Blood test can detect 'toxic' protein years before Alzheimer's symptoms emerge | Hacker News Reader

Blood test can detect 'toxic' protein years before Alzheimer's symptoms emerge

sciencedaily.com

117 pointsCharlesW70 comments

This study indicates that there's a process involving these amyloid oligomers that eventually yields cognitive impairment. But we still don't know if the amyloid oligomers directly cause the impairment or are just a byproduct or calling card. Do I have that right?

I'm trying to understand because I know amyloid beta is both uncontroversially associated with Alzheimer's and very controversial in the way it's associated - is it a direct cause or just a sideshow and massive waste of research money.

I'm personally leaning towards the viral theory I've seen some research about. The general idea is that the brain produces these products as a defense to one of several viruses as a self defense mechanism but that those proteins may do bad things as well. Apparently population studies of people who take antiviral medications for herpes showed a significant decline in incidences of Alzheimer's. I haven't followed it closely lately so I am not sure if that is a return to baseline from an elevated risk (e.x. say that herpes increases baseline risk and treatment restores it) or if it might be generally applicable. Given that most drugs that have targeted Amyloid have failed to produce results so far, something like the Tau hypothesis or viral infection seem to me to be possibilities. Again, I haven't kept up lately so I would be happy to be "corrected" with some new things to read up on.

Yes, there's in fact good evidence that the amyloids are likely an effect rather than the cause, arising from the long history of failure of drugs aimed at the amyloids.

There is very good genetic evidence that amyloid oligomers are causative in the rarer dominantly heritable types of Alzheimer's disease.

The recent positive results of a Lecanemab phase III study, furthermore provides strong evidence that Amyloid Beta is causative in all forms of Alzheimer's disease.

https://en.wikipedia.org/wiki/Lecanemab

With Lecanemab only a relatively small positive effect was able to be shown. With Aducanumab by the same companies, which works similar, even that wasn’t possible even though it’s effective against amyloid oligomers. And there are many more failed treatments targeting amyloid beta.

No matter how the causal relationships are, targeting amyloid beta for treatment does not seem to help enough for treatment.

I would be very interested how genetic evidence can rule out confounding effects.

Lecanemab had an extremely strong effect, from a statistical point of view.

The average clinical efficacy could be stronger. But Lecanemab is definitely the largest step in Alzheimer's disease research in a very long time.

Well, when you have a large number of different mutations in the amyloid beta gene, and in the genes for the machinery for cutting the precursor protein APP to amyolid beta, that all leads to early and fast progressing Alzheimer's disease, which from a pathological perspective is indistinguishable from normal Alzheimer's disease, then the evidence is quite clear.

When you then see that people who have duplicates or triplicates of the amyloid beta gene, also have a much higher risk of Alzheimer's disease and the risk increases with more duplicates, the evidence is extremely strong.

Isn’t the effect small but the significance good?

If I understood it correctly there’s no amyloid beta gene, but genes for APP an genes for proteases cutting APP. As a layman that leaves a lot of other explanations open, for instance other byproducts of the proteolysis, other breakdown mechanisms for APP, …

Biogen made the same claims about Aducanumab and there has been a lot of controversy about its' approval to say the least. Why do we believe this compound is different?

Because the results of this trial is extremely convincing. The result of the Adecanumab trials was fairly unconvincing, and it was quite possible that the positive results were due to a fluke.

The second reason is that Adecanumab did not (as far as I know) differ in approach to many other amyloid beta antibodies which have clearly failed to treat Alzheimer's in trials. Adecanumab binds to and clears amyloid beta tangles or plaques, but there is good evidence that the amyloid beta plaques are not really driving the disease.

Lecanemab is different and specifically targets a form or conformation of amyloid beta. so called protofibrils, which are more much likely to be driving the disease process.

For use as a bio marker the question is somewhat less relevant. However the other comments answer your question well

From what I've read/seen, and take this with a grain off salt because I'm a layperson, amyloid beta is associated with things like Alzheimer's, but there are counterexamples where people have a ton of amyloid beta and no pathology, and drugs targeting it have not been very successful so far.

I think it's something that correlates with impairment, but it could be a side effect of or contribute to some other processes that are causative as opposed to being correlated with Alzheimer's/etc.

