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In 1906, Dr. Alois Alzheimer spoke of a female patient with quote, “an unusual disease of the cerebral cortex.” Her symptoms included memory loss, disorientation, and hallucinations. After she died at age 50, an autopsy revealed that her cerebral cortex was unusually thin and contained what are now known as amyloid plaques, which previously had only been observed in elderly people. The autopsy also showed tangled threads of protein inside the neurons. A few years later, a colleague would name this constellation of symptoms and brain changes “Alzheimer’s disease.”

More than six million people in the U.S. currently live with Alzheimer’s disease, and that number is expected to reach 13 million by 2050. The disease isolates its patients in a twilight world of forgetfulness, confusion, and agitation. To this day, a defining feature of the disease has been the presence of abnormal plaques and protein tangles in the brain. Researchers hunting for treatments have looked to those plaques and tangles as likely targets — but we don’t entirely know what role they play in the disease’s progression, if any.

TARIOT: If you intervene before any significant brain changes have occurred — can you stave off the amyloid and then the other downstream effects? That’s still an open question.

Dr. Pierre Tariot is an Alzheimer’s disease physician and researcher. He’s been searching for answers to this question for a while, in places close to home and as far away as the Andes Mountains, in Colombia. He didn’t find exactly what he was looking for there, but he also didn’t come away empty-handed.

TARIOT: The story isn’t quite over. In fact, it may not be over for a while.

From the Freakonomics Radio Network, this is Freakonomics, M.D. I’m Bapu Jena. I’m an economist and I’m also a medical doctor. Each episode, I dissect an interesting question at the sweet spot between health and economics. Today on the show: many Alzheimer’s disease experts believe that early treatment, before symptoms even begin, could keep the disease at bay.

TARIOT: You know, the time to put out the fire is when it’s on the stove not when the whole house is on fire.

But so far, none of these approaches, which target amyloid, seem to work well. And now, new allegations of research fraud are casting an ugly shadow over the entire field. So, how did Alzheimer’s disease get to this point — and where does it go from here?

TARIOT: My name is Pierre Tariot. It’s a French name.

Dr. Pierre Tariot directs the Banner Alzheimer’s Institute in Phoenix, Arizona. He sees patients with Alzheimer’s, and he also conducts a lot of research in the field. He’s served as principal investigator on more than 50 trials on Alzheimer’s and related conditions.

When you run clinical trials, you occasionally get to witness incredible breakthroughs. More often than not, though, you see failure, or you don’t see anything at all. Just around 14 percent of all clinical trials for drugs and vaccines show positive results.

With Alzheimer’s disease, that number is far lower. The failure rate for treatments has been close to 100 percent. Basically, every drug that’s been tested in a major clinical trial to try to prevent or manage Alzheimer’s disease hasn’t worked — at least not well. As Pierre tells us today, there are some options that can help patients address symptoms, but few drugs that effectively target the disease itself.

And yet, he keeps trying.

TARIOT: To conduct a clinical trial, you have to believe that an experimental treatment has a chance of helping without hurting too much, but you can’t know it already. Otherwise, there’s no point in doing the study. So, that’s called equipoise. You have to be in a state of equipoise.

JENA: How do you get patients to enter a clinical trial? What is it about the recruitment process that’s interesting to you?

TARIOT: You need to tell people “Here’s the story. We are interested in whether treatment with an experimental therapy might slow down or prevent the emergence of symptoms due to Alzheimer’s disease in people who are at high imminent risk because of, for instance, age and genetic background.” So, you can participate in a clinical trial to help answer the question: does this preventive therapy work or not?

JENA: Can you give sort of an example of a typical Alzheimer’s patient?

TARIOT: It’s typically a person in her or his seventies or eighties functioning well, and then over a period of maybe a year or so, it becomes evident to the spouse. “She’s repeating herself. She’s misplacing things. She’s forgetting appointments. And now she’s starting to routinely lose track of her keys and her cell phone. And lately she’s had trouble cooking. And we don’t know how come. Is this normal aging or is something else going on? And by the way, she’s a lot grumpy than she used to be. And that irritability is just not like her to snap at me. That’s never happened before.” Alzheimer’s is a specific brain condition that kills brain cells that we call neurons — prunes connections between them, results in shrinkage of brain tissue, results in misprocessing of some key proteins — one is called amyloid, one is called tau — and that misprocessing results in deposits in the brain tissue that you can see under a microscope, and the disease also results in many other molecular forms of mayhem but a lot of attention has been paid to these amyloid and tau pathways. Clinically, what happens is that this disease process ticks away silently for perhaps 20 years or so before any symptoms are manifest. And then usually over a period of months to years, not days to weeks, difficulty with memory and other thinking ability gradually emerges and eventually results in loss of ability to function normally on a day-in, day-out basis.

