Your assertion, such as it is, is poorly formed. This research did not, as you imply, test 200 potential associations and report the one that was the “winner”. A single /a priori/ hypothesis was formulated and then tested using the data, in accordance with standard statistical methodology. The logical extension of your statement is that no association could ever be found since anything found is just a green-jelly bean association. When multiple tests of hypotheses are performed, accepted statistical practice is to the make the criterion for significance more stringent precisely to avoid the green-jellybean effect you are implying has occurred here.
Similarly illogical is pointing out the size of the questionnaire - as though the number of questions a person is asked has any impact whether eggs have an effect on Alzheimer’s disease incidence.
The questionnaire included 200 food items. Within the study, 9 food categories are listed. No adjustment for multiple hypothesis testing is reported in the methods section.
We have to take it on faith that they did in fact specifically set out to determine if egg consumption was associated with Alzheimer's disease...
A quick search shows that other studies both do [0] and do not [1] link egg consumption with Alzheimer's disease.
Those are impressive! It's worth noting that the photographic technology had advanced considerably between 1848 and 1906.
The exposure time of these kite photographs must have been quite short, given the obvious instability of the platform. They're very detailed, nonetheless.
> What are the practical consequences of this today
Infrastructure degradation. Think overpass collapses or metro rail lines being misaligned.
> what is being done to remedy this
Not enough. CDMX faces the issue of multiple political entities with varying power making management difficult.
A lot of the subsidence happens in informal settlements [0] due to a mixture of political populism (no one would dare demolish an informal settlement and piss off voters).
Beijing used to have a similar issue, but a mixture of hukou, mass evictions, and mass demolitions helped alleviate the issue.
We can also see it play out in other countries, that had solar water pumping for the last ten years, like afghanistan. In the end stage- its water wars with neighbours like Pakistan or Iran.
Note in particular the last one, which is a classic. Roads, buildings, and all underground infrastructure is affected. As well as anyone else who uses that groundwater, as well as future users - because come groundwater reservoirs do not recover, the compaction is permanent.
Unfortunately the evidence that targeting amyloid (e.g. Lecanemab and Donanemab) improves the symptoms of Alzheimer's disease is very weak. See the latest systematic review [0]. This does not mean however that amyloid plays no role in the disease, the treatment may simply be too late.
That systematic review is unfortunately severely flawed. They pooled the old anti-amyloid antibodies (which everybody agrees are inefficacious) and were never used outside clinical trials, with the new anti-amyloid antibodies, that does show modest efficacy in reducing the speed of progression.
While these two classes of drugs target the same molecule, they are developed to target amyloid-beta in very different forms. Pooling all those drugs together, and then showing very weak effect, makes absolutely zero sense, and I hope and expect this review to be pulled soon.
The point of systematic reviews is to be un-biased. So if their question is whether targeting Aβ amyloid is a valid approach they have to include the unsuccessful trails as well as those purported to be successful.
As to the trials specifically for Lecanemab and Donanemab, the benefits are not claimed to be either strong or large, even by those who support it. The current support these receive is more aligned with the concept that an improved targeting of Aβ amyloid might improve outcomes. This remains to be demonstrated.
I don’t quite follow the reasoning behind this being “unbiased”. Studies must be designed to answer specific research question. What is the question being asked by the study in question. If the question being asked is whether AB the right target (in humans), then it would need to consider other forms of human evidence, such as genetic evidence, alongside alternative explanations of failure — bad molecule, wrong isoform, bad cohort selection, etc.
The question asked in the Cochrane review linked to above is whether there is evidence that current treatments targeting amyloid provide relief. Their conclusion is that the effect is too small to be considered beneficial.
Especially when considering the undoubted side-effects, which include edema and micro-bleeding in the brain.
It doesn't ask whether amyloid is causative of the disease.
I wonder. Because if that was the question, why would they include anti-amyloid treatments that were never approved and are not part of any current treatment regimen and dilute the real effect of the approved antibodies? (Not that the approved antibodies are a silver bullet, but clearly they have some positive effect.)
The Cochrane review did not ask the question of whether Lecanemab (for example) worked, it asked the more general question of whether targeting amyloid worked. If targeting amyloid, generally, worked you might expect all approaches to targeting amyloid to show some efficacy. So they included all those for which clinical trials had been conducted. Obviously some treatments didn't pass the threshold required and so were not subsequently approved. If you only included successful trials you would bias the outcome.
It's possible, of course, that some methods of targeting amyloid might work where others failed. But even those that claim success (Donanemab and Lecanemab) have a very modest benefit.
Yes, the new anti-amyloids are not a revolutionary therapy. But they do have a small but definite effect on disease-progression. (something which in a highly noisy indication like Alzheimer's may actually mean a lot more to the patients than it seems by looking at the data. E.g. donepezil and memantine have very modest effects too, but patients and caregivers are still surprisingly positive about them).
And since these were developed using different methods and epitopes, it does not make sense to pool them together when doing a comparison. It's obvious that if you combine modestly beneficial compounds and compounds with zero beneficial effect then the mean effect will be worse than the modestly beneficial compounds.