More broadly, medicine seems to strong prefer testing for specific things and linking those to pathology instead of attributing pathology to things we can't detect or don't understand, so there's been much more research trying to affect things we can measure than trying to find/figure out things we could be missing/not understand.

Does anyone know how to reconcile the amyloid-caused and not-amyloid-caused comments below?

Would be cool if we had wearable patches like Continuous Glucose Monitors, but monitoring for all kinds of diseases. If these were ubiquitous, we'd detect diabetes, Alzheimer's, many types of cancers, maybe heart disease years before they showed symptoms.

Easier to just screen for this during annual or biannual physicals with a blood draw, no? Would be sufficient for all except the most aggressive and fast moving cancers.

There are lots of things I'd really love to have a graph instead of a single data point for. The obvious candidate we already have a solution for is glucose, but I'd also love figure out how well my hormone replacement is working, because my current level is care is "oh, that's a bit high, you took that 1-2 hours before the test huh" (no instructions were given) once a year.

> There are lots of things I'd really love to have a graph instead of a single data point for.

I couldn't agree more.

Fortunately Apple Health is really good at this [1].

[1]: https://www.apple.com/ios/health/

“Wouldn’t it be cool” and “Wouldn’t it be easier“

Well, it would be cool to get more real-time feedback, where possible.

And sure, somethings will be easier when blood is drawn.

So, “yes” to both questions

> Easier to just screen for this during annual or biannual physicals with a blood draw, no?

8% of the US population (about 26.4 million people) don't have medical insurance [1]; there's no annual physical for them. Unfortunately they only get medical care via the emergency department. I bet a lot of them have smartphones.

BTW, 8% is an all-time low.

[1]: https://aspe.hhs.gov/reports/2022-uninsurance-at-all-time-lo...

> Easier to just screen for this during annual or biannual physicals with a blood draw, no?

Short answer: no.

You’re not going to be screened for certain things on your annual unless your age or condition warrants it.

Unless you’re in a high risk group, they’re not going to recommend a colonoscopy if you’re under 50-55 years old. That could change if enough data has been collected to suggest otherwise.

That recommendation changed ~4.5 years ago to be 45 and older.

https://www.cdc.gov/cancer/colorectal/basic_info/screening/i....

And earlier still if you have a family history or certain bowel diseases. From that page:

However, you may need to be tested earlier than 45, or more often than other people, if you have—

Inflammatory bowel disease such as Crohn’s disease or ulcerative colitis.

A personal or family history of colorectal cancer or colorectal polyps.

A genetic syndrome such as familial adenomatous polyposis (FAP)external icon or hereditary non-polyposis colorectal cancer (Lynch syndrome).

Correct; I was responding to correct a conditional which started "Unless you’re in a high risk group..."

If people don't think something is worth checking for annually, why would they check for it continuously?

If we were at the point that wearable, multi-illness screening patches are affordable and available, would it not follow that annual screens would also be just as available?

> Would be cool if we had wearable patches like Continuous Glucose Monitors, but monitoring for all kinds of diseases.

I think we’re well on the way for this.

Already the Oura ring and the Apple Watch are collecting data to detect arrhythmias and other heart issues. During the height of the COVID pandemic, the Oura ring detected infections prior to people having noticeable symptoms.

Thanks to my Apple Watch, I have years of medical data including things that aren’t normally tracked by most medical professionals in the US such as walking steadiness (a metric for the risk of falling), heart rate variability, resting heart rate and lots more that can give doctors a heads up that something not good is happening.

The problem is, unless you’re part of a very progressive medical practice or in a clinical trial, there’s often no way to get the medical establishment to pay attention to this data or get it into their IT systems.

Older doctors especially are conditioned to basically ignore patient reported (or collected) data that’s not temperature or weight.

The issue with this sort of broad-based testing is specificity. If these tests aren't highly specific then you're going to get all sorts of false positives clogging up the medical system. That can be such a large burden that proper care for sick people gets negatively affected.

In countries where medical care isn't the first step to financial ruin, people have regular checkups all the time. This sort of thing could just be used as a basis for further decision making (as are health apps right now), with only things that need immediate action turning into a "go to the doctor right now".

