
The Alzheimer's Enigma - evilsimon
http://mosaicscience.com/node/5
======
pdq
The latest research is pointing to Alzheimer's being another form of diabetes
which attacks the brain, nick-named "Type 3 Diabetes" [1]. The cells in the
brain become insulin resistant, first causing memory loss and brain fog, and
later causing dementia and Alzheimer's.

1\. [http://opinionator.blogs.nytimes.com/2012/09/25/bittman-
is-a...](http://opinionator.blogs.nytimes.com/2012/09/25/bittman-is-
alzheimers-type-3-diabetes)

2\.
[http://en.wikipedia.org/wiki/Type_3_diabetes](http://en.wikipedia.org/wiki/Type_3_diabetes)

~~~
robbiep
There is some research to support this however it is by no means conclusively
demonstrated

More likely there are contributions from multifactorial elements: some
propensity to form Amyloid plaques (from APP mutations or downstream
processing mutations), some contribution from tau; there is a significant body
of evidence to show that APOE3 carriers (cholesterol transport proteins) have
a higher risk (something particularly relevant for myself given I am an APOE3
heterozygote) and the more recent 'type 3 diabetes' studies, which seem
promising however the way they are bandied around by the 'sugar is evil' crowd
my gut feeling is that they push the line a bit more vehemently then the
evidence would suggest at present

~~~
hyperbovine
Honest question: other than that it's tasty, is there any argument whatsoever
for consuming a lot of sugar? If no, then decreased risk of Alzheimer's is,
pardon the pun, icing on the cake.

~~~
robbiep
No there isn't. Certainly a diet consisting of lots of high sugar drinks and
sugary food is a bad idea. Not only is it going to contribute to obesity but
high sugar intake appears to be a much bigger risk factor for atherosclerosis
and coronary artery disease than hyperlipidaemia. But all things in
moderation. It is a pet peeve of mine that there are people who are so rabidly
anti-sugar (the foaming at the mouth types). Yes we know it isn't a good idea
in large doses and yes modern diets promote exactly this but sugar is not
responsible for global terrorism or anything of the sort (to use some extreme
hyperbole).

~~~
tomhoward
I believe (influenced strongly by self-experimentation over a long period of
time) that there's a great deal of mistaking correlation for causation in this
debate.

In my experience, when the body is in a good state of healthy balance, there
is little appetite for refined sugars, carbs, and all the other usual culprits
of the anti-sugar set.

Such a body can happily tolerate some indulgence - eg, a night or two per week
having sugary desserts and cocktails.

But after a certain amount of indulgence, the body responds by feeling bad
(hangovers, brain fog etc), and the this healthy person heeds the signal to
ease off for a few days.

However there's a significant proportion of the population for whom the body
isn't in a state of healthy balance, which causes them to have too great an
appetite for sugar, which leads to exacerbated health problems (diabetes,
heart disease, Alzheimer's, etc).

All my research and experience leads me to believe that excess sugar
consumption is more of a symptom than a primary cause.

------
coldcode
This is one disease that getting it scares me more than almost any other; yet
once someone has it deep it no longer matters to them. I've always wondered if
what you do with your mind during your life has any actual influence on this
disease.

~~~
biehl
It is generally accepted that lifestyle has significant influence on
Alzheimers risk.

[http://www.helpguide.org/elder/alzheimers_prevention_slowing...](http://www.helpguide.org/elder/alzheimers_prevention_slowing_down_treatment.htm)

~~~
mullingitover
My grandmother was a teetotaling vegetarian and came down with it. I'm of the
opinion that the biggest risk factor is aging.

~~~
pdq
See my other post, but if the evidence proves out that Alzheimer's is a brain-
affecting form of diabetes, being a vegetarian would likely be a disadvantage
from meat-eaters. By consuming less protein and fat in general than a
carnivore, and more carbohydrates, you have a higher risk of diabetes. So
vegetarians need to consume less rice and potatoes, and more avocados and
nuts.

