Many people criticize the amyloid hypothese of Alzheimer’s disease, so here’s a good article written in mostly non-technical terms that defends the hypothesis: In Defense Of The Amyloid Hypothesis
In the comments, someone mentioned the lithium orotate article we discussed here as well (see: Lithium Supplementation - #333 by adssx ). According to the blogpost’s author, a plausible mechanism of lithium orotate aligned with the amyloid hypothesis might be:
In the section of the paper titled Lithium and Microglial Function, they describe transcriptional changes to lithium-deficient microglia, which are immune cells that usually help clear amyloid beta from the brain - the last line of that section summarizes their findings as “Li deficiency leads to a reactive pro-inflammatory state and impaired Aβ clearance”.
So I think at least part of the causal pathway here is something like: 1) amyloid starts to build up and form plaques, which start to entangle lithium and reduce cortical lithium levels, which 2) impairs microglial function, reducing their ability to clear amyloid (and increases inflammation), leading to more plaques, and so on in a vicious feedback loop.
The annoying truth is that there are people with a high amyloid load in their brains but no signs of dementia.
The converse is also true; there are people with dementia who, on autopsy, were found to have brains almost amyloid plaque-free.
These facts alone dictate that a simple “amyloid = dementia” hypothesis cannot be correct. It must be either discarded or modified. Introducing other factors (such as lithium) into the mix might be the right way to go.
If amyloid deposition happens 15 years before symptom onset then you’d expect that. They die from something else (heart attack?) when still symptom free. That itself is not enough to refute the hypothesis. Also what does “no sign of dementia” mean? Were these people properly assessed by a cognitive test? Do we have their baseline level from 5 or 10y ago to know how much they should score?
This article is about Alzheimer’s disease. Not all cause dementia. As far as I know nowadays Alzheimer’s is defined by the presence of amyloid plaque so if you don’t have them on autopsy you’d be re diagnosed with another type of dementia (VaD or LBD?).
“You can have abundant plaques and tangles without having Alzheimer’s disease,” agreed neurologist Rudy Tanzi of Massachusetts General Hospital. “The challenge is to figure out how. If we can, then the goal would be to mimic what these resilient people have with some kind of a drug.”
The above quote is from a prominent neurologist. It discusses how/why many elderly people that are autopsied have lots of amyloid plaques and neurofibrillory tangles but are free of Alzheimer’s. I think I’d defer to his opinion before yours.
Amyloid is to Alzheimer’s as cholesterol is to heart disease, and a lot of the controversy around amyloid is that if you treat amyloid when a patient is diagnosed, it’s like only treating cholesterol when you have late-stage heart disease. You had to do that as early prevention.
This is the same type of argument for LDL-C or apoB not being causal in ASCVD if I read it correctly. Causality for complex diseases includes exceptions and differences in response to an exposure, whether genetic or environmental.
Yes, Rudy Tanzi adds on that (see also his analogy with cholesterol above):
So it is possible, theoretically to have plaques and tangles and not get to the neuroinflammation wildfire that gives you the disease, but it’s rare. So the sad fact is, if there’s already plaques and tangles, you have biological Alzheimer’s. How long it’s going to be before you have symptoms is now going to be a function of your genetics.
It’s like people with high cholesterol who don’t get a heart attack.
Alzheimers is an amyloid-induced tauopathy where tangles lead to neuronal cell death and neuroinflammation leading to dementia.
Again, his words. Not that I agree with him but it’s weird to use this specific guy to object to the amyloid hypothesis and the guy is precisely one of the top proponents of the amyloid hypothesis
There are already at least two successful amyloid-based treatments: Kinsula and Lequembi. This bet is for a 75% reduction in cognitive decline, whereas the existing therapis slow it by about 30%. They already do a great job of clearing amyloid: to get to 75%, they don’t need new therapies, but to start much earlier, as Tanzi says.
I will not be drawn further into discussions with people who resort to insults. It’s a form of bullying and reeks of narcissism.
You’re entitled to your opinion.
I just don’t share it.
most insurers in the world refuse to reimburse them because they’re expensive and not literally life-saving. Modified dosing regimens bring down the ARIA rate for Kinsula and subcutaneous injection seems to do the same for Lequembi, and Roche’s new Trontinemab seems safer still — and since ARIA risk seems to be proportional to baseline amyloid load, earlier intervention is likely to lead to reduced risk.
Thanks. If you had a scan showing a high amyloid load but no symptoms, would you start using these drugs? Why aren’t insurers re imbursing in such cases? If you can avoid or delay pheno conversion to proper AD that would result in cost savings for them?
The first GLP-1RAs (exenatide twice-daily) was approved in 2005 but the class only became very popular with semaglutide in 2017. So aducanumab was approved in 2021 and we might have to wait 10 years as well?
It would depend on my age and other risk factors, but if I had a high amyloid load and had the opportunity, I expect I would take them.
None of these antibodies are approved for this scenario yet: they’ve only been tried in and shown effective in people with “mild” dementia or in some cases “mild” cognitive impairment (MCI), which is actually a substantial level of CI. There are trials underway to test this question and presumably get label expansions for both L and K.
Beyond the evidentiary and regulatory issues, the cost savings question is a problem of misaligned incentives: unlike in places like the UK and Canada (and to a lesser extent Germany, Switzerland, and Australia), Americans frequently change insurers in response to job changes or changes in insurance options. So the odds that Insurer A who pays for Lequembi for a sixty-year-old will still be the patient’s insurer when they avoid dementia at age 75 (and therefore reap the cost savings) are very slim — and, as noted, the antibodies are at present very expensive.
My first post in this thread was in response to this:
That’s not an apples-for-apples comparison. The semaglutide bet is to merely be FDA-approved for Alzheimer’s, which Lequembi and Kinsula have already done. The amyloid bet is for a therapy that not only works and gets approved, but slows cognitive decline by 75%.
The markets are giving 58% that Ozempic will be approved for AD. If they asked that question for amyloid therapies, the answer would be 100%, because there are already three amyloid therapies approved for AD.