JENA: Some of those things that you described, you could imagine would be exacerbated with other very common problems that happen in older people — problems with vision, problems with hearing. I remember as a resident seeing a patient who they were in the hospital, they didn’t have their hearing aids, and they were quite combative. And there was a question of whether or not there was an underlying psychiatric diagnosis that was explaining why this person was behaving like they were. Then the daughter comes and brings in the hearing aids and the person’s a brand-new person.

TARIOT: As we age normally, we lose the ability to retrieve specific pieces of information, to process information rapidly, to sustain attention when there’s competing environmental stimuli. I joke that when I merge onto the highway, I’ve got to shut the radio off these days. And that is absolutely going to be magnified by hearing and/or visual deficits. And if those deficits are there for a very long time that can lead into brain circuits not functioning properly and actually contribute to the clinical manifestations of what might have been a less prominent cognitive impairment syndrome.

JENA: Talk to me about the amyloid hypothesis. What are the origins of it?

TARIOT: The amyloid hypothesis rests on a few key scientific pieces of evidence. One is that to meet criteria for Alzheimer’s disease, you have to have the clinical picture during life, and you have to see these amyloid deposits in the brain We know that misprocessed amyloid fragments are highly toxic to surviving neurons. Another important line of evidence is genetics. There are rare forms of genetically induced Alzheimer’s disease that result in a form of Alzheimer’s disease that occurs early in life, kills people at a young age, and affects half of their next generation in the same way. All of those mutations result in amyloid misprocessing. All of them. Conversely, there is a very rare Icelandic mutation that blocks abnormal amyloid processing. And for all practical purposes, these folks never get Alzheimer’s disease. So, those are the lines of evidence. I think it would be unfortunate to create the impression that amyloid is the whole story. I like using the cholesterol analogy. To me, amyloid is to Alzheimer’s as cholesterol is to heart disease. It’s an important player, sometimes sufficient by itself, but by no means the whole story.

JENA: This is sort of a question about causation, then. So, if we see humans who have symptoms of Alzheimer’s, we evaluate their brains and we observe them to have these amyloid deposits. A natural conclusion might be that the amyloid deposits are what is causing the damage to the brain. It’s what’s causing the symptoms, but it could also be that there’s an underlying process that both, A, generates amyloid and B, generates damage to the brain, but it’s not that amyloid causes damage to the brain. How do you establish whether or not amyloid is one of the pathologic factors that injures the brain, that leads to the symptoms of Alzheimer’s, versus a byproduct of some other process that’s doing that?

TARIOT: Well, this is where clinical trials can help. The hope has been that mitigating this abnormal processing pathway in the right way at the right time will result in not only less amyloid burden in the brain, but perhaps less of the other changes that are so frequently seen in Alzheimer’s disease. And maybe we can slow down the clinical juggernaut. So, let’s say I have mild Alzheimer’s symptoms. If I get the right kind of anti-amyloid therapy, maybe I will hold on to what I have longer, hold on to my cognitive abilities longer. And maybe that will preclude things like brain atrophy or tau and tangle deposition. if you intervene before any significant brain changes have occurred — if you intervene with any anti-amyloid therapy — can you stave off clinical manifestations and can you stave off the amyloid and then the other downstream effects? That’s still an open question.

JENA: If amyloid is one of the causal factors that leads to brain injury through these deposits, and to the symptoms, what has been tried in terms of anti-amyloid therapies in clinical trials and have they worked?

