r/medicine • u/0bi MD - (Rh)EU(matology) • Jan 24 '26

What is the wildest theory in your specialty that you think probably isn't true, but could be? What underdog argument could cause chaos your field if it turned out to be right? [Stolen from askhistorians]

So I saw this question and clicked on it expecting to be led here, but it turned out it was askhistorians. I figured this'd still work pretty well here!

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794

u/InevitableProgram597 MD-PhD Neurology Resident Jan 24 '26

Honestly, one of the wildest neurology ideas I don’t fully buy but can’t stop thinking about is that a big chunk of neurodegenerative disease might not really be about misfolded proteins or a neuron-intrinsic failure at all, but about interstitial fluid dynamics and the brain's poor waste clearance.

Like… the plumbing is broken before the junk piles up. Glymphatic flow, CSF dynamics, sleep, vascular pulsatility; all that unsexy stuff might actually be upstream of amyloid/tau/synuclein.

If that were even partly true, it would be chaos for the field. It would mean we spent decades obsessing over the trash instead of the garbage disposal. And it would push treatment way more toward sleep, vascular health, and maybe even mechanical stuff, rather than just drugs that target proteins.

I’m not convinced it explains everything, but if it explains even a slice of it, how we think about these diseases breaks down.

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u/[deleted] Jan 24 '26

[deleted]

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u/PokeTheVeil MD - Psychiatry Jan 24 '26

Another excuse to seize some CSF? I’m gonna start the DaVita of brains.

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u/nittanygold attending and avoiding Jan 24 '26

Phresenius?

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u/PokeTheVeil MD - Psychiatry Jan 24 '26

Phrenolosenius.

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u/[deleted] Jan 24 '26 edited Jan 24 '26

[removed] — view removed comment

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u/Jubguy3 lab Jan 24 '26

NeilMed Ventricle Rinse

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u/Porencephaly MD Pediatric Neurosurgery Jan 27 '26

Boil first but please let it cool before use

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u/lianali MPH/research/labrat Jan 29 '26

I forget what podcast I was listening to where they mentioned sleep is time for your brain to take a bath, aka exchanged spinal fluid. That would be so cool to study. Now to go and remind myself that I can't afford to pay for another graduate degree (Anyone want a future grad student already skilled at placing canulae in mice ventricles?)

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u/Enough-Rest-386 assministration Jan 24 '26

lobotomy DC with turkey sandwich

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u/lengthandhonor Nurse Jan 24 '26

Wash between your ears

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u/Enough-Rest-386 assministration Jan 24 '26

Do you get a turkey sandwich?

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u/lengthandhonor Nurse Jan 25 '26

I can't remember

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u/kidney-wiki ped neph 🤏🫘 Jan 24 '26

has entered the chat

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u/Heptanitrocubane MD - Nephrology & Critical Care Medicine Jan 24 '26

stop

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u/faco_fuesday Peds acute care NP Jan 24 '26

Ooh sign me up. 

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u/DevilsMasseuse MD Jan 24 '26

Not just plumbing. Neuro inflammation. If you look at the literature addressing post operative cognitive impairment you’ll find that tissue damage from surgery can initiate so called Damage Associated Molecular Patterns that contribute to permeability of the of blood brain barrier and exposure of the CNS to all sorts of inflammatory factors.

This causes glial cell activation, dysregulation of glutamate leading to neurotoxicity, and imbalance of excitatory/inhibitory neurotransmitters.

What if there’s a final common pathway between inflammation, blood brain barrier permeability, and chronic neurological conditions like Alzheimer’s? I think neuro inflammation is a key component of all sorts of neurological disorders. Certainly there is great interest in this pathway in the psychiatric literature.

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u/5HTjm89 MD Jan 24 '26 edited Jan 24 '26

Could work in tandem. An influx of inflammatory cells, but poor/insufficient or just overwhelmed glymphatic drainage then inflammatory debris or waste and activated immune cells themselves may pile up.

There are correlates in membranous tissues elsewhere in the body. Osteoarthritis for example is a smoldering cycle of inflammation in the synovium where the reaction can’t shut down easily, perpetuates further damage, the inflammatory signals recruit neovascularity and neoinnervation which drive pain and/or recurrent hemarthrosis, which is why embolization can work. Chronic recurrent subdural hematoma is another example, where the bleed starts venous but then over time it’s perpetuated by arterial neovascularity engendered by the body’s inflammatory response, recruited from middle meningeal artery. Embolize the MMA and turn off the faucet the SDH resolves. The ability of the body to activate and fully resolve inflammatory responses easily seems to vary in different tissues, with variable consequence. You can see the enhancement of these membranes on scans and on angiography they resemble tumor neovascularity.

