Researcher says we have Alzheimer's wrong
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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.
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.
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.
Pharma continue to throw billions at AD therapy.
1. http://pipeline.corante.com/archives/2014/01/23/alzheimers_t...
2. http://pipeline.corante.com/archives/2015/03/20/biogens_alzh...
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).
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.
https://www.hta.gov.uk/guidance-public/brain-donation
http://www.alzheimers.org.uk/site/scripts/documents_info.php...
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.
[1]: http://media.biogen.com/press-release/corporate/biogen-idec-...
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 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?
I've developed multi-atlas methods for segmentation, boundary shift integral (BSI) and Jacobian (TBM) for longitudinal atrophy computation, etc.
What kind of processing do you do? What tools do you use?
"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.
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.
Here's the NICE guidance: http://www.nice.org.uk/guidance/cg90
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.
"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."
https://clinicaltrials.gov/ct2/show/NCT01931566
"Estimated Study Completion Date: April 2019"
I am confused about one point the writer makes though:
"But unlike other cells in the body, neurons can’t reproduce."
I thought exercise had been shown to produce neurogenesis in the brain? Or is the writer referring to mature neurons' inability to replicate?
Anyone ?
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.
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.