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Comment by louprado | Hacker News Reader

The documentary "Under our Skin" details Alan MacDonald's breakthrough research on how Lyme disease causes Alzheimers. The 4 minute trailer is worth a watch[1], but basically Lyme disease is found in 7 or 10 brains of Alzheimers patients (small sample set). The Lyme disease spirochete literally drills countless pathways in the brain and that causes slow dementia. That spirochete also creates a biofilm which makes it challenging to detect in a living patient. His research is from a decade or two ago.

Also I wonder how a citizen scientist like Gates does a deep dive on this topic a like this. There are 10's of thousands of research papers on the subject[1] and countless books.

[1] https://www.youtube.com/watch?v=GCLwauRh2gQ [2] http://archive.sciencewatch.com/ana/st/alz2/journals/

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Former Alzheimer's researcher here.

I've never heard of this before. Some cursory googling only turns up a sole author publication by Alan MacDonald in Medical Hypotheses and a few news pieces by dodgy organizations like the Spirochaetal Alzheimer's Assocation.

Despite what a lot of people learn in undergrad psych classes, the evidence linking amyloid beta and tau to AD is quite good and getting stronger with every new molecular paper that comes out.

BTW, there doesn't seem to be a correlation between Lyme disease incidence and AD https://www.ncbi.nlm.nih.gov/pubmed/24840565

There is a fair amount of more recent research in support of a microbial contribution to Alzheimers, and rather than just mediating through inflammation, disrupting metabolism in ways that accelerate amyloid deposition. I believe this ties more closely with research into vascular amyloid, if you look at who is involved, which may be why you haven't encountered it.

You might see https://doi.org/10.3389/fnagi.2017.00336 as a sample review paper that talks about oral bacteria that are capable of spurring amyloid formation in addition to spirochetes.

Lastly one of the complaints I've heard from someone involved in the cerebrospinal fluid drainage side of Alzheimer's research is that it is really, really hard to fight the amyloid clearance by immunotherapy dominant faction to get any funding or attention for alternatives. They just don't want to hear it.

Maybe there is no correlation because Lyme disease is severely underreported. A couple years ago, the CDC stated that official numbers were likely underreported by a factor of 10. From 30,000 yearly cases to 300,000 https://www.cdc.gov/media/releases/2013/p0819-lyme-disease.h...

There was also the case of actor/songwriter Kris Kristofferson being misdiagnosed with Alzheimer's for years. He had Lyme. This is anecdotal of course. https://www.cbsnews.com/news/kris-kristofferson-misdiagnosed...

Under-reporting of Lyme actually shouldn't impact a finding of no link as as far as I can tell. Despite the under-reporting, we still know where Lyme is more or less prevalent in the US, and I believe there will be very big differences due to climate and where ticks who carry Lyme tend to live. If prevalence of Alzheimers doesn't correlate with those big differences, that seems pretty clear.

(edit) Thinking about it more, I think the anecdote you mentioned is a bit different from the parent posts. The anecdote is about a misdiagnosis (he only had Lyme, not Alzheimers), while the parent posts are about people actually having both diseases.

The worry for me is the way this thread plays out is pretty much the textbook case for how pharmaceuticals manufacture demand for a drug.

1) Develop a drug (or find one to remarket). Find a disease that it treats or invent one.

2) Pump money into advocacy groups devoted to the disease.

3) Find research that supports the use of your drug.

4) The advocacy group spreads awareness of the disease, even if it's made up, and people start asking their doctors to test for it. Some may even receive a diagnosis.

5) Public pressure reaches the FDA, AMA, et al to consider the use of the drug for treatment.

3a) If research doesn't exist, find some impecunious person with a PhD and pay them to create some.

> "evidence linking amyloid beta and tau to AD is quite good"

About 100 discontinued clinical trials targeting amyloid beta disagree with you there, https://www.nature.com/articles/nrd.2017.194

Correlation need not be causation, but does imply linkage.

> the evidence linking amyloid beta and tau to AD is quite good and getting stronger with every new molecular paper that comes out.

Sure, but what causes the amyloid beta? Why wouldn't a long-standing syphilis-like bacterial infection in the CNS cause that sort of protein buildup?

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4399390/

It's a little shocking to see a "former Alzeheimer's researcher" presume that tau buildup and bacterial infections are mutually exclusive..

That's like saying heart disease can't be caused by arterial scarring because it's caused by plaque buildup.

Sure, but what causes the amyloid beta?

