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Chapter 1: What recent advancements have been made in early detection of Alzheimer's disease?
You may have seen the news recently about two new FDA-approved blood tests that may detect Alzheimer's disease in the early stages. Early detection is important for any disease, but especially for Alzheimer's, which can take root for 20 years before symptoms develop. These symptoms, as you probably know, include memory loss and other cognitive, physiological and behavioral issues.
The reason I say that you probably know these symptoms is because Alzheimer's affects more than 7 million people in the U.S., most of them over 65. Age-related memory loss has been seen throughout human history, but the disease was not formally documented until 1906 by the German physician Alois Alzheimer.
When Alzheimer autopsied the brain of a woman who had had memory loss and hallucinations, he found that her brain had shrunk and withered with numerous tangles and what he called peculiar deposits.
Chapter 2: How has the history of Alzheimer's research shaped current understanding?
Scientists have been trying to figure out those deposits and tangles ever since. The National Institutes of Health spends around $4 billion a year on Alzheimer's and dementia research. That's up from around $1 billion a decade ago. And that puts it second only to cancer spending, which makes sense because the elderly population in the US is big and getting bigger.
Much of this Alzheimer's research is centered around one dominant theory of the disease. But what if that theory is flawed?
Chapter 3: What are the implications of flawed research in Alzheimer's studies?
No one's getting better with these drugs. Every scientist who works with them, every clinician, will say the same. If they don't, they're lying.
So is flawed even the right word, or should it be fraud?
Cheaters tend to cheat. When we find clear, overt problems in a paper or in a group of papers, often it propagates through somebody's entire work.
Today on Freakonomics Radio, we follow an investigation that found decades of problematic Alzheimer's research. And we ask, with some sense of earned optimism, where does Alzheimer's treatment go from here?
Chapter 4: What environmental factors contribute to the risk of Alzheimer's disease?
This is Freakonomics Radio, the podcast that explores the hidden side of everything with your host, Stephen Dubner.
The story we are telling today is a sobering one and an important one. We'll hear from two people. We had hoped there would be more, but in the end, the others did not want to talk. You'll understand why as we go. Let's start here.
My name is Charles Piller. I am an investigative journalist with Science Magazine and author of the book Doctored.
The full title of Piller's book is Doctored, Fraud, Arrogance, and Tragedy in the Quest to Cure Alzheimer's. Charles Piller has been a journalist pretty much his entire adult life.
I grew up in the Chicago area. I became interested in reporting kind of the way that so many people, boomers like me, did, being inspired by the Watergate investigations. I was too young to be a journalist then, but not too young to be inspired and thinking about things, particularly during the Vietnam War period and all of the societal challenges there.
Pillar is 71 years old. Before coming to Science Magazine, he wrote for the LA Times, the Sacramento Bee, and the life sciences news outlet, Stat. For the past several years, his reporting has been focused on Alzheimer's research. I asked him why.
Well, the answer is, to me, pretty clear, and that is that unlike cancer, diabetes, heart disease, and myriad other ailments that afflict us, Alzheimer's disease is something that the nation and the world has spent tens of billions of dollars on in recent decades, and yet we have no cure.
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Chapter 5: How does the amyloid cascade hypothesis explain Alzheimer's progression?
that arrests or reverses the terrible cognitive decline of the disease. And so even though there may be corruption in cancer research or in heart disease research, we've seen enormous advances in those diseases and sometimes even real cures for specific ailments that have benefited society dramatically.
We have not seen that in Alzheimer's disease, and that makes it not just more tragic but also terrifying for people who are facing those possible symptoms.
What is the thinking on potential environmental drivers of Alzheimer's disease?
Yeah, it's a great question. And I would say that care and prevention is one of the key things that I think our society should be increasingly concerned about. It's well known that people who are subject to highly polluted environments are experiencing Alzheimer's at a higher rate and also at a more severe age of onset, earlier age of onset.
Secondly, I would say that like so many ailments in our society, Alzheimer's is in part a disease of inequality. Now, of course, anyone from any economic level can get the disease, but it's more prevalent among people who do not have the same level of economic opportunities.
To what degree would that be caused by less or worse medical care itself? In other words, how much advantage is there to early or constant monitoring and then whatever kind of treatment there may be?
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Chapter 6: What ethical concerns arise from the whistleblower's investigation?
Or are you saying that low-income people may have in their lives drivers that are responsible for Alzheimer's?
I think it's both things. Clearly, problems like obesity are important in Alzheimer's disease. The other thing is that they've found over and over that the higher educational attainment that people have, it has a benefit that can reduce the severity or the age of onset for the disease.
