Do viruses trigger Alzheimer's?
economist.com
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Memantine is an antiviral/nootropic (NMDA agonist) that's considered one of the best conventional therapies for Alzheimer's. For e.g., https://pubmed.ncbi.nlm.nih.gov/32914577/
Amantadine is a related compound that's seemingly more potent as an antiviral, and less potent at the NMDA receptor.
Medical hypothesis: This makes me wonder if amantadine might be an effective drug in Alzheimer's treatment. It would come as a total shock to the med chem community if memantine's activity had to do with its suppression of viral replication, and much less to do with its activity at the NMDA receptor.
As an aside, the Russians have a similar drug called bromantane which is sold OTC as a sort of mental energy booster. It's not really a stimulant, and its effects are mild enough for daily use. It might also be very interesting in this context. https://en.wikipedia.org/wiki/Bromantane
NMDA agonists and acetylcholinesterase (they inhibit the breakdown of the neurotransmitter acetylcholine) in general.
Benadryl (DPH) and first-generation antihistamines are the opposite of that, they can cause delirium (and it messes up your memory and cognition in general) and whatnot, they are anticholinergic, some more than others. I had anticholinergic toxicity from DPH before.
I take Alpha-GPC (a very soluble form of choline) and Huperzine A for cognition / memory, others couple it with racetams (e.g. piracetam, pramiracetam, aniracetam, etc.).
But Zyrtec is second-generation. It shows 20,000-fold or greater selectivity for the H1 receptor over the five muscarinic acetylcholine receptors, and hence does not exhibit anticholinergic effects, so it should be OK. May still cause drowsiness, however.
From Wikipedia:
> At very high doses, it is also an antagonist at various subtypes of the muscarinic acetylcholine receptors. This effect is not relevant for the drug's action at therapeutic doses.
Thus, it is an anticholinergic only at very high doses, and it does not readily pass the BBB, therefore drowsiness is NOT likely (probably at very high doses only). At any rate, it does not affect the CNS at therapeutic doses, so memory / cognition issues, along with drowsiness are not an issue.
FWIW "2% of Caucasians and 18% of people from African descent are desloratadine poor metabolizers.", meaning "In these people, the drug reaches threefold higher plasma concentrations at seven hours after intake, and it has a half-life of 89 hours (compared to a 27-hour half-life in normal metabolizers). Adverse effects were reported at similar rates in poor metabolizers, suggesting that it is not clinically relevant.".
I think perhaps the genetic variation in the enzymes involves in its metabolism like UGT2B10 and CYP2C8 may contribute to differences in metabolism. There is just no conclusive identification of specific SNPs that definitively determine poor metabolizer status. The precise genetic variants (if any) have not yet been definitively pinpointed.
For all we know, the differences may be attributable to variations in study design, sample sizes, definition of what constitutes a "poor metabolizer", and genetic heterogeneity among populations. Some reported rates of poor metabolizers vary, some studies report around 7% overall and 20% in African descent individuals, while others suggest the figures I have mentioned. There was a somewhat recent randomized study in healthy Chinese subjects, and found no statistically significant association between the UGT2B10 or CYP2C8 genotypes.
What is clear is that while genetic factors are likely involved and poor metabolizer phenotype exists for the drug, no single genetic marker has yet been found to predict poor metabolism of this drug, and there is a notable interethnic difference in desloratadine metabolism.
TL;DR: Currently there is no definitive evidence linking specific SNPs to poor desloratadine metabolism, but genetic variation in enzymes like UGT2B10 and CYP2C8 is implicated, but further research is needed.
I hope this answers your question, but the bottom line is that more research is needed. If you know something, let me know though!
- For example nothing happened from 190 x 1 mg alprazolam + 0.5 L whiskey.
- None of the psychiatric medications worked for me (tried almost all there is, it took a long time). No pros, nor cons.
- Opiates do not cause euphoria, nor sedation for me. Without tolerance.
- The list goes on...
I have never figured out why medications affect me extremely differently from other people.
