it really depends on the size, the amount and the distribution of it, the terms that we use.

Miller: OK, so back to what the still pretty new, and exciting in a lot of ways, medications can do. So, what can they do?

Duff: The first one was approved by the FDA in 2021. Another one came out in 2023 and the third one came out in 2024. So again, these are all very new. But what all three of them have shown that they can do is that, when an individual is on these drugs for 12 months, 18 months, perhaps longer, that it reduces the amount of amyloid within the brain. It clears out those amyloid plaques and deposits, such that, when we do a follow-up scan, we actually don’t see a sufficient amount of amyloid that we would continue to diagnose this person with Alzheimer’s disease. So it really does clear out the target that it was hoping to clear out.

Miller: If it’s preventing the buildup of this amyloid, does it also then halt the progression of the disease?

Duff: That has been the trickier part, is that in the clinical trials, the studies that they’ve done looking at these drugs – again, they have found that it reduces the amyloid. They’ve also found that it seems to slow the progression of the cognitive and functional difficulties that we see in Alzheimer’s disease on some composite measures. However, those composite measures of cognitive and functional abilities are continuing to decline. They’re just declining at a slower rate than people who are on a placebo.

Miller: Which is not nothing at all.

Duff: Exactly.

Miller: It slows the progression of a very scary and terrible disease. It is a great breakthrough, but it’s not a cure and it doesn’t even fully stop the progression, let alone bringing back cognitive function that’s been lost. Is anything helping or does anything seem possible to do that right now?

Duff: Not right now. Again, what’s going on within drug development, I think, is taking some of these compounds and trying to refine them so that we can continue to see the reduction in the amyloid, perhaps slow down or even arrest the progression of the illness. I think we’re still quite a ways off from being able to return people to where they were before the illness. But still, if we could stop it completely it would be a huge savings for financial, societal, for patients and families. It would really be tremendous.

Miller: To go back then, to combine these two strains of conversation that we’ve been having right now – early detection and promising, although still early, medications – how big a difference might it make if somebody is diagnosed and maybe gets on these medications as soon as they’re experiencing symptoms or even before, based on family history, as opposed to years into the obvious onset?

Duff: That’s definitely the direction that I think these drugs and treatment in general, is going – earlier and earlier in the course of the disease. Currently, the drugs that are approved, that we’ve been talking about, are actually only indicated by the Food and Drug Administration and by the pharmaceutical companies that produce them, for individuals that already have diagnosable cognitive symptoms. So you couldn’t get them if you just had a family history but on cognitive testing you are completely fine.

Miller: And that’s not an off-label prescription people are already using?

Duff: Not at our offices. I don’t know if people are finding a way around that system, but technically these drugs are really only approved for once the disease has started. Now, that being said, they are much more geared towards the earliest phases of the illness, what we call mild cognitive impairment or mild Alzheimer’s disease. Once somebody progresses to moderate to more severe stages, then these medications really haven’t been tested and really haven’t been shown to be as effective.

Miller: To turn to the federal funding picture for a second, over the last 15 months or so, we’ve had a lot of conversations about federally-funded researchers and all kinds of disciplines seeing their grants slashed or, in some cases, rescinded. It’s caused just a ton of turmoil in all kinds of scientific disciplines. Has that happened with Alzheimer’s?

Duff: Alzheimer’s disease has been somewhat spared from some of the challenges that the rest of the federal funding agencies have suffered from.

Miller: Why do you think that is?

Duff: I think that, one, the size and scope of the problem, that there are so many people that are struggling with Alzheimer’s disease or related conditions, and that number is expected to double in the next 30 to 35 years, that I think people are looking at, “We need to continue to do something about this.”

Miller: Do you think there’s also something about the fact that we are, at this point in our country essentially a gerontocracy, we are run by old people?

Duff: I firmly believe that, even though I’ve never heard this from anyone, that yeah, the people that vote on these bills, many of them may be thinking, “Is this in my best interest to continue to do research focusing on older adults and the diseases that affect them?” I think that there’s a lot to that.

Miller: OK, so back to what people can do. Aside from early testing and some new medications, what do you recommend that all of us do as we age to give ourselves the best chance of preventing the progression of Alzheimer’s?

Duff: I think the key definitely is preventing the initiation of the disease as soon as possible. Despite all the research that we’ve talked about so far with these brain scans and these drugs that can reduce the amyloid within the brain, there’s a number of different lifestyle interventions, factors or programs that people could engage in that do seem like they have a large body of research evidence to suggest that they can actually prevent or at least slow down the development of conditions like Alzheimer’s disease.

I group these into three categories. The first is physical exercise, the second is cognitive stimulation and the third is social engagement. Those three things alone or in combination have been shown to be very effective in healthy individuals in maintaining brain health, as well as for people who have already started to develop some early symptoms to perhaps slow the progression of those things.

Miller: I feel like I’ve heard more in recent years about the physical piece of that and the cognitive piece, getting some exercise and, say, doing various kinds of numeric or word-based puzzles. What’s the social component?

Duff: I think social is an underappreciated avenue for addressing some of these issues. You had mentioned for the cognitive piece doing something like crossword puzzles or Sudoku, or taking a course online. That all seems like it makes sense – it stimulates the brain, it stimulates the memory. Sure, I get that, but why would social activity? In a lot of ways, I think that it taps into a lot of the same things that we see with cognitively stimulating activities.

That is, let’s say that you meet somebody new for the first time, and they’re telling you about themselves and what they do and what their background is. If you’re paying it … One, that requires attention, and two, that requires memory to hold that information long enough to then generate questions about that person that makes sense, and then maybe to remember that person’s name and some of those details for when you meet them later. So I think that social engagement, especially less typical social engagement – meeting somebody for the first time – has a lot of the same kind of cognitively taxing, demanding activities that something like crosswords or Sudoku would.

Miller: Just briefly, I mentioned this Wednesday event that you’re gonna be a part of. It’s free. What can people expect there?

Duff: There are three different speakers that will be presenting. In addition to myself, there’s also a great presentation about communication in patients with different types of cognitive changes later on in life. And that can be one of the real challenges of those individuals is that, as they start to lose memory and other cognitive abilities, it becomes more and more challenging for them to share what they want, what their needs are. So one of the speakers is an expert who’ll be talking about that.

The third one is an elder law attorney who is gonna focus on some of the challenging issues of dealing with a family member who has maybe lost their capacity to manage their finances or make legal decisions for themselves. Maybe a home needs to be sold, maybe that person has to transition to an independent living facility, how to navigate some of those really important challenges.

Miller: Kevin, thanks very much.

Duff: It was my pleasure. Thank you very much.

Miller: Kevin Duff is clinical neuropsychologist and the co-director of the Layton Aging and Alzheimer’s Disease Center at Oregon Health and Science University.

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