TARIOT: So far, nothing has proven to be clinically effective and safe for widespread use. The only exception is a drug called Aducanumab, a synthetic monoclonal antibody, primarily targeting these amyloid plaques was studied in global phase three studies, that got stopped early. It’s quite a saga. Of the two studies, one showed the required clinical benefit, which was slowing of decline in cognitive performance and daily functioning performance. one of the trials didn’t show that. A real dilemma for the field and for the F.D.A. The F.D.A. convened an advisory committee that, did not support approval of the drug, for marketing. The F.D.A. later made a decision to offer accelerated approval. This isn’t considered sort of the last word on what anti-amyloid therapies will or will not confer in terms of clinical benefit.

JENA: What do you think the future holds and are there clinical trials that are expected to read out that will hopefully provide more definitive answers?

TARIOT: There are five other “kissing cousins,” I might call them monoclonal antibodies targeting various aspects of the amyloid cascade . Two of these programs are reading out in 2022. Couple of others in the months to come. Several of them in people with symptoms due to Alzheimer’s already, and several of them in people who don’t have symptoms yet, but who are at elevated risks. So, we’re going to get a lot of answers fairly soon.

JENA: Suppose it is the case that anti-amyloid drugs end up not being effective. Does that suggest then that there are other pathways that are both generating the amyloid problem and also causing brain injury that have not been targeted that should be looked at?

TARIOT: It’s extremely likely that even if anti-amyloid therapies are successful, they won’t be the last word in therapy. They will probably only have modest effects at slowing progression. Perhaps modest effects at delaying onset in people at elevated imminent risk of symptoms. So, we absolutely need other targets. But I think your question is a really profoundly more basic one, which is what precedes all of this? How come these pathways get unleashed in the first place? And there’s some intriguing clues. People with hypertension are at very elevated risk of having cognitive impairment later in life and if you treat hypertensives aggressively in mid to late life, you have a strong chance of reducing new-onset cognitive impairment. So, that’s just one clue.

There are other clues too. Pierre explained that fundamental changes within our brains can set off a domino effect that eventually leads to the formation of amyloid deposits and tau tangles. Coming up after the break: what if this domino effect never happened at all?

TARIOT: It would be great if we were smart enough to discern the changes that are probably occurring as early perhaps as our thirties and forties.

I’m Bapu Jena, and this is Freakonomics, MD.

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More than a decade ago, my guest Dr. Pierre Tariot and some of his colleagues began studying a large, extended family in the mountains of Colombia. This family shares a rare genetic mutation that causes individuals to develop Alzheimer’s disease in their 30s or 40s — decades earlier than most Alzheimer’s cases.

Pierre’s hope was that these patients with accelerated Alzheimer’s could help researchers understand how the disease operates, and how it might be prevented.

TARIOT: My colleagues at Banner and I launched something called the Alzheimer’s Prevention Initiative, and our basic thinking was, “Gosh, if an experimental therapy has a chance of working, maybe it’s best to apply it before the brain is ravaged.” You know, the time to put out the fire is when it’s on the stove, not when the whole house is on fire. We started with people at virtually certain risk of getting symptoms due to the disease because of an autosomal dominant mutation causing early onset Alzheimer’s disease. Now, these folks are rare. A few thousand such individuals live within a few hundred miles of each other in the Andes mountains in Colombia, and an extraordinary doctor named Francisco Lopera and his team have partnered with these families over the years, helped prove that their condition was due to a —mutation.

We met the families, who had never heard of terms like placebo, controlled trials, health authority approval — things like that — but readily understood the proposal and said, “We’re in.” And so, over a period of years, Dr. Lopera identified over 6,000 living members who had relatives affected by this type of early onset Alzheimer’s disease, genotyped them and we identified over 1,200 living carriers of this mutation and invited those who appeared eligible into a prevention trial.

JENA: Tell me a little bit about the process of the trial because my understanding was that, because of this population, people may not want others to know that they have this predisposition towards Alzheimer’s. So, that affected how the trial was conducted.

TARIOT: Oh boy, we could write a book about the implementation of this huge small study. We had to have an outreach campaign to promote awareness. We had to train prospective volunteers and their study partners and staff on all things related to conducting a rigorously controlled clinical trial. Had to get approvals from multiple agencies in the U.S. and in the Colombian government. We were dealing with some folks who lived in rural areas who had limited formal education. Very, very bright people, but they had no reason to go beyond, let’s say, about the third grade, because they could manage the dairy farm with that level of arithmetic and writing. So, our partners in Colombia created what you might call a “comic book” companion document to help give people adequate informed consent. We had to create the technical infrastructure. There needed to be certain types of M.R.I. scans, certain types of PET scan.s So, there were actually over 800 timelines that had to be achieved in a certain sequence in order for the trial to begin.