Which countries are those? There are a few screening and preventative care services which have proven valuable, and are covered in the US at no cost to the patient. But regular check-ups are pointless for most of us.

https://www.healthcare.gov/coverage/preventive-care-benefits...

If a doctor would ignore a positive result if they saw one then they shouldn't order the test!

I worry for the day we have this, but all the measurements needing to be stored on someone else's computer to be able to do the detection.

I use Apple’s Health app; it connects to my medical provider’s Epic system. Epic is like the Oracle or SAP of the enterprise medical records world with 300 million patient records.

All test results are automatically downloaded.

The Health app acts as a repository of data; a user can grant access to 3rd party health apps to analyze specific chunks of data if desired.

Apple makes available onboard machine learning hardware + APIs; using them, apps can at least provide guidance for certain conditions, maybe even before your doctor knows.

I suspect Apple will continue to innovative in this area, especially as they add more sensors to the Apple Watch and AirPods and make better use of the existing sensors.

you'd be up to your ears in false positives, which can often be worse. screening is hard.

having many data points over the past month is arguably better for a physician than having a single data point from a visit

But only if the false positive rates are low enough, and/or the interventions required to follow up a false positive is small enough, and the benefit of earlier intervention in the case of true positives outweigh those risks.

Large scale testing is highly dicey and requires careful consideration because it often takes very low risks from false positives to outweigh the benefits.

We seem pretty great about not having false positives with blood glucose and diabetes. There are of course lots of false positives in other areas. But I'm sure we could dial in many of those type-1/type-2 errors, or just look at the ones where we're confident in the ratio and that there's a net benefit.

Of course there are false positives. Any time you do anything at scale there will be, be it due to precision of equipment, equipment failure, or user error.

When a true positive is rare, the false positives can easily swamp them. E.g. one Canadian paper claims a glucose test for diabetes gives a false positive rate 6 times higher than true positive in the general population [1] (the numbers will of course be much better in a group where risk factors are present).

A challenge is that becoming confident of the ratio is difficult. What do you count? Routine mammography has been scaled back some places because even miniscule false positive rates seemed to rack up enough downsides alongside surprisingly low benefits (you caught things earlier, but the difference turns out to have less impact on survival rates than you might think) when the true positive rate is also tiny.

The end result is that the candidate pool for large scale screening programs where we can be confident of a net benefit is surprisingly small, and it may well be we'll see further declines in use of large scale screening rather than increases, as improved treatment often further cuts into the net benefit of early detection.

[1] https://pubmed.ncbi.nlm.nih.gov/9368868/

There's a whole literature and backstory supporting my statement, if you want to engage do the backing research.

It's not reasonable to demand people do legwork if they want to reply to your naked claims. This is not a forum exclusively for people who are well-versed in the research you're familiar with.

it's not a naked claim; it's a well understood problem in the field that is trivially researchable and this comes up over and over again on HN.

HN is not in "the field," and if it's trivially researchable then you can include links to it yourself. It's not constructive to demand other people are read up on research before interacting with you here.

This is "me-too" research, basically copying what has already been done.

A blood test for AD has already been tested and approved:

https://medicine.wustl.edu/news/blood-test-for-alzheimers-hi...

I wish we put more energy into preventing Alzheimer’s and sharing what we know. There’s a lot known about populations that barely get it and lifestyles that have reduced occurrences of it.

There’s just no/limited money in prevention

Prevention through life style changes is difficult to implement on a population scale - money doesn't quite have anything to do with it. See how successful we are at treating obesity/diabetes through "lifestyle intervention" on a population level, despite the much much clearer connections.

Do we try to treat/prevent diabetes?

The CDC doesn’t tell people about any link or to lose weight if they are obese.

I know multiple people being treated for type 2 diabetes. Few of their doctors have talked with them about weight or obesity being linked.

The general solution in the US is to be regular on diet so your insulin done can be regular.

I do know one person who was recommended to change their diet and weight. In a matter of months he was no longer a diabetic. I told other diabetics about it and they didn’t believe me.

We, as a society, try to keep people on regular insulin and monitoring instead of trying to cure or minimize type 2 diabetes.

