Bayesian Investor Blog

Book review: The End of Alzheimer’s, by Dale E. Bredesen.

Alzheimer’s can be at least postponed for years in most people, and maybe fully cured.

The main catches: It only works if started early enough (and Bredesen only has crude guesses about what’s early enough), the evidence is less rigorous than I’d like, and it’s not a medical treatment, it’s a quantified self approach on steroids ketones.

My guess is that the book is roughly 70% correct. If so, that’s an enormous advance.

The protocol involves more tests than I want to count. These are almost entirely tests that are standard for some health-related reason. Bredesen suggests small changes to how to interpret those tests, and large changes to how much we should value optimizing the things they measure. It’s a strategy that says “normal” health is unacceptable, we need to do better. This part of the protocol seems to be backed by decent research indicating that we should expect some sort of health benefits from it. Most biomarkers are less reliable than is commonly reported, but as long as they point in the right general direction, it’s better than not to improve them.

The protocol also includes an even larger set of ideas about how to optimize those biomarkers via lifestyle changes, vitamins, supplements, and maybe prescription drugs for a few people. Here, Bredesen appears to be using a much wider mix of science and fads. E.g. there’s plenty of evidence that exercise is healthy. But for bone broth, he cites an article from mercola.com that’s rather weak about providing evidence for bone broth’s benefits. As these examples suggest, the protocol is probably safer overall than the average American lifestyle, even if a few parts do a little harm.

And we only need to trust him a tiny bit about the interventions he recommends, because he advises us to check carefully whether those interventions improve the biomarkers.

I first noticed Bredesen in late 2014 (thank you Andy McKenzie!). It looked more promising than most Alzheimer’s research, but I was suspicious of his advice that ApoeE4 patients consume coconut oil (he now admits he doesn’t know if it helps or hurts), and his other advice overlapped enough with things I was already doing for cardiovascular health that I responded with only tiny changes to my lifestyle.

He now has stronger evidence of benefits, and a more sophisticated protocol, so I’ve decided to put significantly more thought into improving my sdLDL and homocysteine levels.

2.

How plausible is it that a complex set of interventions work where single interventions have consistently failed? My understanding of Bredesen’s model implies that careful tests of individual interventions should show small benefits.

Wait a minute! Bredesen didn’t actually say that single interventions have failed! He said that single drugs have failed.

So I did a little research. Wikipedia pointed me to evidence about exercise, including a small RCT which shows important benefits (but needs many caveats). A bit more searching, and I find an RCT of B-vitamins showed some benefit, and this paper says that benefit happened mainly in people with adequate Omega-3s. I’ve already blogged about zinc and copper, where a small RCT showed weak evidence of benefits. Overall, single interventions seem to have better evidence than Bredesen led me to believe. Where are the large-scale trials that would be prompted by this evidence if we had a medical community that cared about preventing Alzheimer’s?

3.

My initial impression of the book was that it’s too good to be true. So, how could its most important claims could be wrong?

• Could he be intentionally dishonest? There’s no foolproof way to discredit this hypothesis, but also little reason to think it’s more likely than with typical research. He’s virtually guaranteed to attract more scrutiny than most – that would be a strange strategy to pursue if he had something to hide.
• Could he be cleverly only accepting patients who mistakenly think they’re developing Alzheimer’s? If true, this would imply that he has some pretty unusual skills, and that there are serious problems with how some other doctors diagnose dementia. I can’t rule out this hypothesis.
• Could he be selective reporting only the good results? I can see how he might be overstating the benefits this way, but I don’t see how it could explain his results if there were no benefits.
• Could he be measuring dementia poorly? There’s a weak sense in which most of the measurements are subjective. Maybe a professional poker player with a diagnosis of mild cognitive impairment could be mistaken about whether his poker improved. But his case studies include some pretty strong claims, including one report of a big increase in hippocampal volume measured by MRI, and one patient whose neuropsychologist advised him to “wind down his business and plan for the full-time care he would soon need”. Two years later that neuropsychologist measured the patient’s memory as having improved from the 3rd, 13th, and 24th percentile on three tests to the 84th, 79th, and 74th percentile, and the patient expanded his business.