JENA: And were there instances where you offered placebo drugs to individuals who you knew were not at high risk of developing Alzheimer’s to prevent disclosure of the fact that an individual might be at high risk? Like, so, if someone’s participating in the trial, everybody around them would know this person’s at high risk of having Alzheimer’s later. So, did you do something to protect those individuals in some respect?

TARIOT: Yeah, great question. At the time we initiated the study, learning one’s genetic status for this type of condition was not acceptable in the community. So, we had to create a trial design that did not force disclosure of genetic information. And so, working with an ethics committee of our own, including folks from Colombia, as well as ethicists and genetics experts from elsewhere, we came up with a design that enrolled groups of both mutation carriers and non-carriers.

JENA: I had read about that, and I was fascinated because I’d never heard of that kind of thing being implemented into a clinical trial design, but it makes sense given the setting.

TARIOT: So, in 2013, we began immunizing people who were cognitively unimpaired against Alzheimer’s disease, if you will, with an anti-amyloid immunotherapy called crenezumab, and, continued this — treatment in the study for roughly eight years. It wrapped up in 2022 and the top line results were that we didn’t achieve our primary objectives of showing delayed worsening of memory and other thinking ability on two key outcomes. but there are some tantalizing clues in favor of drug versus placebo. But these do not reach statistical significance. The story isn’t quite over. In fact, it may not be over for a while. We feel a great responsibility to understand the relationship between magnitude of exposure to drug and clinical benefit

JENA: When you do a trial and you find “no effect,” it doesn’t mean that there’s not an effect in particular subgroups of people or at higher dosages of the drug or at more frequent administrations, and then sometimes the data may give you a clue as to where to go next, but I’m curious why at the top line, you don’t think that you found anything in terms of clinical impact?

TARIOT: Either the drug doesn’t work, or exposure was insufficient or the sample size was too small. In other words, we might have been underpowered, which was always a concern. These folks are so scarce, that it’s difficult to identify a sample size large enough. So, with one of our primary outcomes, if we had had roughly 50 percent more people enrolled, it actually could have been statistically significant. So, probably underpowered.

JENA: Could you talk a little bit about what other types of drugs or behavioral interventions might be beneficial for Alzheimer’s disease? I’ve seen some recent observational studies mentioning A.D.H.D. medications. Is there any plausible pathophysiologic mechanism by which they might work?

TARIOT: There are lots of other shots on goal for the treatment or prevention of Alzheimer’s disease. And let me break them into a few buckets. One bucket would be: can we attack the underlying pathobiology? So, amyloid is a target. Tau and tangles are targets. Oxidative stress, blood vessel functioning, membrane functioning, neuroinflammation. Then there are completely different shots on goal. Can we sharpen somebody’s thinking ability? Even if it’s only for a matter of months or a year or two, that would be a therapeutic victory. And that’s actually what we have marketed and approved by the F.D.A. now, is cognition enhancers that can bump us up from where we start or slow down loss of functioning. Frequently overlooked is the relief of neuropsychiatric features. There’s about a 100 percent risk of experiencing significant anxiety, depression, disturbance in visual perception, hallucinations, disturbance in thinking that we call delusions, agitation, apathy. These things are very morbid, and sometimes incredibly distressing for the patient and secondarily for loved ones or other care partners. And we don’t have a very good therapeutic toolbox for those symptoms. So, we need them. But while I’m on this theme, non-drug interventions go a long way toward relieving these types of symptoms. And so, having better and better studies of how to alter the environment or how to alter communication between a caregiver and a patient,, how to distract the patient in a soothing way. Techniques like that, are being studied and need to be better studied.

In medicine, research begets more research, and trialists like Pierre rely on earlier studies to conduct new ones. Recently, the field of Alzheimer’s disease was rocked by allegations that falsified images were used in several important research papers. Those accusations don’t target Pierre’s work, but some observers say they cast doubt on the amyloid hypothesis. Pierre disagrees.