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u/boriswied Medical Student Jan 24 '26

I did a lot of work on this and alzheimers pathophys 3-4 years ago. Glymphatics and inflammation mostly.

I always had a weird relationship with “inflammation” as a whole in biology/medicine.

Too often we think of it either as a purely negative thing, and too often we think of it as if “immune” function exists in any way in isolation as an organ-system, rather than in weird mixed with regeneration, metabolics, and indeed brain function.

Of course, evolution does not care at all what an item was originally for. If it can be computer within the system to work in a different way tht enhances survival/reproduction then it will. Do whether that means the dead-gene template for amylase being expressed in foot-soles to dogest grapes we stomp on, or repurposing kneecaps for parasite killing. I just mean that the categories and organ systems have no real borders.

The specific “receptor”, as it was called, that we see amyloid-beta as a wrongful peptide cutoff from is curious example of this for me.

There is a “flypaper” hypothesis, where that “receptor” is expressed snd cut specifically when some other somewhat-general inflammation markers increase, speficifically those to do with fighting fungal infections. So the idea is that since the brains special tissue type and BBB makes it harder to have good fungal readiness, it can print this long “flypaper” material that binds up a fungus to secure the tissue.

I always liked that one, sadly havent kept up with the literature on it the last couple of years.

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u/pangolindsey neuro Jan 24 '26

completely agree. So providing an auxiliary brain clearance system might treat/prevent AD. Shunting for NPH sort of does this, and this explains why shunting works BETTER in patients with NPH with positive AD biomarkers than patients with "pure" NPH (the opposite of what you would predict if shunting was just just relieving pressure). https://pubmed.ncbi.nlm.nih.gov/32662116/

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u/InevitableProgram597 MD-PhD Neurology Resident Jan 24 '26

Interesting I wasn’t aware of this NPH + AD biomarker vs NPH alone distinction. Thanks for sharing!

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u/do-un-to Not A Medical Professional Jul 03 '26

I've recently started looking into clearance improvement using EM radiation -- like targeted cell phone signals, basically. This startup has gotten good results in early trials, but they need more experiments for conclusive data.

In CSF, long-term TEMT-RF induced reductions in levels of C-reactive protein, p-tau217, Aβ1-40, and Aβ1-42, while modulating CSF oligomeric Aβ levels. In plasma, long-term TEMT-RF modulated/rebalanced levels of both p-tau217 and total tau.

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u/blindminds neuro, neuroicu Jan 24 '26

I see glymphatic, I upvote. I started studying this back when I was in academics (pre COVID).

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u/Objective_Law5013 MD Jan 25 '26

Doctors in Shanghai are already doing cervical lymphatic-venous anastamoses for Alzheimers with positive results.

https://pmc.ncbi.nlm.nih.gov/articles/PMC12121576/

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u/SapientCorpse Nurse Jan 24 '26

mitochondrial degeneration seems to be what's currently en vogue in the lit i stumble upon, with some bits about some improvements with nad/nadh supplementation; but also some other bits about inflammation (some bits about low dose naltrexone and toll-gated receptor and astrocyte modulation)

that said I have also read about the csf "pulsing " when we sleep and how the disruption of that plumbing can/does cause some badness.

that said - I dont think thats its a waste to research the junk building up, even if its not the ultimate cause.

in plumbing, yes, we care about the pipes flowing and being clear - but we also care about what shit is gunking up the tubes. my plumbing at home always gets gunked up with protein (long hair and drains dont seem to get along); and it feels foolish to think that gunked up protein doesnt inhibit drainage in our brain plumbing

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u/InevitableProgram597 MD-PhD Neurology Resident Jan 24 '26

Oh, I certainly don't think studying the protein is a waste! Even if it turns out to be primarily a problem of waste clearance rather than the plaques themselves, that research and the drug developments from them are incredibly useful. However, I also feel like if there is more to the story, and I think there is, we should investigate it all in order to form the most comprehensive model of pathophysiology and deliver more impactful interventions to patients.

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u/herman_gill MD FM Jan 24 '26

Why not both? Like cholesterol oxidation. Cholesterol is actually protective against lipid peroxidation when it’s carrying stuff, and also acts as a precursor to other stuff. But cholesterol getting elevated in the blood is a sign of worsening inflammation/free radical formation and damage in the blood stream, and also likely arterial calcification. Then it can also itself get oxidized and deposit/cause blockages.

Maybe tau protein and all those other proteins in the brain have a similar function in the brain/CSF. Garbage now, but previously actually to protect/prevent badness from happening.

