I'm a neuroimaging researcher and I can tell you that Roses' perspective is hardly new. Very few people researching neurodegenerative disease believe that Amyloid is the underlying etiological (causative) factor for AD (or other neurodegenerative diseases).
Also we know that APOE and TOMM40 are relevant in some sub-populations of patients but certainly do not account for all (or even the majority of people with AD/neurodegenerative disease).
Amyloid is one of a number of agents involved in a cascade of processes that ultimately lead to the clinical manifestations of AD. Some of these include:
- Amyloid deposition
- phosphorylation and deposition of Tau protein
- vascular factors including blood-brain barrier breakdown, reduced cerebral blood flow and hypoxia.
- neuronal dysregulation through multiple mechanisms.
If you're interested in a better understanding of this I would suggest reading a few nature neuroscience reviews.
I think the major problem being made is people assuming Alzheimer's is one disease. Look at the history of cancer research for a comparison - it started out with all the researchers thinking cancer was a single disease and each researcher had their own pet theories as to the cause. We now know that each cancer is an unique swam of related cancers and the best treatment is found by identifying and exploiting the particular mutational weaknesses the swam displays.
You might wonder why this matters - the problem is if Alzheimer's is more than one disease then it is very hard to develop effective treatments as any new treatment will only work on a sub-population of patients. This makes it very hard to prove to the FDA that your treatment should be licensed.
Yes, disease classification is a rapidly moving target.
First off, AD is one of several currently classified neurodegenerative diseases. Others include frontotemporal dementia, "Parkinson's Plus" syndromes such as Lewy Body Dementia, Multiple System Atrophy and Supranuclear Palsy.
Some people classify vascular dementia(s) as a set of separate entities such as multi-infarct dementia, cerebrovascular small vessel disease and so on. It is however becoming increasingly clear that vascular factors affect most (if not all neurodegenerative diseases).
These classifications are based mostly on clinical evaluation which is tremendously unreliable. Bloodwork, CSF, genetic studies and imaging contribute to the clinical diagnosis (mostly neuroimaging - most notably MRI and PET scanning).
All the aforementioned diseases overlap to some extent and have patient subgroups within each of them, sometimes based on clinic feature (such as tremor-dominant parkinson's) and some on imaging features (such as limbic dominant AD).
Newer imaging methods are moving us towards dividing patients up into different phenotypes based on for example, patterns of tau deposition. Increasing genomic knowledge will likely also have a huge impact in this regard.
Yes until we get the sub-populations sorted it is going to be very hard to get anywhere with AD. Combine that with poor animal models, late diagnosis, and the need for large and very long human trials it is not surprising almost all pharma companies are avoiding AD.
From my understanding only one one major (Eli Lilly) now has a serious AD program - all the others have effectively walked away after losing tens of billions [1]. I have to say that Biogen’s antibody [2] is looking interesting. If I had to invest my own money in AD I would spend it on better early detection/sub-population classification and then on developing monoclonal antibodies targeting each sub-population.
Thank you for this. Really interesting blog, hadn't seen it before.
I can vouch for the fact that at least two other majors continue to invest heavily in AD diagnostics and/or therapeutics. You're right though that all have thrown a ton of money at this without much ROI yet (apart from those producing diagnostic radio-pharmaceuticals).
True, it's not "new" if your perspective is the last five years. But Roses was one of those people in the wilderness beating this path for 20 years back when the amyloid dogma was overbearing.
It's only been recently now that all the targeted amyloid drugs have not panned out as effectively as hyped, that the dogma is crumbling. Being anti-amyloid is quite hot right now. The actual evidence is still quite mixed.
My conclusion then was that this is a case of conflict between two paradigms. Until believers in the hypothesis that beta-amyloid is critical run into crisis, alternate theories will have a hard time being funded and heard. No matter what the facts may be.
Sadly there is a history in science of people who were right being marginalized for decades before anyone else noticed. To name an example, Barbara McClintock in the 1930s managed to prove that genes can move around in the genome. She stopped publishing her work in the 1950s because it was too hard to convince other scientists to pay attention to her apparently impossible results. In the late 60s and 70s many other researchers replicated her results in different organisms and biology was finally able to figure out the mechanism. She began to get awards at that point, finally resulting in the Nobel in 1983.
If you want to donate your brain to this kind of research it'd probably be useful. Supplies in the UK are running low.
You might want to i) talk to your family about what your wishes are ii) document those wishes. This needs to be done on top of any organ donation (for transplant) stuff that you're doing.
I honestly don't know a thing about all of this but wouldn't finding better ways to harmlessly map and study living brains provide more useful information? Maybe a chemical substance a patient could drink that would (really no idea here) excite neurons and make the ones that are having problems stand out more during the test?
If the Amyloid hypothesis is wrong, why does this drug[1] seem to work so well?