I took 5 x 50 mg DPH, nothing happened, then the next day I took it again, and I got anticholinergic toxicity. Perhaps it accumulated in this case, but yeah, it was one of the worst experiences I have had (delirium with dysphoric hallucinations, cognitive decline, memory issues). Took me months to recover. I have had auditory hallucinations for a couple of days, too.
What cholinergics and anticholinergics have you tried and what were your experiences?
As for what you said regarding alpha-GPC, it is somewhat true:
> Although alpha-GPC is largely considered to be safe due to its structural feature, multiple studies have indicated that a high plasma choline level is associated with an increased risk of cardiovascular disease through trimethylamine-N-oxide (TMAO) produced by gut microbiota from choline. Some studies have highlighted that TMAO increases the likelihood of stroke and cardiovascular disease.11
> In line with this observation, a recent animal model study revealed that even though alpha-GPC supplements improved neurological functions, they increased the risk of atherosclerosis in hyperlipidemic rats. In the future, scientists must elucidate the possible mechanism that associates alpha-GPC with increased cardiovascular risks.
https://examine.com/supplements/alpha-gpc/?show_conditions=t...
https://www.news-medical.net/health/Alpha-GPC-What-Science-S...
https://pmc.ncbi.nlm.nih.gov/articles/PMC8708068/
https://www.sciencedirect.com/science/article/pii/S002192582...
That said, "However, the currently available evidence is preliminary in nature, so randomized controlled trials and large cohort studies are needed to confirm these findings.".
Memantine has been useful for slowing down Alzheimer's and temporarily improving responsiveness. However, Memantine has not shown any effectiveness in reversing Alzheimer's or fully stopping its progression (sadly). Memantine does seem to increase self-awareness clarity but, counterintuitively, seems to also disrupt memory recall. Word of caution, in one rat study, I had read that Memantine could have long term side-effects of hindering memory recall.
Amantadine has a fascinating structure, but it seems like it's not super useful by itself from studies. It seems more like a very promising 'base structure' to build future compounds upon (like Memantine and bromantane).
Anyways, this family is rather interesting for a number of its properties and are still not very well known or understood. Please do share any more insights.
- Unlike amantadine, chemically-related tromantadine is potently effective against HSV. https://pmc.ncbi.nlm.nih.gov/articles/PMC185716/
- There's another paper which may shed some light on the herpes-Alzheimer's connection, and it notes that treatment with tromantadine (among others) is starkly beneficial: https://pmc.ncbi.nlm.nih.gov/articles/PMC5935641/
- If the connection is established, it could be that a tromantadine-like molecule with activity against herpes simplex -- plus mild activity at the NMDA receptor reducing excitotoxicity and protecting neurons -- could potentially be a good prophylactic against Alzheimer's.
- It would be interesting to test amide-linked amantadine-phenylalanine and memantine-phenylalanine conjugates. Such things would probably penetrate the BBB very well, as they could take advantage of amino acid transporters. (The LAT1 transporter in particular.) And they resemble tromantadine -- where it is said that the amide itself is a necessary moiety in countering HSV. Structure: https://i.ibb.co/7tS4MGGL/Amantadine-Phe.png
edit: Fun fact, the side effects were so bad I made a very big mishap that destroyed a (very very expensive) f-class flight simulator.
It made me wonder how much of aging is mediated by damage from infection, which we fight off, but come out of weaker for it.
It certainly makes me want to double check all my vaccines, and once my kids are older, practice a little better hygiene including things like masking up in tight spaces (pretty much impossible with a 6 and 9 year old in the house, they are the vector right now).
We're sick far less often nowadays. Common illnesses were more common in previous generations. Back in the day "everyone got measles".
While people fear being "too clean" there is also a downside to being "too exposed".
The hygiene hypothesis does not suggest that having more infections during childhood would be an overall benefit
If you start looking into it it's due to an immune response that occurs in people with the https://en.wikipedia.org/wiki/HLA-B27 gene and that gene is associated with a large number of athritis risk factors (but also resistance to a lot of things including HIV).