  Those seem to be stretching the limits of what I can believe for measurement error.

Many people have strong priors about Alzheimer’s which lead them to find Bredesen’s claims less plausible than these hypotheses, based on past experiences with Alzheimer’s “cures”, plus stereotypes about what approaches to disease work.

Those priors might make some sense if researchers had tried many independent approaches. But it looks to me like the failure of most Alzheimer’s research can be explained by a small set of problems: reliance on rodent models, when hindsight tells us that Mouzheimer’s has different causes than Alzheimer’s. The inadequate exploration of different paradigms can be explained by an ordinary amount of groupthink plus bias toward approaches that support continued funding of areas that existing experts know best.

So it’s not wildly implausible that someone could find the equivalent of a trillion dollar bill (or maybe a ten billion dollar bill if he has overstated the benefits a lot). It’s not as if the bill was in plain sight – it’s more like it was torn into dozens of pieces, and hidden in leaves.

4.

What causes the widespread reluctance to adopt the kind of functional medicine that Bredesen advocates?

• Often patients wouldn’t do anything valuable in response to most of the tests that he suggests. I don’t expect doctors to like detecting suboptimal health and then watching helplessly as patients continue the lifestyle that caused the problem. Why would patients fail to follow the protocol? Partly because things like pizza and cookies are somewhat addictive. Partly because there are important social costs to admitting that we’re not healthy enough to eat at a typical restaurant or party. [1]
• These tests are mostly not patented, done by markets that are competitive enough that no company would get much from marketing them, and combined with FDA restrictions on marketing that require expensive evidence if anyone wanted to market them.
• Status quo bias (it’s hard to find other explanations of why people don’t switch to cholesterol tests that focus on the harmful forms of cholesterol)
• Functional medicine is associated with some conspicuously reckless doctors. (Mainstream doctors are sometimes reckless – not washing their hands, or saying that patients can’t do anything about Alzheimer’s, when they could say something like “regular exercise may improve your odds”. Somehow those mistakes stay less conspicuous than functional medicine’s recklessness.)

I’m unclear what the current reaction is from mainstream Alzheimer’s researchers. Bredesen seems to have gotten a mix of help and hostility in the past from mainstream institutions. The Buck Institute (of which Bredesen is the founding president) gets a good deal of NIH grant money, and he doesn’t appear to have trouble publishing peer-reviewed papers related to his Alzheimer’s ideas. But IRBs denied him permission to conduct a trial that involved an early version of his protocol (because it would have tested too many things at once).

That mainly seems like additional evidence that IRBs are unethical. It’s quite possible that his protocol hasn’t been stated clearly enough to qualify as a set of scientific hypotheses, and that it might end up testing some mix of articulated hypotheses and also the skills of the people involved [2]. If that was the IRB reasoning, it seems like a really awful reason for rejecting a trial. Even if it mostly ended up testing doctor’s skill at giving advice, a positive result would falsify the claim that Alzheimer’s cannot be prevented, cured or even slowed. [3]

5.

Bredesen presents a nonstandard biochemical model of Alzheimer’s. I’m not sure what to make of it. It doesn’t seem particularly helpful for understanding why the protocol works. It does explain why the simple amyloid-beta hypothesis is wrong, but it’s hardly the only hypothesis to explain that.

He classifies Alzheimer’s into three semi-distinct subtypes. I’m fairly convinced that Alzheimer’s refers to more than one disease, but I don’t get the impression that anyone knows how many subtypes can be usefully identified.

6.

Bredesen seems confused about the diet that humans evolved to eat. “[H]umans evolved to handle only small amounts of sugars (about 15 grams per day”, and his figure 10 says that humans had a low-carb diet for the 7 million years before agriculture (and what does “God Gene” mean?). We don’t have good evidence about human diet over that period, but it looks pretty likely that humans relied mainly on fruit during the early part of that period, and relied on high-carb roots during some parts of that period. Some modern hunter-gatherers (Hadza) eat way more honey than that 15 gram limit would allow.