I think everybody should humble themselves a bit and recognize that we don't fully understand the mechanisms of Alzheimer's yet. It's a complicated disease, and a lot of the techniques we use to understand it are still in development.
(Full disclosure: I have been involved in MRI and PET imaging arms of industry-funded trials such as this one).
First off, there's no question that Amyloid plays a role in the development of AD.
It is however becoming increasingly clear that it does not play the primary causative role. Its exact role is currently unclear: its likely both a secondary neurotoxic agent and an epiphenomenon. It's also non-specific (ie. Amyloid deposition is seen in several other disease states as well as in many cognitively normal controls).
There are certainly other agents and mechanisms that are both more important in the development of AD and arise earlier in the time course of the disease.
This particular drug has a modest effect (From this study - it slows down disease progression, at least in the first year). The several dozen other anti-amyloid agents that have been trialled, at billions of dollars of expense, have either had little or no effect or demonstrated a modest effect in the first 12-24 months treatment before becoming ineffective again.
Its also worth noting that the manufacturers have a very limited understanding of the mechanism(s) of action of the drug. So, there's no guarantee that any effect is actually attributable to the reduced amyloid deposition, and not some secondary process.
I'm a neuroradiologist, so I mostly interpret images (MR, CT and PET mostly).
I'm involved in various research studies where I am involved in study design, sequence selection, image interpretation, clinical correlation etc.
Most of the techie stuff gets done by physicists and some of my collaborators in other areas of neuroscience but I do enjoy doing some of my own (rather rudimentary) pre- and post-processing of MRI data.
What sort of image processing do you program for? VBM?
It's an interesting article and I unfortunately don't know diddly-poop about neuroscience, but this statement:
"Yet, some researchers attempting to replicate Roses’ work have failed to find an association between TOMM40 and the age of Alzheimer’s onset. Roses has countered that these groups aren’t performing his research correctly and that the work involves complicated diagnostic methods. 'Because TOMM40 [research] is not as easy to replicate as ApoE4 [research] was,' Roses says, 'the first thing they say again is the data is wrong.'"
sets off my kook detector rather strongly. That is exactly the situation that many false claims find themselves in, and it's exactly the response that the investigators make just before the wheels start coming off.
From other parts of the article, I don't know or even believe strongly that Roses is wrong, but if you're a future scientist in an experimental field, be very cautious about saying things like that.
While I don't have the expertise to know if this theory is potentially valid, I've long suspected that maybe we are focusing on fixing the symptom instead of the cause when discussing the biochemical basis of certain neurological conditions. In particular, ADHD and depression.
So, the "we" there talks about wider society. People involved in health care mostly recognise that "chemical imbalance" is not useful for most people.
That's why national standards bodies recommend a talking therapy over medication for several types and severities of illness; and a talking therapy combined with medication for many of the others.
NICE is an organisation that assesses the evidence base for treatments of all kinds, then makes recommendations on whether the cost of that treatment can be justified. Health trusts in England don't have to follow NICE guidance, but if they don't they need to carefully describe why they've chosen not to follow it.
I know next to nothing about ADHD, but if by this you're referring to so-called "chemical imbalance", know that it is widely accepted to be an oversimplification of an inadequate explanation.
"the biggest test of Roses’ algorithm is a 5,800-subject, five-year, double-blind, randomized, placebo-controlled trial currently underway through a collaboration between his startup Zinfandel Pharmaceuticals and Japanese drug firm Takeda Pharmaceutical."
What do you guys think? Who is right? I guess the main quote is:
> We showed that if you use human neurons made from stem cells and you grow it in a gel that mimics the brain, that indeed amyloid causes tangles. So now there’s no doubt. And if you stop the amyloid, you stop the tangles.
Ask around at your local biomedical graduate program. Just got out of one myself. There are LOTS of 'easy' programming tasks that are being undertaken by very bright people with no ability/expertise in programming. It slows down the research they are good at. Each individual task is not difficult, but would take some time and investment in order to understand the problem correctly.
Or donate efforts to clean up and make nicer some of the major OSS scientific projects like uManager [1]. These efforts help towards learning about things like Alzheimer's way more than you'd expect. And though they're not specific to Alzheimer's, that's a good thing - they help ALL drug/disease related work.
Also we know that APOE and TOMM40 are relevant in some sub-populations of patients but certainly do not account for all (or even the majority of people with AD/neurodegenerative disease).
Amyloid is one of a number of agents involved in a cascade of processes that ultimately lead to the clinical manifestations of AD. Some of these include: - Amyloid deposition - phosphorylation and deposition of Tau protein - vascular factors including blood-brain barrier breakdown, reduced cerebral blood flow and hypoxia. - neuronal dysregulation through multiple mechanisms.
If you're interested in a better understanding of this I would suggest reading a few nature neuroscience reviews.