Okay, so that was Charles Piller on a few potential drivers of Alzheimer's. So how does the disease itself work? For that, we need a neuroscientist.
My name is Matthew Schrag. I'm an associate professor of neurology at Vanderbilt University Medical Center. I take care of patients who have strokes and memory problems, and I run a laboratory trying to understand how blood vessel diseases contribute to memory problems like Alzheimer's disease.
Describe for me how much of your work is... what a layperson like me might consider Alzheimer's-related?
Most of it. Our perspective is that blood vessel diseases contribute to Alzheimer's disease. We don't think of Alzheimer's disease as a blood vessel disease, but that's one of the issues that we've been working on is trying to understand the degree to which these other factors that have been largely overlooked may play a key role in how this disease works.
So just walk me through quickly all the schools you attended and all the degrees you got.
I was at the University of North Dakota for my undergraduate work. And then I went to Loma Linda University and I got an M.D. and Ph.D.
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Chapter 7: What challenges do researchers face in developing effective Alzheimer's treatments?
there. And then I went to Yale for my residency work.
Were you wanting to be this kind of scientist since the time you were a kid? Did your family or school or background encourage you?
Not really. You know, this happened partly because I sat down with somebody when I started getting serious about trying to get into medical school. and said, what are the things I should do to improve my odds of getting in? And one of the things they said is, well, you should do some research. I went and knocked on my professor's office and said, can I do some research?
And he said to me, son, they didn't mean botany. And so he very graciously didn't take advantage of me and shuttled me to a more appropriate laboratory.
The lab that Schrag got shuttled to was run by a neuropharmacologist named Othman Grebe, who studied Alzheimer's.
I really enjoyed the atmosphere in the laboratory. I really loved the ways that you could try to study things that were too small to see and try to infer how complicated systems worked.
The research that Schrag worked on with Grebe looked at the potential impact that diet could have on the onset and progression of Alzheimer's. In 2006, they and a few other co-authors published a paper in the Journal of Neurochemistry called Deposition of Iron and Beta Amyloid Plaques is Associated with Cortical Cellular Damage in Rabbits Fed with Long-Term Cholesterol-Enriched Diets.
So what was the idea of this paper?
The idea of this paper was that cholesterol accumulates in the brain. We had raised a group of rabbits and fed them a high cholesterol diet, which was thought in some ways to mimic Alzheimer's disease. And the thought with this paper was that cholesterol levels would accumulate within the neurons themselves and that that could have a toxic effect on the neurons.
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Chapter 8: Is there hope for future breakthroughs in Alzheimer's research?
Where did the tau cells come in in that scenario? Tau is inside the neurons. It's a protein that is involved in the structure of a neuron. And if you think back to high school biology, you know, the neuron is this big, complicated cell that has a very long tail on it. It's one of the biggest cells in the body, and they have to live for your entire life.
And the tau protein is part of how the cell gets that unusual structure with the long tail that allows it to function like an electrical wire. So if you have tau clumped together and no longer participate in maintaining the skeleton of the cell, the cell doesn't function properly.
So that's the second key piece of what's going on in Alzheimer's disease, that the neurons are structurally destabilized. So for at least since, I would say, about 1990 in round numbers, the main thought in this field is that the plaques, this little beta amyloid protein that clumps outside of the cells, is the primary driver of the disease.
And a huge amount of the effort related to drug development has been dedicated to preventing it from accumulating or breaking it up and clearing it from the brain. The general idea is that plaque is the first domino, and then there's a complicated series of events leading up to the neurons dying. But the plaque is the primary driver of Alzheimer's disease.
This domino effect is known as the amyloid cascade hypothesis. And that is the hypothesis toward which many billions of research dollars have been directed. So what's the problem with that?
The problem is, one, the idea may not be correct. And two, the biology of this is likely much more complicated. And I think that this is the primary issue, is not that beta amyloid has nothing to do with what's going on, but most diseases at the end of your life are not simple. I can't think of another disease where there is one single first domino that falls that causes the rest of the cascade.
By targeting just one very specific factor, I think we're not having a big enough impact on the disease.
Schrag's own research, which looks at the connections between Alzheimer's and blood vessel diseases, is a pushback against the amyloid cascade hypothesis. And Schrag has also been pushing back as a whistleblower. I understand that outside of your work at Vanderbilt and your work within the academic community generally, that you also work as an independent research integrity consultant.
Are all four of those words correct and in the right order?
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