Maybe American lifestyles create a need for that strict limit, but that need isn’t inherent in our biology.

While evidence from hunter-gatherers weakens some of Bredesen’s specific advice, it strengthens his claim that Alzheimer’s depends on lifestyle choices: there’s moderately good evidence that hunter-gatherers don’t get adult-onset dementia [4].

7.

The book has somewhat inadequate warnings for people who want to wait until they get more severe symptoms: readers might imagine that a delay in implementing the protocol will just make recovery slower and/or more expensive. NO!! The protocol is already pushing the limits of what we have the mental capacity to implement (in some people; the difficulty will vary unpredictably from person to person). Delaying until the symptoms become noticeable makes it harder to learn new habits, harder to track whether you’ve taken the right pills, harder to prepare new recipes, etc.

8.

What do I expect if he’s right?

I expect an expanded number of doctors using his protocol over the next few years to reach something like 10,000 people who are at risk of Alzheimer’s. I expect a similar number of patients to see doctors who doctors who try to follow the protocol without being trained by a Bredesen-approved teacher. I expect these doctors to report widespread improvement in these patients, and I expect those reports to be controversial due to risks such as selective reporting. I expect these doctors to report that around 30% of patients didn’t comply well enough to get good results.

I expect some sort of clinical trial to be completed within three years, using an algorithm that implements something like 75% of the advice described in the book. I expect it to report results that look about 1/4 as impressive as this book reports, with a bit less that half the patients complying fully with the protocol.

I recommend that the trial be evaluated in two separate steps: a test for biomarker improvement, and test for cognitive changes given some pre-specified biomarker improvement. My hope is that will distinguish problems with patient compliance from issues of how improved biomarkers affect dementia.

I’m unclear how the average doctor will react after those trial results are released. But among doctors that are relatively open to new ideas, I expect a profusion of competing protocols, with poorly documented claims about how well patients comply with the protocol.

I expect that as the number of patients using these protocols exceeds 100,000, patient compliance will drop to about 50% for the most effective protocols (the earlier patients were way more motivated than the typical patient).

I expect that by around 2023 to 2025, at least half a million patients will use one of these protocols, and that will be sufficient to a decline in the overall number of people developing Alzheimer’s.

Conclusion

The book seems slightly careless about details such as citing good references, as if it were rushed to print (rushing does seem appropriate). I suspect he exaggerates the benefits.

He errs slightly in the direction of allying too much with alternative medicine. Mainstream medicine has some major flaws, but it’s still important to persuade mainstream institutions to listen to the book’s ideas.

But it’s good enough to persuade me to experiment with significant changes to my diet and supplements, and maybe enough to convince me to donate to the Buck Institute.

footnotes

[1] – the book won’t tell you directly whether it’s safe for you to eat at restaurants and parties. It will tell you how to get evidence about whether those are safe for you.

[2] – the book outlines the protocol well enough that a highly motivated person will usually be able to follow it, but it doesn’t look like a complete algorithm. E.g. my current guess is that the book doesn’t include enough advice to get my sdLDL down to good levels. But the book did get me to look at apoe4.info, and find ideas that seem more directed toward my situation.

[3] – That’s from the top result in my Google search for Alzheimer’s. That page has an automated(?) list of recent news headlines. These two showed up on the same alz.org page as the “cannot be prevented” claim when I visited it:

• Healthier living could reduce worldwide dementia by a third, report says – The Washington Post
• One in three dementia cases ‘could be prevented by lifestyle changes’ – London Evening Standard

I hope this is a sign that cognitive dissonance on the subject has reached a maximum.

[4] – see Lindeberg, Food and Western Disease. There are important limits to how reliable this evidence is, but the researchers were able to get decent evidence that some hunter-gatherers lived into their 80s, that hunter-gatherers did have people whose cognitive ability was impaired from childhood, and consistently did not know of late-onset cognitive decline.

Beware that “it’s due to modern lifestyles” doesn’t guarantee there’s a reasonable strategy to avoid Alzheimer’s. Modern population densities support infectious diseases that hunter-gatherers don’t get.