As for pathogenic viruses in the gut, immune boosting supplements, glutamine, and collagen should help with treatment.
I had a post viral effect after Covid. But maybe 2 months. Then I finally took it easy with working out and it went away.
Outsider view: while I'm excited we're making progress, I can't shake a feeling of sadness that the best we could manage was a study this small, started 7 years ago. If it's as pivotal as the article suggests, one would hope we could get more than 60 people in the experimental arm (IIUC this antiviral is widely prescribed, well-tolerated, and off-patent). Nonetheless, excited to see the outcome
Let's be honest, this is a longshot.
Well there’s your problem: no one can make money off of it, unless they develop a new delivery mechanism, etc.
Patents encourage developing new medicines, but not developing new knowledge about (never mind use of) old medicine.
The solution (in the US) is obvious: federal funding of research that stands to help lots of people but not make lots of money. Since most of these patients (in the US) are going to be on Medicare, there could be huge potential cost savings to the taxpayer: memory care is EXPENSIVE, so even the paltry amount covered by Medicare racks up (and the opportunity costs of people paying for private memory care is enormous).
But instead of increasing funding for this kind of life- AND MONEY-saving research, this administration is freezing and slashing research funding, and specifically targeting Columbia for political/Trump’s-petty-grudge reasons.
But both the federal and state govts do fund tons of such research. Some states have specific Alzheimer's trials and funds. I would think they could handle dirt-cheap therapies like this without getting into sweeping political changes. Though I suspect the solution is much harder than just run a trial with the drugs we have, or else we would already be hearing about mountains of evidence from doctors using the medications off-label.
Having said that, I think you're right that under this system, research/capital definitely gets directed in a different way.
mRNA vaccines, semaglutide, mAB therapies, none of these would have happened without patents as an incentive.
Another interesting one is [1] where they asked readers of the BMJ to vote on the top 15 most important medical milestones. Of the 15, only the contraceptive pill and Chlorpromazine had anything to do with patents.
In [2] the "Chemical and Engineering News magazine" collected a list of top pharmaceuticals (46 total). To quote the book I linked:
> Patents had pretty much nothing to do with the development of 20 among the 46 top selling drugs [..] . For the remaining 26 products patents did play an important role [..]. Notice though that of these 26, 4 were discovered completely by chance and then patented (cisplatin, librium, taxol, thorazin), 2 were discovered in university labs before the Bayh-Dole Act was even conceived (cisplatin and taxol). Further, a few were simultaneously discovered by more than one company leading to long and expensive legal battles, however, the details are not relevant to our argument.
Regarding the cost of drug trials, they cover this well in Chapters 9 and 10, I found it quite interesting.
Regarding how else companies make money without being granted temporary govt-backed monopolies, Chapter 6 covers both the theoretical and real-life examples.
[1] https://www.bmj.com/content/medical-milestones [2] https://pubsapp.acs.org/cen/coverstory/83/8325/8325list.html
With Alzheimer's though, the clinical trials are going to take a long time. Probably 10 years at least, because our current understanding of the disease is that it begins in your mid to late 40s, and only manifests as severe memory loss decades later. Our current method of trying to treat it is like putting someone in pallatiave care with stage 12 cancer through chemo. Just doesn't work.
But drug companies have no choice because if they run 10-15 year trials, their drug will be off patent before the FDA/EMA even looks at it.
If I were King for a day, one thing I'd do is a blanket 40 year patent life on Alzheimer's drugs. It's worth the cost. This disease will bankrupt every nation otherwise.
I agree with you in principle though - if all that were stopping us from achieving a cure were a 40 year patent, I would support your 1-day monarchy in a heartbeat.
Chapters 9 and 10 of the book cover this in more detail if you're interested (very self-contained).
You hit the nail on the head. Ketamine is a generic drug that costs next to nothing; Spravoto (ketamine-derived nasal spray) is already a billion dollar/year drug for Johnson & Johnson, with prospects of $5 billion/year.
