Dementia and the modern research universe

On delaying philosophical death as long as possible

Dementia, it has been said, is a kind of philosophical death, rather than a biological one

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. Dementia takes from us many of our most human parts: our connections to one another, and to our own past, and to a future that is no longer conceivable. It leaves a living shell.

Memory often softens with age, fraying around the edges—where are the keys, what is that word, when was the celebration so many years ago. In some people, though, memory becomes brittle and jagged—a piece breaks off, puncturing other memories as it shatters, leaving gaps and wounds where once there was history and meaning. Why is a stranger here, saying that he loves me? Who is that person looking at me in the mirror?

Yet even those with the sharpest minds, those most capable of insight and analysis, and still young, forget most of what they know and experience. We need to forget most of what we experience, lest we become like Funes the Memorious

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, the protaganist of an eponymous short story by Jorge Luis Borges, who remembered absolutely everything, every “leaf on every tree of every wood…even every one of the times he had perceived or imagined it.” Funes, precisely because of his memory, was incapable of synthesis:

“I suspect, nevertheless, that he was not very capable of thought. To think is to forget a difference, to generalize, to abstract. In the overly replete world of Funes there were nothing but details, almost contiguous details.”

If you remember every tree, you cannot make out the forest.

A life full of seeing both trees and forests unravels when dementia arrives. The opposing condition, in which a person becomes incapable of forgetting, is a rarity, whereas some form of dementia happens to so many as we age. And so, as the human population ages, scientific researchers are hard at work to discover ways to halt the disintegration of memory.

Much effort has gone into unearthing what the problem is, and how to stop it. Some of that work has been fraudulent

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. Much of it has looked for the magic bullet that stops Alzheimer’s

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in its tracks. Alas, searches for magic bullets in complex systems are generally in vain.

This week, new research was published which claims to find that exercise is the best way to reverse much of the gene dysregulation implicated in Alzheimer’s Disease

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This is, in one way, very good news indeed. If we do what we should all be doing anyway, what all of our ancestors did until recently—move our bodies, frequently, with variation in intensity and duration—this will help allay the risk of dementia.

But the published research gives me substantial pause, and at risk of going simultaneously too far inside baseball for some, and not nearly far enough for others, allow me to explain why.

The paper is a chaos of complicated model-driven methods which are essentially unassailable unless you specialize in those very methods. To what degree did the peer reviewers and editors a) understand the work, b) critically assess the work, and c) truly have no competing interests? The research is published in a Nature property

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which, while impressive, does not mean what it once did, when Nature was one of the two most acclaimed science journals on the planet. And perhaps publishing in Nature never actually meant what it once seemed to. To what degree is reputation earned, I wonder, and to what degree is it assumed? How many Potemkin institutions are there, and was there ever anything behind the façades?

I don’t claim to be able to fully assess this research. My interpretation of the paper is compromised by my lack of familiarity with the methods. But one thing that jumped out is that, from over 250 “treatment datasets,” the top three in reducing dysregulation of genes implicated in Alzheimer’s symptoms did in fact involve exercise, but at the sixth position among 250 we find safflower oil

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. Really? High consumption of a seed oil helps with Alzheimer’s

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? Color me skeptical. This result causes me to question further the intricate web of models and methods used.

Furthermore, the research lacks a hypothesis. This, alas, is a standard approach in model-heavy papers, especially in bioinformatics, and is all too often what “data-driven” means: let pre-existing data inform you, the researcher, of what you think is going on. That’s not how science is supposed to work

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. A hypothesis (preferably several hypotheses) should come first. The researcher then tests those hypotheses, the tests yield data, the data are analyzed, at which point they have either falsified, or failed to falsify (and thus provided some support for), said hypothesis. Absent a hypothesis, though, what do we really know here? Apparently, one thing that we “know” from this approach is that a diet high in safflower oil may be protective against Alzheimer’s.

The research is also highly reductionist, which is, similarly, typical of a model-heavy, bioinformatics, data-driven approach. It takes longer to do science that isn’t reductionist—sometimes longer than the time scale of a career. Non-reductionist science almost always takes longer than the funding cycle for granting agencies, and often longer than tenure review committees are inclined to wait. Reductionism facilitates both the use of metrics (which are easy to parse, measure, and communicate) and short research timetables. Faster results means more publications means more grants means more prestige, on and on and on and on. But faster, as should be well apparent by now, does not inherently mean more accurate. Too often, it means less accurate.

Not only doesn’t faster mean better, more tech and more names for things don’t mean better, either. From the paper published this week, we have, again, the finding that, among hundreds of genes known to be “dysregulated” in patients with Alzheimer’s Disease (AD), exercise reversed their expression, suggesting a return to normalcy. Looking at connections between Alzheimer’s and exercise, the legend for figure 3 explains helpfully that “CDC42, STAT3, NOTCH1, SNCA, YWHAZ, and MAPK8 were among the genes with the most connections.”