Recent research shows that lack of sleep increases both amyloid beta and tau. One of them increases after a single bad night. The other takes a few days of too little sleep to start spiking.

There may be other factors, but the research suggests we need to work on sleep hygiene for at risk populations. This is a non drug intervention that I can wholly get behind.

I found a study to back this up [0]

> "Spinal taps showed that the more deep sleep people missed out on, the higher their levels of A-beta in the morning. Tau levels didn’t budge because of just one night of slow-wave sleep disruption, but people whose activity monitors indicated they had slept poorly the week before the test also had higher levels of that protein."

https://www.sciencenews.org/article/just-one-night-poor-slee...

I.e. "But dudes, just WHY is the garbage piling up faster than it can be cleared, now?"

Love your plaque line - although plaque is compensation and amyloid beta and tau are not, or not per se.

Not per se, correct.

The plaques seem almost similar to remnants of an incomplete chemical synthesis. For instance, glutamate is synthesized in the brain and is used as a neurotransmitter.

If a bacterial infection prevented glutamate synthesization (potentially by utilizing some crucial component for it's own propagation), you'd see a build-up of otherwise useful amino acids that would manifest as plaques.

The plaques should hypothetically be cleaned by neuronal autophagy but something could be throwing that off as well.

And if neurotransmitter production is degraded, of course cognition will suffer. You seem similar symptoms in Schizophrenia as well.

Below I am reinterpreting your first sentence as "Not 'per se', correct." (Your original has roughly the opposite meaning of this interpretation, but I've been known to omit metaspeech-indicating quotation marks, myself.)

Your answer is interesting. For those following I should note that compensation means a curative or attempted curative event (as opposed to a disease event such as bacterial infection.)

As what is probably an aside, neurotransmitter production being actively downregulated as a compensatory mechanism (to lower local metabolism needs) is possible, and an interesting thought (whether my thought or your thought) (just not one that creates a buildup of tau etc.) I haven't encountered any evidence that this is compensatory and not just a downstream effect. Your mileage may vary. The evidence that mental activity reduces disease progression might be taken as disconfirmation of such an hypothesis - except that mental practice could be helping mask the underlying (progress of the) disease by increasing skill/adaptation.

Re schizophrenia, I now think of it as a definition affected by a kind of "publication bias." The underlying disease process (or processes) may have rather random results depending on just what part of the brain is most affected - only when the amygdala is strongly affected is a patient likely to get a diagnosis of Schizophrenia, since this can make them (or make them seem) "a danger of self or others."

Re Gates; he and his staff identify Subject Matter Experts (SME) for the topics he’s interested in. As you can imagine he has a good network. SMEs are always looking for funding, so he’ll use one of his funding vehicles to invite the SME to apply for funding or meet with the organization. By the time you meet with Bill Gates he would have read your most recent papers and competing theories and will be prepared to challenge you on your approach. Pass his final intellectual test and you are added to his collection of SMEs. <source: me, I’ve seen the process>

Edit: When I had the pleasure of watching Bill Gates do this, it was one of the most impactful moments in my life. When he would question a SME on a topic he came across as knowledgeable as the SME who has dedicated years to the topic. Bill Gates literally will have read all around the topic and his mind operates like a poker player or chess player who is thinking on multiple levels. His questions are probes to see how many levels you are thinking on, and I think it also informs him of other angles. He’s a brilliant guy.

Here's an account of what being grilled by Bill Gates looks like: https://www.joelonsoftware.com/2006/06/16/my-first-billg-rev...

SME seems be "subject matter expert".

I think it's "small and medium-sized entreprises" aka SMB

Fascinating. Any suggestions for how us "average Joe's" might get closer to his level of insight about anything when tackling new topics for self-driven education?

I feel like I could improve how I approach learning things in fields that are completely new to me, or where I'm far from an expert. From everything you have said and that I've read elsewhere, Gates and others at his level seem to have really honed their approach to learning and becoming able to have an informed conversation with an SME.

Did you watch him question someone who was an expert in a subject that you were also an expert in?

I did, but based on my limited experience he only goes deep into questioning when he’s vetting someone or when he sees or hears something that doesn’t seem right. He’s a stickler for details. With an engineers mind for logic and reasoning. You can’t bs him because he is investing in things he is actively studying from multiple sources. You need to know the details and logic behind your approach. The people I saw stumble on the subjects I knew about tended to get flustered when put on the spot and couldn’t provide a logical explanation that made sense or showed attention to detail.