Virta Health has been able to put type-2 diabetes into remission for many patients through dietary interventions.

https://www.virtahealth.com/reversediabetes

One of the biggest problems is that such talk about "lifestyle interventions" usually comes with a motivation killing lack of empathy and the treatment model clearly doesn't work for everyone, be it because they can't starve off hunger with it or it simply doesn't work despite adherence. It doesn't really matter, the diet failure rate speaks for itself.

I've experimented a lot with my diet and slowly figured out which food combinations work and do not work for me. And it is much less intuitive than anyone would assume. I used to eat a certain kind of junk food that is on the "definitely bad for you" list and I would always lose weight on it. I know it's still bad in other ways, but it made me question why I was trying so hard and still failing, while some junk food made it effortless.

It's something that the "calories in calories out" crowd really loves to dismiss outright.

I don’t buy fad diets. I also learned that places a western diet goes there are increased healthcare costs. Learned this reading about studies in Barons (which is really for investors).

I changed my diet. Eat a lot of food. Am regularly full. My numbers are all great. I feel better than I have in a long time. And I eat the types of food the people who live the longest (on average) and have the best long term vitality do.

It wasn’t easy but I’m delighted now

Same. Eating a massive caloric surplus at the moment while lifting 6 days per week (3600-4200 calories/day) -- eating about 60% animal protein, vegetables, and dairy. Rice/pasta on occasion.

Don't really try and stop myself if I want to splurge on the weekends: ice cream, maybe some pizza, etc.

Bloodwork is fantastic currently.

The problem with bloodwork is it doesn’t look at artery build up. Heart disease is the #1 killer on the US. Our numbers can look great on the way to atherosclerosis

> There’s just no/limited money in prevention

Hard disagree.

If I know I’m in at high-risk for Alzheimer’s, I will spend money to help prevent it.

Unfortunately this is a growing market; anyone who’s watched a parent or grandparent with Alzheimer’s, it’s a no-brainer.

The issue is that preventing it doesn’t really cost. Lifestyle change isn’t something VCs can make a big return on. Whole population groups prevent it without taking any drugs. Where is the money to be made?

Whole population groups around the world get it in a really limited capacity and only at extremely old age if they do. We know how they live and what they eat. Groups have been studied in the US who are similar and they get really low rates of Alzheimer’s compared to the surrounding population.

The changes people need to make for this just aren’t those you can get a high rate of return on.

> Where is the money to be made?

Drugs are the most obvious. I'm personally familiar with the drug Gleevec, the multi-billion dollar blockbuster drug for Chronic Myelogenous Leukemia, which only about 4–5,000 people get in the US each year. Compared to heart disease and the more well-known cancers (breast, lung, colon), this is a rounding error. When it launched, the cost was $10,000 for a 30-day supply in the US.

Novartis' annual revenue for Gleevec was $4.7 billion dollars before it became a generic drug after patent expiration [1].

The number of people in the US who get CML per year is 5,000; the number who get Alzheimer’s is 100 times that—500,000.

I'm not suggesting revenue of 100x of $4.7 billion to a comparable drug for Alzheimer’s; but 10x isn't out of the question.

Due to the COVID pandemic, Alzheimer's disease dropped from the sixth to the seventh-leading cause of death across all ages in the United States.

This is big market.

> Lifestyle change isn’t something VCs can make a big return on.

It's much more complicated:

    Having at least one APOE e4 gene increases your risk of developing Alzheimer's disease
    two- to threefold. If you have two APOE e4 genes, your risk is even higher, approximately
    eight- to twelvefold. But not everyone who has one or even two APOE e4 genes develops
    Alzheimer's disease.

Sure, there are lifestyle issues at play, combined with genetics. At some point, this will get figured out and there will certainly be a way for investors to make a lot of money on "the cure", testing, diagnostics and the required intellectual property.

If these blood tests pan out, the next step will be wearable devices (like glucose monitors) to test for Alzheimer’s markers or including that tech in a future Apple Watch or other future device.

As an example, Apple has already bought several health-tech startups [3]; if a startup develops Alzheimer’s tech Apple can incorporate into it's ecosystem, they'd be ripe for an acquisition.

> Whole population groups around the world get it in a really limited capacity and only at extremely old age if they do.

