
Researcher says we have Alzheimer's wrong - tokenadult
http://www.pri.org/stories/2015-04-30/do-we-all-have-alzhemers-completely-wrong-man-says-yes
======
neuro_imager
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.

~~~
danieltillett
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.

~~~
neuro_imager
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.

~~~
danieltillett
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.

~~~
neuro_imager
Um, what?

Pharma continue to throw billions at AD therapy.

~~~
danieltillett
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.

1\.
[http://pipeline.corante.com/archives/2014/01/23/alzheimers_t...](http://pipeline.corante.com/archives/2014/01/23/alzheimers_therapies_a_reasonably_gloomy_update.php)

2\.
[http://pipeline.corante.com/archives/2015/03/20/biogens_alzh...](http://pipeline.corante.com/archives/2015/03/20/biogens_alzheimers_data.php)

~~~
neuro_imager
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).

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btilly
I ran across this story over a decade ago. See
[http://forum.iwethey.org/forum/post/151431/](http://forum.iwethey.org/forum/post/151431/)
for my thoughts then.

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.

------
DanBC
There's an image of a guy holding a brain.

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](https://www.hta.gov.uk/guidance-public/brain-donation)

[http://www.alzheimers.org.uk/site/scripts/documents_info.php...](http://www.alzheimers.org.uk/site/scripts/documents_info.php?documentID=1103)

~~~
jebblue
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?

------
joelthelion
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.

[1]: [http://media.biogen.com/press-release/corporate/biogen-
idec-...](http://media.biogen.com/press-release/corporate/biogen-idec-
presents-positive-interim-results-phase-1b-study-investigational)

~~~
neuro_imager
(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.

~~~
joelthelion
What do you work on? I work on image processing algorithms for structural MRI.

~~~
neuro_imager
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?

~~~
joelthelion
I work for an imaging CRO, so I primarily work on imaging endpoints for
clinical trials: hippocampus volume and atrophy, etc.

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?

------
mcguire
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.

------
jinushaun
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.

~~~
DanBC
> maybe we are

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](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.

------
acqq
And the main message is:

"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](https://clinicaltrials.gov/ct2/show/NCT01931566)

"Estimated Study Completion Date: April 2019"

------
akeck
Fascinating article! Buying people five years of extra clarity would be
amazing for such a devastating condition.

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?

~~~
rsync
I also thought that the notion of the inability to grow new neurons had been
shown to be false...

Anyone ?

------
mrfusion
And here's a recent counterpoint:
[http://news.harvard.edu/gazette/story/2015/05/new-clarity-
ag...](http://news.harvard.edu/gazette/story/2015/05/new-clarity-against-
alzheimers/)?

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.

------
mrfusion
Does anyone know if there's a way to donate some programming talent to these
kinds of projects? It seems like something I'd like to do when retired.

~~~
toufka
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.

[1] [https://www.micro-manager.org/](https://www.micro-manager.org/)