Example, I’m making this up, but it’s a similar type of question I saw, someone is explaining how their application stores data, he will ask, “are you encrypting it?” Response: yes “how?” Response: using XYZ “why not ZYX?” Response: well, we haven’t thought a lot about that yet Response: “well what’s the impact on the processor when encrypting?” Response: not sure...

The engineer thought he was building a app to do X but Bill Gates is operating at a different level, perhaps he has a theory on the future of hardware, or how he wants to deploy this in developing countries. Or he read a recent paper where researchers highlighted the impact of encryption for this specific type of application that he thinks you missed. If he respects you, he will point you into a certain direction and it’s a peer to peer discussion and sharing of ideas, if he doesn’t...it’s painful to watch.

The way it was explained to Joel Spolsky in the article linked earlier is that Gates just pokes away at increasingly fine details until he finds some question you can't answer, and uses that to make you look dumb. Its actually just a form of intellectual bullying, like a jock who challenges you to an arm wrestling contest before he'll let you out of the changing room.

Thats not to say that Gates isn't extremely intelligent and hardworking, just that his approach isn't necessarily the best. Also, Spolsky's anecdote is from a few decades ago. Gates will have matured a bit since then.

I've heard the same regarding Jeff Bezos. A designer I think met with him and described him just like that.

But isn’t Lyme disease just in the eastern us? How would 70% of worldwide alz sufferers acquire it?

Lyme disease is not just in the eastern US. It is mostly diagnosed in the eastern US because doctors there are more familiar with it. There is a huge under diagnosis problem in the rest of the US. https://www.usnews.com/news/best-states/new-jersey/articles/...

There is actually quite a lot of lyme disease in Northern California. http://ipm.ucanr.edu/PMG/PESTNOTES/pn7485.html

Good question!

That’s why we need research. We don’t know if they have a common cause or just a common mechanism of action. They very well could be the same disease; Lyme Disease is not well understood and has been implicated in all sorts of neurological diseases such as Multiple Sclerosis and Alzheimer’s.

But the link isn’t quite obvious enough and the potential treatments, which rules out government money; and aren’t considered to be profitable, which rules out commercial money. Good for Gates stepping in here

What about this town in South America that has the highest concentration of Alzheimers in the world? The genetic mutation E280A seems to guarantee you get early onset Alzheimers ( at least I think it's 100% , couldn't find any info on what percentage with the mutation get it )

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4019728/

https://www.newscientist.com/article/dn28514-conquistador-br...

Wasn't there a vaccine for lyme disease btw? My understanding was that it was not high in demand so it was stopped being manufactured. So if lyme disease is implicated in any of this, the is already a treatment.

https://www.historyofvaccines.org/content/articles/history-l...

In short, they stopped manufacture because the demand was not high enough to defend the lawsuits - even though science was on the side of the vaccine (though this is partially hindsight, it takes years to do good science much less time to file a lawsuit based on a correlation)

There is a new vaccine entering trials now. I hope it works, but only time will tell. (for all I know it may have failed trials - success will take more time, but failure can be quick and I wouldn't always find out)

Thanks. I’m still not understanding how so many people could acquire Lyme disease and not have any of the other symptoms.

Because Lyme is often asymptomatic, other than the initial rash!

Lyme can be asymptomatic for _years_ and in many cases it doesn't even cause the initial rash!

Lyme disease is just one of a major class of bacterial infections. Syphilis is another. And there are several others...

https://en.wikipedia.org/wiki/Spirochaete

They aren't just limited to the Eastern US.

Although I have no clue how the body absorbs it, it seems that stevia (the alternative sweetener known as truvia) is remarkably good at curing lyme in vitro vs antibiotics[0].

[0]: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4681354/

Another interesting potential cause or contributor being researched is BMAA produced by blue-green algae and various other sources.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3295368/ [2012]

http://rspb.royalsocietypublishing.org/content/283/1823/2015... [2016]

It's really hard for a medical layman such as myself to sift through all the science. This source is interesting for the story of its discovery via ethnobotany even if it doesn't end up a smoking gun cause of Alzheimer's or other neurodegenerative diseases.

As for how a citizen scientist proceeds, go to pubmed.com and read the abstracts of at least 400,000 medical articles. I did.

quality > quantity

I doubt there are 400,000 papers worth reading in all of medicine. A major skill in research is understanding what to read, and how carefully.