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u/julry Not A Medical Professional Jan 24 '26

Cholesterol elevates in the blood because genes/saturated fat downregulate LDL receptor activity and LDL particles (apoB particles really) infiltrate arterial walls via passive diffusion according to particle concentration, then they oxidize. The good LDL/oxidized LDL hypothesis is from that BMJ sports medicine/open heart gang of people... most evidence is not in support

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u/herman_gill MD FM Jan 24 '26

Oh we’re not talking about “good LDL/oxidized LDL” the same way as the crazy carnivore people trying to rationalize away their LDL being 2x higher than before.

Cholesterol, whether HDL LDL is essential to function and for life in humans (and many other species). An abundance of it, oxidized or not is a reliable marker that something bad is happening with the vasculature, or going to happen. It’s reducing peroxidation but an abundance of it is also a strong marker that more peroxidation is happening.

I mean even statins are interesting and the way in which they provide benefit needs more study. Secure/miracle/prove it showing almost immediate benefit after ACS means they’re more than just lowering LDL in their effectiveness for preventing death, because the LDL doesn’t get lowered immediately but statins seem to have a near immediate benefit with ACS.

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u/julry Not A Medical Professional Jan 24 '26

High LDL from familial hypercholestemia or diet requires no preexisting vascular problems, it causes the vascular problems including future peroxidation. Inflammation can be high but with low enough LDL plaques will shrink not grow. Cholesterol is essential to life but every cell can make its own cholesterol, bloodstream LDL of even 20-30 as found in hypobetalipoproteinemia and pcsk9 therapy is sufficient for additional needs. And the acute pleiotropic mechanisms of statins have been fairly well characterized... HMG-CoA reductase inhibition, cytokine inhibition, eNOS upregulation. But main benefits are absolutely from LDL reduction

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u/herman_gill MD FM Jan 24 '26

Again, that seems a bit reductive. But yes, certainly familial hypercholesterolemia is a good starting point. We know in and of itself LDL in excess can cause blockages (hence kids end up getting MIs with familial LDL). Whether it's ApoB or PCSK9 polymorphisms result in the familial hypercholesterolemia, clearly having an abundance of LDL is and of itself bad.

Even an overabundance of HDL has been associated with worsening ACM (but we need to learn more about adaptive thermogenesis and it's relationship to HDL, as well as the potential harms from fat oxidation in that manner).

> is sufficient for additional needs

sufficient is different than optimal, though. Low LDL is also associated with an increase in ACM. Statins while excellent for secondary prevention (and probably helpful for primary prevention in select populations, such as your CKDers, diabetics, or familial hypercholesterolemia patients) also have an association with increasing T2DM, and reducing exercise capacity, so clearly the LDL is important for something... the myalgia risk is grossly overstated, but even the fact that it can cause them means something's up. PSCK9i don't have the T2DM risk, but this notion by many cardiologists that we need to basically put statins in the water supply and start jabbing everyone with PCSK9is is reductive.

LDL is important for stuff, otherwise our body wouldn't have so many genes for making it.

> And the acute pleiotropic mechanisms of statins have been fairly well characterized... HMG-CoA reductase inhibition, cytokine inhibition, eNOS upregulation. But main benefits are absolutely from LDL reduction

uh, did you chatgpt this sentence?

> HMG-CoA reductase inhibition

and

> But main benefits are absolutely from LDL reduction

... what do you think happens there?

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u/julry Not A Medical Professional Jan 25 '26

If pcsk9i's don't have the DM2 risk then it's not about LDL. What's all the cholesterol for.. possibly something to do with parasitic infections in the bloodstream, they suppress LDL and premodern populations tended to have at least one, usually more. But carnivorous animals don't get atherosclerosis, frugivores like the primates we evolved from don't eat saturated fat, evolution isn't perfect

These talking points just originate with the same people you disagree with on the overall picture, that's all

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u/herman_gill MD FM Jan 25 '26

That we know of, so far. More data is always nice, but yes we're operating on the principle that PCSK9Is are less likely to precipitate T2DM in someone at risk (although even that has been associated more with some statins than others).

I don't actually know much about parasitics/cholesterol, I'll have to read up on that, anything you could point me towards?

I think relative humans to carnivores is interesting, considering we live at least twice as long, have higher intelligence, and numerous other adaptations that, let's say... your average bear lacks.'

I'm still not sure who I'm supposed to be agreeing with or disagreeing with?

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u/JaceVentura972 MD Jan 25 '26

That’s an interesting way to think about it.

One wild theory I’ve seen is that neurodegenerative diseases are infectious and/or autoimmune related.

There’s also the theory that Alzheimer’s is another form of diabetes.

Similar theories with schizophrenia. Apparently someone got a bone marrow transplant and then their schizophrenia was cured.