Source: https://archive.ph/rzqxt [Wall Street Journal]
You can patent new applications of an existing drug. This has been somewhat of a problem, as companies can just look at how drugs are being used off-label, and patent some of these uses.
They barely had to do any new science. It just took some creativity and almost $250m worth of clinical trials.
The 7 years time duration probably comes from the size of the study and also how long it is believed to take to get benefit if there is one. I would think if it really worked they would have stopped early for ethics reasons because they should also give the treatment to the placebo arm rather than watch them decline while knowing how to prevent it.
The amyloid hypothesis doesn't have to be wrong for the T3D to be true, and the viral potential to also be true if we are looking at 3-5 different diseases that have similar presentations. This also somewhat suggests why it may be the most common form of dementia.
I work in the neurotech/sleeptech space (https://affectablesleep.com) and there is a strong link between sleep quality and Alzheimer's. It is theorized that AD is more common in women due to the lack of sleep through child-rearing and menopause, which decreases the brain's ability to remove amyliod/tau. Of course, this is only relevant to the amyliod hypothesis.
It makes sense: the viral pressure has increase by a lot due to both increase in population density and increased travel across the world. At the same time there has been an increase in many autoimmune diseases, many types of cancer, Alzheimer's disease, etc. Also, from some proven cases, we know that viruses can trigger serious diseases (MS disease, type 1 diabetes).
Contrast this to the modern day where more often than not, hardships are attributed to personal failings (“You should’ve worked harder if you didn’t want to be stuck working abusive under-compensated jobs!”) and people perpetually teeter on the edge of a knife suspended over a bottomless pit. If anything goes wrong, it’s treated as nobody’s fault but your own, regardless of the reality of the situation. It’s almost a type of psychological torture.
https://en.wikipedia.org/wiki/List_of_common_misconceptions_...
Casey Means is an American functional medicine/holistic medicine physician, entrepreneur and author.
Means withdrew from her medical residency at age 30. She has attributed this decision to the lack of training she received about nutrition and the underlying causes of chronic disease. Means dedicated her practice to functional medicine, which focuses on the root causes of disease.
in other words : someone telling someone to practice yoga to relax and reduce their heart rate 200 years ago was a quack right up until the point that modern doctors decided to include it in their repertoire?
it's a cute joke but it skips over the fact that there seems to be an 'alternative medicine -> real medicine' pipeline, even if a lot of it turns out badly.
In other words, the quote is exactly referring to your "pipeline."
Tim Minchin's "Storm" monologue: https://www.youtube.com/watch?v=KtYkyB35zkk
Breath exercises, and physical therapy for relaxation were mainstream in 1960-s.
> it's a cute joke but it skips over the fact that there seems to be an 'alternative medicine -> real medicine' pipeline
Not really. Most of the non-medicine (I refuse to call it "alternative") stays non-medicine: acupuncture, homeopathy, all the "energy meridians" nonsense, ayurveda, alkaline foods, etc.
And even with activities like yoga, it's not more effective than other types of similar physical activity. There is some very weak evidence that yoga _with_ physiotherapy might be more effective than just increased levels of physiotherapy.
I looked into one of the links and apparently she pushes fairly mainstream preventive medicine stuff, diet, exercise, and screening tests. The only questionable thing I saw was the continuous glucose monitoring thing which the jury may still be out on when it comes to non-diabetics.
What has changed is the sterility of our environment. Better bathing, more hand washing, food safety rules, etc. There have been theories that autoimmune diseases might be increasing because we aren't exposed to enough "normal" pathogens.
I'm highly suspicious that higher viral pressures are the cause of increasing dementia rates, as it seems we're exposed to less today.
Not to mention we're poisoning ourselves with all sorts of novel stuff, especially poor hi-carb nutrition, ultra processed food and pollution from various sources that act as endocrine disruptors and God knows what else.
Yes, we probably get way less pathogens overall than we used to, but at the same time we get more pathogens that live exclusively on humans (such as respiratory viruses).
