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Why has there been so little progress on Alzheimer's disease?

freakonomics.com

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Re: Why has there been so little progress on Alzheimer's disease?

#121

...because Alzheimer is a dormant side effect of a virus, not of a messenger chemical. But that doesn't go well in studies and "self populism" of what funded research wanted to hear. If you study effects and not causes due to lack of measurements for reproducibility in any field of research, that's what comes out. Also check out how the new and promising correlation started by observing the Wales eligibility for mand…

Not always. Genetic causes are known.

... which kind of points to the indicator that "Alzheimer != Alzheimer", implying that too many diseases with the same side effects are categorized together?

A lot of virological and parasitical components have historically been wrongly associated with genetic markers, too. Toxoplasmosis parasite comes to mind.

[1] https://en.wikipedia.org/wiki/Toxoplasmosis

[2] https://en.wikipedia.org/wiki/Toxoplasma_gondii

Re: Why has there been so little progress on Alzheimer's disease?

#122
post #92
post #35

Earlier quoted context omitted.

> Problem was, the model was wrong. I thought despite the fraud, it's still the best model we have[1]? The fact there was fraud doesn't mean the model is immediately incorrect. At best, it means its foundations are shakier than we thought, but it's not a slam dunk repudiation. [1] https://www.astralcodexten.com/p/in-defense-of-the-amyloid-h...

Many in the research community realised the model was wrong a long time ago. This is a great read about the reasons why: 'How not to study a disease: the story of Alzheimer’s.' by Karl Herrup.

Wrong or incomplete?

The current findings seem consistent with "both plaques and tangles are significant components of the pathology" and "our interventions are typically late and the accumulated neurological damage is already extreme by the time clinical symptoms show".

Attacking the plaques wasn't completely worthless - findings show that this often slows disease progression, especially in early cases. There are pre-symptomatic trials ongoing that may clear the air on whether "intervention is late" is the main culprit in treatment underperformance.

Re: Why has there been so little progress on Alzheimer's disease?

#123

It's because there is little progress in uncovering the mechanisms of the disease. Alzheimer's et al are tau-opathies and Parkinson's et al are synuclein-opathies. Both are degenerative and we wait for their common base in a Grand Unified Theory. I like to view degeneration of any tissue as death due to (premature) aging. So, if we treat it, we achieve immortality by applying it to all body. This is something hard.

There has been massive progress in neurodegeneration research. We now understand that the brain has a complex system for processing metabolic "trash." Like all systems it has a number of components, each of which can fail. This is why a single "silver bullet" drug will likely never exist. A multi variable systems failure can not be fixed with a single variable solution.

Alzheimer’s occurs when Amyloid/Tau debris accumulates faster than the glymphatic system can export it.

Parkinson’s occurs when α-synuclein (Lewy Bodies) accumulates because the cellular recycling system (Mitophagy) has failed.

While Choline is a critical bottleneck for Alzheimer's, Glutathione and GBA enzyme activity are the primary bottlenecks for Parkinson’s. But in both cases it depends on the person and their genetics and what matters the most. If someone is at high risk for Alzheimer's a multi-pronged approach will probably be very common. For example a post menopause woman who is not on HRT, but at high risk due to parents should be getting Choline due to the low PEMT expression, but they might have a higher risk for neuroinflammation via NLRP3 and so need to also combat that too.

To say no progress has been made is to ignore the fact that we have learned a ton about the various components of these systems and how they can break down.

Here are the two approximate decay equations that you can put into an online latex viewer.

Alzheimer's

\Psi_{AD} = \int_{0}^{t} \frac{[(\mathbf{K}_{\tau} \otimes \mathbf{K}_{A\beta}) \cdot \mathcal{I}_{NLR P 3}]}{[\mathcal{G}(Li \cdot GSK3\beta^{-1}) \cdot PRO(ER\alpha \cdot \text{PEMT}) ] \cdot \Omega_{ATP}} \cdot e^{\left( \frac{\Gamma_{\text{fibrosis}} \cdot \text{PAI-1}}{EPA \cdot \text{Natto}} \right)} \, dt

Parkinson's

\Psi_{PD} = \int_{0}^{t} \frac{[(\mathbf{K}_{\alpha\text{-syn}} \otimes \mathcal{I}_{LRRK2}) \cdot \mathcal{I}_{NLRP3}]}{[\mathcal{G}(\text{Parkin} \cdot \text{PINK1}) \cdot PRO(\text{Dopamine}_{\text{flux}})] \cdot \Omega_{ATP}} \cdot e^{\left(\frac{\Gamma_{\text{Oxidative}} \cdot \text{Iron}}{\text{Glutathione} \cdot \text{GBA}}\right)} \, dt

And for good measure here is cancer

\Psi_{Onco} = \int_{0}^{t} \frac{[ (\mathbf{M}_{mut} \otimes \mathcal{G}_{growth}) \cdot \mathcal{I}_{STAT3} ]}{ [ \mathcal{G}(p53 \cdot \text{PTEN}) \cdot PRO(\text{Anoikis}) ] \cdot \Omega_{ATP}} \cdot e^{\left( \frac{\Gamma_{hypoxia} \cdot \text{VEGF}}{\text{Repair}_{DNA} \cdot \text{Immune}_{flux}} \right)} \, dt

The point of these isn't to give an exact equation, but to make the understanding of the systems and their components radically simpler for humans to understand which can help with treatment leading to questions like "Where is the bottleneck in this patients system?”