Okay, but what do these genes do? Does anyone know? Here’s what the authors have to say about the first gene on their list:

“CDC42 (down in AD) is of interest as it had the greatest number of interactions with other genes reversed by exercise for the top two exercise datasets (Figs. 3, 5). CDC42 is a small GTPase of the Rho-subfamily and is connected to multiple pathways relevant to AD, including MAPK signaling, actin organization, cell junction, and CNS development. The possible role of CDC42 in AD may be complex as one line of research suggests inhibition as a pathway for treatment, while another suggests activation as an approach to offset AD-like pathologies.”

If you read that and think: “ooh, lots of big words and invocation of data, I’d better trust their conclusions,” that is the wrong response

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. Basically, the quoted section means this:

The gene CDC42 is prominent in our research results. Research that came before ours has characterized it molecularly. Other research has indicated that CDC42 is involved in myriad biological functions which appear to be relevant to Alzheimer’s. Some of the research is contradictory, however: one line of research proposes downregulating the gene for treatment of Alzheimer’s, while another proposes upregulating the same gene in pursuit of the same end.

Put another way: We know details about this system, and we may now know some associations between some of those details, but we don’t have a big vision, or insight, into what all is going on in this system, and messing with it may result in us doing exactly the wrong thing.

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Out of a reductionist, data-driven, model-obsessed research universe comes the result that exercise may protect against, or even reverse, Alzheimer’s. If true, that’s awesome.

Some people will get sick with the worst diseases no matter how exemplary their health, diet, activity, and behavior. But if you remember your history, and know that never before have we lived such slothful, processed, pre-digested lives, you will recognize that you can mitigate the risks of getting the terrible diseases, even if you can never reduce the risks to zero. We can all mitigate our risk of disease, with a bit of intelligence and awareness of trade-offs, and without compliance to flat grey authorities.

At the end of every episode of DarkHorse, I say these words:

Be good to the ones you love,

eat good food,

and get outside.

Be good to the ones you love. Put down your tech. Look people in the eye—both the ones you love, and the ones you don’t. Imagine what it is like to be them. Have conversations.

Eat good food—real food, food that still bears the signature of its ingredients, ingredients that were recently alive. Prepare your food with attention, or appreciate those who do it for you. Eat it with gratitude and gusto, and take your time.

Get outside, into the sun, and the wind, even the rain and the snow and the cold. Be exposed. Allow your body—force your body—to respond to the elements, and watch as your body becomes more resilient, more anti-fragile.

Move your body, swiftly and slowly, morning and evening, day and night. Ask it to do things you haven’t asked of it before, or don’t ask of it often. Find the joy in not knowing if you can accomplish what you are trying to accomplish. Discover the answer.

Inquire of yourself what you should be doing. Do you create? Discover? Heal? Explore? Listen? Lead? Help? What is the contribution that you most want to make, that you are best positioned to make, to an individual, or a family, or humanity, or to the beautiful planet that we call home? Work towards that.

And may biological death and philosophical death arrive simultaneously, as late as possible.

1. Yang et al 2016. History of Alzheimer's Disease. Dementia and neurocognitive disorders, 15(4): 115-121.

2. This and other Borges short stories can be found in Ficciones (orig pub 1942, John Sturrock ed; 1st English translation: Grove Press, 1962; reprinted by Alfred A. Knopf/Everyman, 1993, pp83-91).

3. I discussed fraud in Alzheimer’s and other research here on Natural Selections, on August 23 of this year: On Fraud: And Being Science-ish.

4. I am going to use the terms dementia and Alzheimer’s Disease somewhat interchangeably. While the latter is considered a disease, and the former is not, these categories feel forced to me, and likely at least partially wrong. “Disease” is defined in part by having a known cause, which Alzheimer’s does not.

5. Hill & Gammie. 2022. Alzheimer’s disease large-scale gene expression portrait identifies exercise as the top theoretical treatment. Sci Rep 12: 17189. https://doi.org/10.1038/s41598-022-22179

6. Also? Used to be that Nature was Nature—one of the top two premiere scientific journals in the world. Now Nature has (…Oversees? Has editorial input into? Owns? I do not know) a whole slew of more specialized publications—Nature Genetics, Nature Human Behavior, Nature India, and Nature Machine Intelligence, to name just four, in alphabetical order, from a stable of more than 150 journals, as of this writing.

7. The comparison to safflower oil was only to (a diet high in) flaxseed oil, however, so this result is of limited generality.

8. Also in the top 25: cocaine and methamphetamine.

9. I have discussed the scientific process in many places, including most recently here, on September 6: Science Misunderstood: and left to fail by those who would claim to be its champions.

10. If you read the quoted text wrong, that’s not surprising, both because it’s a mess of jargon and abstruse detail, and because we have all been encouraged to follow authoritative pronouncements without hesitation. It is useful to authorities to have a quiescent, compliant populace. But democracy depends on there being an informed populace filled with people who ask for evidence, who are, furthermore, willing to wait for said evidence before acting.