This seems like pure conjecture to me, and without any actual evidence to support it, I'm disinclined to believe it. My guess is that the number of people any one individual interacts with has gone down considerably since the beginning of the century, and earlier. Before the advent of the car, shared forms of travel were much more common. People do much less forms of basic shopping than they used to given the rise of the Internet. Air travel, while much faster, is much less crowded that the ship travel of earlier generations.
Think of it this way: more total numbers = more opportunities for viruses to grow or mutate = more chances for runaway or novel infections. Runaway infections are dealt with fairly well by government entities. Novel infections... might be harder to discover because they're, well, novel.
Maybe in the US. Definitely not in most of the world. For my grandparent 70 years or so ago, the way to travel long distances was riding a donkey. Now travel by bus, train, subway, etc. is really common and something that most people experience often. 100 years ago of course there were trains, stagecoaches, boats, etc. but they were for a tiny minority of society or for special occasions (like to migrate a different continent to not return in decades, etc.). I'm also pretty sure air travel has a much higher penetration than ship travel would have 100 years ago.
As further anec-data points, there are much more massive gatherings now (concerts, sports, etc. - church used to be the major gathering, but churches tend to be ample and ventilated). And every parent knows that daycare and kindergarten are a major vector for pathogens. I used to get like a cold a year with 2 days mild congestion, and since my kid started kindergarten (he didn't go to daycare) we all started getting sick like monthly or so, for a couple of years. Putting dozens of kids in a closed space for hours is something that just wasn't a thing in previous generations either.
So personally, yes, I would bet that chances for pathogen spread have increased greatly.
For T1D, it’s similar - there’s a notion that you’re genetically predisposed to it and certain types of infections during adolescence can cause it to manifest.
I’ve had discussions with researchers in the space and apparently certain autoimmune diseases happen less often in “grubbier” parts of the world (their words, not mine) even when the population density is high, and an inference here is that >early exposure< to certain infections might not trigger some of these problematic autoimmune reactions.
Side note: these diseases aren’t fun, especially when working in tech. I’m appreciative of those dedicating their lives to researching autoimmune disease.
Is that corrected for mortality? It seems like an analysis like that would be quite prone to survivor bias.
(Although the article takes pains to say that obesity is multifactorial, conflicting evidence in humans, etc.)
Realistically immune systems are extremely complex and I suspect there are probably lots of environmental triggers beyond viruses and bacteria as well
Is the theory now that Alzheimer's just actual brain rot, of which their are multiple causes, and that beta amyloid plaques are just detritus of a losing battle?
The last time I read up on this it was basically that we all have some predetermined risk of developing an Alzheimer's type disease, but that modern environmental variables raise that risk to such a high likelihood that it's become something it never used to be.
Interesting to think about.
Well, yeah, because more people get old enough to get it.
The real question is what is going on and how do we fix it?
Apparently viruses and also bacteria and fungi getting in the brain and causing problems are quite common.
Compare this to something like HIV, where we were able to quickly understand that the virus attacks CD4 cells, and limits the body's ability to defend from disease.
With Alzheimer's, we're still in the - is it amyloid and tau? is it inflammation? is it viral?
This is compounded by our limited understanding of the brain.
Another hypothesis which I ascribe to is that we are lumping multiple diseases under the label of Alzheimer's because we don't understand it enough.
I equate it to how our understanding of the body has changed over time. When we understood fluid dynamics, we looked at the body as a series of pumps and magical fluid called blood which carried nutrients. When we discovered electricity, we slapped our foreheads, and thought "of course!! it's electric!!" and now we relate everything to our understanding of electrical activity AND hydrodynamics. I am sure there is a time in the not to distant future where we will discover how the mind works is related to our understanding of quantum...and we'll continue down the rabbit hole.
"confer" is something you use for a proven link with an interventional study, not for some random link you found within the thousands of variables you went fishing for in your observation study dataset.