And when you do so just because they were aimed at the same molecular target, not even considering if anyone claims that the old, unapproved antibody-therapies, with no positive studies to support them, have any effect, what you are doing is somewhere between extreme ignorance and deception.
All the trials included in the Cochrane review demonstrated removal of Aβ amyloid from the brain. Side effects were relatively modest, except for edema and micro-bleeds. So they are all legitimate tests of the hypothesis that removing Aβ amyloid would be beneficial.
No you would not expect all efforts to target AB to work. You can have the right target and the wrong molecule. Look at GLP1s as an example. Multiple pharma companies tried GLP1 receptor agonists for more than a decade and it was not until recently that Novo and Lilly got them to work.
But has only weak/moderate effect on weight loss compared to semaglutide, tirzepatide and retatrutide.
Alzheimer is a lot more difficult to measure than weight and amyloid-beta in the brain obviously significantly harder to target than the GLP-1 receptor in the body.
Also, a review pooling together all GLP-1's (including those that failed in development) and concluding that they as a class have only moderate or weak effect on weight loss, would obviously be badly misleading.
If you grouped all GLP-1 agonists that had entered clinical trials, they would be shown as successful [0]. No GLP-1 receptor agonist has failed to reduce appetite in clinical trials, but some were better than others.
The point about the anti-amyloid trials is that they all succeeded in removing amyloid. But they did not improve cognition, and only some resulted in a slightly slower rate of decline in cognition (people still declined).
>Forty-seven RCTs were included, with a combined cohort of 23,244 patients. GLP-1 RAs demonstrated a mean weight reduction of -4.57 kg (95% CI -5.35 to -3.78), mean BMI reduction of -2.07 kg/m2 (95% CI -2.53 to -1.62), and mean waist circumference reduction of -4.55 cm (95% CI -5.72 to -3.38) compared with placebo.
Your meta review has like 80%-90% of the studies on semaglutide and liraglutide. When finding random effect per drug, they even say this:
> Hence, the drugs eligible for meta-regression were semaglutide (subcutaneous injection, once weekly) and liraglutide (subcutaneous injection, once daily), which both showed a dose-dependent treatment effect in terms of weight and BMI.
And the class-effect is much more modest than semaglutide by itself would have shown, exactly as I said. What is the point?
Both meta-analyses above cover all eligible clinical trials for the respective strategies, targeting the GLP-1 receptor, or targeting amyloid.
For the GLP-1 strategy, Table 1 in the above paper shows that all drugs were clearly effective. Some were better than others.
For the amyloid strategy, only some of the drugs were effective, and that efficacy was very weak, even when all the drugs removed amyloid. This brings into question the hypothesis that removing amyloid would alleviate AD, i.e. the slender benefits of Lecanemab might not be caused by amyloid removal. The same cannot be said for the GLP-1 receptor agonists.
Agreed, especially in some subpopulations. I think the strong case today is to research it's use in people with Dawn's syndrome (accelerated development Alzheimer's Disease due to 3 copies of the APP gene). Target it only to people with those 3 copies.
It's legimate as people with DS have a hugely increased risk of AD.
Their risk increase seems likely related specifically to Amyloid.
Many with DS can consent to it.
In general my completely gut feeling is that once we can target Tau we might find that targeting amyloid is needed to fully curtail progression.
Agreed, using these anti-amyloid treatments at an early stage in people with a high risk of early onset Alzheimer's disease, such as those with Down's syndrome, is likely the most robust test available of the theory that Aβ amyloid is directly causative of this disease.
Trials are currently ongoing. The results should start trickling out in a few years...
Unable to read the full article, however the amyloid hypothesis is not without solid scientific foundations.
Alzheimer's disease may occur either due to inherited mutations in the genes for APP or presenilin, in which case it can occur as young as 40 yrs old. Or it may occur "sporadically" in those over 65yrs old. The brain pathology of both is similar. Notably, amyloid is derived from APP in part by the action of presenilin, which cuts the APP protein to release the amyloid peptide (Aβ).
Currently, the amyloid hypothesis is the only known way to reconcile the similarity of pathology (for both amyloid and tau) between early onset inherited AD caused by mutations in either APP or presenilin, and later onset sporadic disease. Furthermore, all the mutations in APP that cause Alzheimer's disease are located within or adjacent to the region that corresponds to Aβ amyloid, and not in the remaining 95% of the molecule.
Until another way of unifying these observations is found, the amyloid hypothesis will always find supporters.
All Souls College doesn't have any students, graduate or otherwise. It's primarily a place where people can conduct research into any topic, most often in the humanities.
It frequently hosts journalists, politicians, lawyers, etc, who have had successful careers outside of academia and who may have no academic qualifications other than an undergraduate degree, and sometimes no degree at all.
It's missing the characteristic element of a periodic table, which is both a visual and explanatory representation of the relationship between the composition of the different substances and their properties.
The concept is there, but it is presented as a regular table, not the classical periodic table.
The notion of "missing e̶l̶e̶m̶e̶n̶t̶s̶ cheeses" is entertaining, and the only real reference to the actual periodic table.
reply