Prepping to write a review usually involves about 150 articles, for me. About 50 of them just need a cursory look, and the abstract often suffices. Another 80 or so need some more attention; you might be looking for patterns in the methods used, cross-referencing results, figuring out what labs are doing what, tracking authors over time, etc. This is how you understand the state of a field.

The last 20 or so are the bulk of your time. A few are genuinely excellent and will be a highlight of the review. Some are simply solid work that requires a good amount of attention. A fair number are terrible and highly misleading. These are the papers that look okay, but have some flaws that need to be addressed by the field at large. It takes some tact to write about these, but it's usually not too bad.

Finding good authors, especially ones that write good reviews, can get you up to speed in a field in an afternoon. An evening chasing down citations and digging a bit on your own, and you're probably about where Bill was with this. Since Alzheimer's is a pretty big subject requiring familiarity with a variety of topics, I'd give it two weeks.

There probably are that many worth reading in all, but remember I read in medicine as a whole with one particular disease as a touchstone and as stated, I read the abracts of 400,000 and took notes on over 100,000; so there were some worth reading, by no means all! It's amazing how much is published, and how no-one is paid to just go read and wander through them. If you decide to just accept the standard consensus view of any moment in time, that will of course be a remarkably narrow view compared to the actual empirical evidence and might be covered in a day, starting with Wikipedia 'cause stereotypes are like that. I was reading, of course, in order to avoid just that problem. Look at everything published in a month or week on a fairly narrow medical subject and lots of tangents from and to that, and your eyes will likely open wider, too.

Very important studies are usually unexpected - that's part of what makes them important so we're verging on a tautology, there. So it's a matter of hindsight, in every field which contemporary articles are in fact "the classics." Your certainty and trust in current authorities broad knowledge and open-mindedness is a product of not knuckling down to read the abstracts of a few hundred thousand unrecommended journal articles - as well as a profound ignorance about the history of medicine.

That history more than suggests that if you want quality>authority (of contemporary publications) you'd better start reading, and reading nearly everything.

You read 400,000 abstracts? That would take something about 3 years full-time no?

At an hour per abstract (seems like a reasonable amount of time to understand the abstract), I get:

400,000 hours = 50,000 days (at eight hours a day) = 208 years (at 5 days a week, 48 weeks a year)

If the abstracts wern't really read and understood, just skimmed, perhaps it would be possible to do in a tenth of the time, so 21 years.

I calculated 1-2 minutes per abstract, since abstracts are usually not more than 1-2 paragraphs?

It depends - maybe three quarters of the abstracts took about a minute, sometimes less, since many are unreliable reports of drug tests that are closer to ads than info; there's also citation mongering resulting in three articles from exactly the same study, by the same authors saying the same result differently; plus many studies are confirmations from one population to another or are unique to tiny genetic lineages without broad implications; also many are review articles just in a new language or me-too studies. Others concern such topics as patient education improvements as opposed to changes in base medical knowledge. As for preliminary studies, these were a good source of gems, but unless they said something truly interesting they were easier to click past since not all that reliable. Finally there were some "we didn't find anything new" studies published; but not nearly enough get published (which has helped to cause the replication crisis.) Still some do.

In other words, there's a LOT of dross, but there are real gems lying there unread and uncited, too.

So only one in ten or a hundred articles might take an hour or more.

Average for all but the vital or good articles (after accumulating a good background and vocabularly), when I timed it back then: 100 an hour without losing any significant information. The vital remainder of 100 abstracts viewed took me (more of a guess, now) on average not more than double that amount of time, again; perhaps less time. That varied a lot because I was looking most keenly for overlooked knowledge(studies) and pairs of studies that were significant only once linked. Therefore I sometimes was willing to follow tangents to tangents just in case and could speed up at that point because it was nearly all dross.

Back when I was in university supposedly studying the history and philosphy of science and language, I had to visit medical libraries and use the CD disks from the then-private company Pubmed, and walk back and forth to a large, printed medical encycopedia chained to a pedestal and the desk-sized CD reader Pubmed provided. I don't include that reading as I took no surviving notes and wasn't counting abstracts way back then. Being able to research online when I returned to medical reading a couple of decades later was an immense relief. Switching tabs to get to a medical dictionary isn't nearly as much exercise, but it is a lot faster. Printed medical dictionaries for professionals have a LOT of pages to turn, in addition to the walking.

About ten years, all in, fulltime - because I read a lot of full articles and took notes on many; I have notes with keywords for over 100,000 articles. (Edit: Actually ten years probably got me to 250,000+, the rest since that time when I could devote all my time to that one task.)

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