It's likely partial because vaccines only confer resistance against one subset of virii and there may be nonviral Alzheimer's too. in any case causality is not really in question in that study
Going in detail to the claim that 'appear to confer' is biased, even if we take such a strict understanding of confer, compare the semantic effect of affirming and negating the sentence with and without 'appear to'
1. 'the vaccines conferred protection'
2. 'the vaccines did not confer protection'
3. 'the vaccines appeared to confer protection'
4. 'the vaccines did not appear to confer protection'
Which of the sentence above is closest to the truth, and which is most inaccurate?
Double blind randomized controled trial or it didn't happen.
Perhaps people with early symptoms are not given the vacine because it's too expensive and not mandatory?
Perhaps people with the vaccine are younger becase it's a recent vaccine?
Perhaps people that has no money for the vaccina had no money for therapies to slow the sympthoms?
'The first double-blinded randomised clinical trial to test the effectiveness of antivirals against dementia is now under way. A group of researchers mostly based at Columbia University are testing whether valacyclovir, an antiviral used against HSV1, can slow down cognitive decline in people with early stage Alzheimer’s. Between 2018 and 2024, the researchers recruited 120 patients and treated half with the antiviral. They expect to publish their findings later this year. John Hardy, whose research forms the basis of the dominant amyloid theory of Alzheimer’s, and who has been a critic of the virus theory, says that a positive result in this trial would begin to convince him otherwise. If Dr Geldsetzer and his team can secure the funding, a similar trial of the shingles vaccine may soon follow.'
https://taggs.hhs.gov/Content/Data/HHS_Grants_Terminated.pdf
The problem is mixing the real protection of the vaccine against shingles that has been tested in RTC and new aplications that have not been tested enough.
If there are too many false provisional anouncements, people will not thrust medicine.
The article then proceeds on the history of the scientific debate on whether the HSV1 virus has a causal link to Alzheimer's and the level of acceptance of the hypothesis.
Finally, the article concludes describing how an RCT is taking place to find whether an antiviral which is used to treat HSV1 has an effect on the development of dementia.
It all ties together with the theme of the article, which is about the possibility that viruses may trigger Alzheimer's and the reason why research is being carried out in that direction. That open question is literally expressed in the headline.
I honestly cannot understand the problem you are seeing in the article. How else would you express the same information?
This is just cargo culting. Read the original source paper and you'll understand why the causal relationship makes sense without an RCT.
I found https://www.nature.com/articles/s41591-024-03201-5
They compare people that got the old vaccines in 2014-2017 with people that got the new vaccine in 2018-2020. Some strange parts:
They say they are analyzing 6 years, but for the second group the 6 years period has not ended. This makes the comparison difficult.
These periods includes the covid-19 epidemic in 2020, with lock downs, changes in death rates and new vaccines. This makes any comparison difficult.
The comparison in figure "1 e" have very different initial slopes. I'd expect dementia to be a slow accumulation of small problems in the brain, so I'd expect an initial equal slope and after some time a difference. They start the comparison after 3 month, but I expect a slower effect.
Figure "1 f" has the same initial slope difference, but there is also a strange slope change in d=1750 and the red line is more noisy probably due to the unfinished 6 years period).
They rule out the objections in your top post — as well as whether people chose to get the vaccine, which would be a huge confounder for a disease that affects cognition.
Probably more than 90% of the reads would be human, but still.
It's bad enough that people fail to contextualize or deeply consider the reality behind sensational headlines, but when you open the door to vague questions as headlines, you are somehow journalistically allowed to memetically plant a known lie into the zeitgeist of the majority of internet users who read the headline but dont click to read the article.
The very fact that the last sentence of the article is expressed as a conditional is also consistent with the use of a question for the headline:
> 'If antiviral treatments can indeed slow, delay or prevent even a small subset of these cases, the impact could be tremendous.'
[0] https://en.wikipedia.org/wiki/Betteridge's_law_of_headlines
It's an open question, surely worth writing about and getting people's attention on right? No? Right because scientifically meaningful distinctions are the only way to understand underlying scientific process.
This is not philosophy class.