False—the rate of Alzheimer's is growing globally. It's 50 million people now; at current rates, it will exceed 152 million by 2050 [2].

Like many diseases of old age, people are getting it at increasingly earlier ages.

For example, we used to call Type 2 Diabetes "adult onset Diabetes"; that term is quickly fading in relevance since children get Type 2 Diabetes pretty often these days.

The theory from David Sinclair that diseases of old age, including Alzheimer’s, are the result of a lifestyle the promotes premature aging, people who are genetically at increased risk for Alzheimer’s (by having at least one APOE e4 gene) will continue to get it at earlier ages.

[1]: https://en.wikipedia.org/wiki/Imatinib#Economics

[2]: https://www.brightfocus.org/alzheimers/article/alzheimers-di...

[3]: https://www.beckershospitalreview.com/healthcare-information...

My guess is such a study would end up recommending what is already known to be good for our health. Yet most people refuse to do it because it takes effort. Exercise your body and your mind. Keep your weight in check. Don't smoke. Don't drink much. Eat a variety of foods and avoid junk food. Once you've done those, then maybe there is some supplement that might squeeze out a little more benefit.

It reminds me of cycling "weight weenies" -- people who obsess every gram on their bike frame, eg spending 3x for their caliper brakes because it uses an alloy that saves 20g. Yet most of them are 30 lbs/15kg overweight. They should lose the weight and only then worry about a few hundred grams from their bike frame. Additionally, losing that weight would pay all sorts of dividends unrelated to biking.

So if it is detected, can it be reversed?

Chronic diseases break our medical R&D model and our society is prone to normalizing these as if they were some immutable constants of life.

Without reconsidering our attitude to research & development & incentives, and corresponding massively increased efforts the favorable outcome is unlikely here.

If you are interested, read this FAQ: https://www.fightaging.org/faq

In my opinion we should use AI/AGI, high-throughput methods and massive clinical trials on volunteers to accelerate the medical R&D as much as possible.

Massive clinical trials cost billions of dollars. Where will the funding come from? AI technology can't do much to cut the cost of clinical trials.

Reversing “it” is not necessarily the goal, the goal is holding off Alzheimer’s. Diet, sleep and exercise are lifestyle remedies that may achieve this, and pre screening for risk might provide additional motivation

we dont even know if they are actually involved in causing the impairment, but you can bet thats what big pharma will try to sell you 20 years ahead of old age.

If there's plausible (lower standard than credible) connection, I'll be happy to take their pills for 20 years after seeing the long declines brought about by Alzheimer's in several older people that I knew well.

I'd even be prepared to take drugs with a not unsubstantial risk of shortening my life expectancy if there was a plausible connection, after having seen both my grandmother's effectively being gone because of Alzheimer's for a decade before they physically died.

You can imagine that proving the efficacy of the drug over dozens of years is going to be especially challenging. No clinical trial ever does that.

And what if those pills come with serious side effects, as most do?

Taking pills for 20 years has a financial cost, and drugs typically cause side effects anyway (you dont have efficacy for free). That sounds like a bad calculation.

At some point, it’s simply a matter of research, right?

Having a longer window provides more opportunities to study the disease and for treatments

the article suggests not at this time

>But research has shown that the seeds of Alzheimer's are planted years -- even decades -- earlier, long before the cognitive impairments surface that make a diagnosis possible.

How many decades before this test is available to doctors, or even better OTC?

It's a blood test, so probably never OTC. There's already a test approved: https://medicine.wustl.edu/news/blood-test-for-alzheimers-hi...

Isn’t the biggest research topic in Alzheimer’s the questioning of the amyloid hypothesis?

I think the research topic is to determine whether amyloid is a cause or symptom of the disease. It seems to me the test would be useful in either instance?

hint for Alzheimer's prevention: check Benfotiamine ! https://en.wikipedia.org/wiki/Benfotiamine

Research:

"Benfotiamine and Cognitive Decline in Alzheimer’s Disease: Results of a Randomized Placebo-Controlled Phase IIa Clinical Trial" ( available in PMC 2021 Feb 12 )

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880246/

"Conclusion:

Oral benfotiamine is safe and potentially efficacious in improving cognitive outcomes among persons with MCI and mild AD."

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