Re: Why has there been so little progress on Alzheimer's disease?

#124
It's not just that one paper may have been wrong; it's that a fragile consensus can redirect billions of dollars and decades of work. Alzheimer's is also a brutally complex disease, so the opportunity cost of narrowing the search too early may have been enormous

Re: Why has there been so little progress on Alzheimer's disease?

#125
post #30

They had a biological model. They had multiple drugs that were showed activity against that model, and effectiveness in humans. Problem was, the model was wrong. Pharma’s burned billions chasing this as it’s possibly the biggest market imaginable. Whether it was fraudulent or just incorrect is a different question. We don’t know all of the details of human biology. We don’t even know what all we don’t know. Most gues…

A wrong model is not the same thing as fraud, and biology is full of plausible models that later turn out to be incomplete or misleading

Re: Why has there been so little progress on Alzheimer's disease?

#126

https://www.statnews.com/2019/06/25/alzheimers-cabal-thwarte... "Despite being described as a “cabal,” the amyloid camp was neither organized nor nefarious. Those who championed the amyloid hypothesis truly believed it, and thought that focusing money and attention on it rather than competing ideas was the surest way to an effective drug. It has not worked out that way. Research focused on amyloid, and the developmen…

The scary part is that everyone can be acting in good faith and still produce a monoculture

Re: Why has there been so little progress on Alzheimer's disease?

#127

It's because there is little progress in uncovering the mechanisms of the disease. Alzheimer's et al are tau-opathies and Parkinson's et al are synuclein-opathies. Both are degenerative and we wait for their common base in a Grand Unified Theory. I like to view degeneration of any tissue as death due to (premature) aging. So, if we treat it, we achieve immortality by applying it to all body. This is something hard.

The "premature aging" framing makes sense, but I wonder if it risks hiding the disease-specific parts

Re: Why has there been so little progress on Alzheimer's disease?

#128

Earlier quoted context omitted.

I think you are wrong, for several reasons. From the human perspective, researchers are people, and they do have their incentives. Making a breakthrough, of any kind, is important for them - even if for their career (but many do genuinely care and want to help humanity as a whole). From marketing and sales perspective, look at what happen to pharma companies capitalization when Ozempic appeared: a relatively small El…

Which illnesses have been cured? Diabetes, cancer? > From the human perspective, researchers are people, and they do have their incentives. Making a breakthrough, of any kind, is important for them - even if for their career (but many do genuinely care and want to help humanity as a whole). Researchers are people, but they are paid and directed. They can't go off and do what they like. The corporation directs them, a…

Imagine your role is allocating spending on $10B/year of medical research and you are presented with two strategies: spend everything searching for the cure for one poorly understood condition, or allocate to treatments improving standard of care for 100 conditions.

Improving standard of care for 100 is less risky/more profitable because you have more shots at an expensive process with a high failure rate. And it is a lower bar to improve patient care than to permanently fix a medical mystery. But there is another factor. Focusing on treatment/management over cure most likely maximizes the positive impact on patients within the the constraints you work under.

There have been at least three new major treatments for a chronic thing I have that received FDA approval over my lifetime. Those treatments have had a massive impact on my quality of life, ability to have a career, etc. I don't believe that happens for me if we allocate to cures.

Re: Why has there been so little progress on Alzheimer's disease?

#129

Earlier quoted context omitted.

I think you are wrong, for several reasons. From the human perspective, researchers are people, and they do have their incentives. Making a breakthrough, of any kind, is important for them - even if for their career (but many do genuinely care and want to help humanity as a whole). From marketing and sales perspective, look at what happen to pharma companies capitalization when Ozempic appeared: a relatively small El…

I agree with you but Ozempic is a bad example here. Part of the reason it is so valuable is that patients usually must take it for the rest of their lives. Its actually the perfect example of “evil” pharma since patients slmost akways regain the weight if they stop taking it. This leads to dependence or people searching for grey market sources. An example of “good” pharma would be Hepatitis C. We can now cure that. A…

> I agree with you but Ozempic is a bad example here. Part of the reason it is so valuable is that patients usually must take it for the rest of their lives. Its actually the perfect example of “evil” pharma since patients slmost akways regain the weight if they stop taking it. This leads to dependence or people searching for grey market sources.

Not really. Note that it's not taking ozempic for life vs taking nothing for life, but actually taking ozempic for life vs taking ozempic and 5 different medications for life when obesity related illnesses bite you in the ass. So generally ozempic still is "good" pharma (and the plot twist is that almost every pharma is good pharma!).

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