TARIOT: I think at the moment what seems to be lost in the flying shrapnel is that none of these allegations amount to more than a cosmetic crack in the argument that amyloid is a player in Alzheimer’s disease pathobiology. It’s not a total sideshow, but it isn’t central. I think the most unfortunate thing is — that there are allegations of misconduct that cast a cloud over all of science and to a certain extent, the science of amyloid, but it’s far from the whole story.

JENA: Assuming the images were not real, would it change your assessment of amyloid as a possible target for Alzheimer’s treatment?

TARIOT: No, it would not. No. it’s a small piece in the overall puzzle. It’s unfortunate, but I would not call this information central to the amyloid hypothesis.

As Pierre told us, his work in Colombia didn’t yield the results he and so many others were hoping for. But he doesn’t see this research as a disappointment, or a rebuke of the amyloid hypothesis. When we spoke to him, he mentioned that there were more results from the study that would be released soon, and in the time since our interview, that data has been made public.

The drug that was studied, crenezumab, did not slow cognitive decline or improve memory function in the trial participants, but it did prove to be incredibly safe. Other medications for Alzheimer’s disease, including the controversial F.D.A.-approved drug Aduhelm, have shown risk for adverse events. In an email, Pierre noted that “essentially every biomarker outcome numerically favored drug over placebo.” But as he told us earlier, none of the changes seen in patients who took the drug were statistically significant. And as he also told us, he doesn’t believe this story is over. Pierre and his team continue to analyze the data, to search for trends, to think about what happens next.

A successful Alzheimer’s treatment would be hailed as one of medicine’s most important discoveries to date. It would also come with a pretty substantial economic benefit. Alzheimer’s is the most expensive disease in the United States, projected to cost 322 million dollars this year alone. The disease also takes an immense toll on families and loved ones, not just because of the care they provide but because of the way that the mind, memories, and ultimately, relationships are affected. A drug that could delay the disease’s onset by a few years— or even just a few months—could have major implications.

TARIOT: Just think about prevention for a second. If quote, “all we do with a preventive therapy is delay the onset of symptoms by five years,” we will cut the incidents and prevalence of the disease in half. There are far-reaching consequences of relatively small-sounding changes.

That’s it for today’s show. I learned a lot and I hope you did too. I’d like to thank Dr. Pierre Tariot for joining us today.

Coming up next week: More than 180 rural hospitals in the United States have closed since 2005, and more than 800 rural hospitals are at risk of closing in the near future.

CARROLL: There are these significant costs when a rural hospital closes, and patients have to travel farther for care. But, of course, that’s not the whole story.

What’s the whole story? It turns out, hospital closures may not impact all patients equally. And in rural areas, a loss of services could be a win in some unexpected ways.

WHITE: It might just be that, accidentally, providers were using the best practices, but we didn’t know that those were the best practices at the time.

So, what does the future hold for rural hospitals and rural health care? That’s all coming up next week on Freakonomics, M.D. Thanks again for listening.

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Freakonomics, M.D. is part of the Freakonomics Radio Network, which also includes Freakonomics Radio, No Stupid Questions, and People I (Mostly) Admire. All our shows are produced by Stitcher and Renbud Radio. You can find us on Twitter and Instagram at @drbapupod. This episode was produced by Julie Kanfer and mixed by Eleanor Osborne, with help from Jasmin Klinger. We also had help this week from Lyric Bowditch. Our staff also includes Neal Carruth, Gabriel Roth, Greg Rippin, Rebecca Lee Douglas, Morgan Levey, Zack Lapinski, Ryan Kelley, Jeremy Johnston, Emma Tyrrell, Jacob Clemente, Alina Kulman, and Stephen Dubner. Original music composed by Luis Guerra. If you like this show, or any other show in the Freakonomics Radio Network, please recommend it to your family and friends. That’s the best way to support the podcasts you love. As always, thanks for listening.

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TARIOT: We’re near some military bases, so there will be some flyovers every now and then. There’s that new movie that was set here.

JENA: Wait. So, what was the movie? Was Top Gun filmed there?

TARIOT: Yeah. we’re about five miles from the base where it was filmed.

JENA: So, were you — were you an extra, or no?

TARIOT: Ah, no, I was —

JENA: Too busy.

TARIOT: — a body, you know, in the sea.

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  • Pierre Tariot, director of the Banner Alzheimer’s Institute in Phoenix, Arizona.