That would very much be a very interesting news article, and I hope it is published.
I'm hoping that AI helps sort this stuff out. It can read the papers and say hypothesis A is most likely even if professor Y had built an empire on it being hypothesis B.
Without directly testing for a connection it’s extremely rare to get unexpected data that confirms an alternate hypothesis.
Even if the statistical tools are there, they can’t make up numbers that we haven’t collected yet.
E.g., https://www.science.org/content/article/potential-fabricatio...
https://www.science.org/content/article/research-misconduct-...
https://arstechnica.com/science/2024/07/alzheimers-scientist...
https://stanforddaily.com/2023/02/17/internal-review-found-f...
If the research was in anyway paid for with federal dollars all this data should be public. Not only that, if true it is a waste of federal dollars.
It's probable that the widening mistrust in science is due to this a sort of behavior and the resulting administration.
Waste due to inefficiencies is one thing, waste due to fraud, data hiding, misdirection is something else.
It's that certain damaging proteins are a line of defense against the HSV1 virus, that something sometimes sends those proteins into overdrive, that this is influenced by genetics broadly, further influenced by a particular gene, and that it's a second infection with shingles that can reactivate the proteins, worsening it.
Given that this is the interplay of something like at least 5 factors, and there may be more, it's not surprising it's taken this long to put together, even with all our statistical tools.
If you gather EHR or medical claims record data for vaccines for example, you have to take very seriously the biases and impact of missingness inherent in the data. Is that person you have no evidence of disease for truly not diseased or do they just have missing data? IS it missing because they just didnt go to the doctor because they're healthy enough to kick the disease on their own or because they're so financially unstable that they can't afford to consistently see their primary care doctor. Is the data missingness itself actually what's more correlated with the disease than the vacciation you are looking at?
Example: If your outcome is dementia then may be using cognitive tests that have a high level of variability due more to social class, education, test taking ability. Is receiving a fancy vaccine is more likely in an affluent area? Could be that correlation itself might completely explain away the positive effect that vaccine has on cognitive test scores.
In Alzheimer's you're often trying to correlate things that happen in early life with long term damage that only surfaces many many years later. Retrospective studies where you go back and ask sick or healthy people have recall bias where the sick ones remember more issues with themselves early on than healthy ones do even with the same early life issues.
Not trying to say epi is perfect or that there isn't room for improvement in tools (there absolutely is). But just like often happens when crossing over into the biological sciences there's a lot stickier problems than people outside the field realize.
For vaccinations specifically the CDC Immunization Gateway can be a good place to start. Most states also maintain their own immunization registries that can be queried through standard HL7 V2 Messaging and/or FHIR APIs if you have the appropriate permissions.
There are certainly clear-cut cause-effect relationships in biological systems, but even they will have edge cases and random chance to muddle the picture.
I would posit that the human body is far more complex than even the largest codebase, not least because it was jury-rigged together with no architect or style guide.
Also, in general, the more common the exposure, the harder it is to find a link; try finding a control group of people who have never been exposed to PTFEs, or HSV, and who also aren’t like hunter gatherers.
Also, adding complexity is the difficulty or even literal impossibility of observing the direct interactions of elements of the system, which operate at a quantum scale, that you would disturb and do disturb when attempting to observe.
> It’s more like a vibrating causal cloud than a chain of causality.
DNA is where we get our physical attributes (modulo environment).
No, a lot of DNA is "junk," i.e. we don't yet understand what it does.
No, a lot of functional DNA is turned on or off by the epigenome.
No, a lot of our metabolism is affected by our biome — thousand of species of bacteria that turn up or down various reactions, or produce other chemicals that we need...
No. Not only is it not "debunked", it is not even "a theory".
> cannot be true because that would mean that they are caused by inflammatory insult
No. Something being caused by a virus does not imply that the mechanism is "inflammatory insult".
> and that would mean that vaccines contribute to or cause certain diseases
No. That certain viral infections may cause ill effects by means of inflammatory processes does not imply that "vaccines contribute to or cause certain diseases".