~~~
mullingitover
That's interesting because my dad (other side of the family) is diabetic and
was able to keep his blood sugar under control, to the point of no longer
needing supplemental insulin, by switching to a vegetarian diet. He tried
going vegan, but his blood sugar got _too low_ with a vegan diet.

~~~
voidlogic
Its not impossible to eat a vegan ketogenic diet, but its much harder then if
you consume animal fats / protein. Vegan and non-vegan ketogenic are already
very restrictive, making a ketogenic vegan much more restrictive then either.
Also, many people in ketosis have very low blood sugar as their body is mostly
running on ketone bodies like β-hydroxybutyrate in lieu of sugar.

------
jtmoulia
For a stretch I helped research Alzheimer's effects the olfactory system --
one result of the cascade of Alzheimer's described in the article is that
olfactory sensory neurons start mistargeting their downstream glomeruli [1]
[2]. Alzheimer's patients correspondingly perform poorly on odor
identification tests, though the confounding factor of dementia makes it a
poor diagnostic tool.

More generally, while this article mostly discusses treatment, the physical
symptoms of plaques, tangles, and neural degeneration occur before a patient
starts displaying dementia. Assuming an Alzheimer's treatment can't reverse
the damage done, it would have to be coupled with an early diagnostic,
something which doesn't exist yet.

1\.
[http://en.wikipedia.org/wiki/Olfactory_receptor_neuron#media...](http://en.wikipedia.org/wiki/Olfactory_receptor_neuron#mediaviewer/File:Gray772.png)

2\.
[http://www.nature.com/ncomms/journal/v3/n8/fig_tab/ncomms201...](http://www.nature.com/ncomms/journal/v3/n8/fig_tab/ncomms2013_F7.html)

~~~
irremediable
> Assuming an Alzheimer's treatment can't reverse the damage done, it would
> have to be coupled with an early diagnostic, something which doesn't exist
> yet.

I'm actually starting a PhD in a group that's hoping to use imaging (e.g.
ASL/DCMRI) for just this purpose! Very early days in this, both for me and the
group, but there are a lot of different things that can be tried.

~~~
jtmoulia
Very cool -- it would be fantastic to see a regular Alzheimer's checkup that
fit into someone's medical routine. Well, especially once there's a treatment.

It's a growing 'epidemic', though strangely due to improvements in medicine:
we're living longer. Best of luck.

------
bthornbury
A long but interesting read. The parallels with the mystery novels didn't make
sense to me at first but then I understood that the evolution of such novels
to greater complexity was being compared to the growing complexity of our
understanding of alzheimer's disease.

I prefer to draw a comparison to CS. The Tau vs Amyloid camps are essentially
defining two spaces where potential solutions may exist. It seems like the
research is doing brute-force depth-first searches across potential solution
spaces. Viewed in this manner, and given the lack of results, I wonder if a
more comprehensive (breadth-first) approach might be more appropriate.
Accounting for all sides of the puzzle rather than focusing on only one.

Undoubtedly more funding will be required in any case.

~~~
jacques_chester
Funding resembles variations on hill climbing algorithms. It converges on the
sharpest gradients in promising outcomes.

~~~
bthornbury
This is disappointing as this is almost definitely converging on a local
maxima.

------
et2o
Frustrating article. Attempts at communicating biology in popular science are
invariably incomplete. Additionally, we must realize that identifying targets
is far different from developing effective drugs for these targets.

Scanning the comments: No one really thinks that Tau is responsible anymore.
The problem is that we only rather recently realized soluble AB oligomers are
the most distal causative agent. T3 diabetes is again a distal effect of the
etiologic agent of AD; what causes T3 diabetes?

I would encourage anyone who is interested to begin with this paper:
[http://www.cell.com/abstract/S0092-8674(13)00387-5](http://www.cell.com/abstract/S0092-8674\(13\)00387-5)
(Zhang et al. Cell 2013).

~~~
pcrh
Tau pathology is the best pathological correlate with Alzheimer's disease.

What is often overlooked in the study of Alzheimer's disease is the APOE gene.
This comes as three forms, each differing from the other by only a few amino
acids. These are called APOE2, APOE3 and APOE4. The most common form is APOE3,
APOE2 and APOE4 are each present in about 6-10% of people (heterozygous).

People who are homozygous for the APOE2 form almost never get Alzheimer's
disease, whereas those who have the APOE4 form have a more than 50% chance of
getting Alzheimer's disease before they die.

So... there must be a link between the APOE gene and tau... since both are the
strongest correlates with the disease, in pathology and genetics,
respectively.

However, you would be hard pressed to find a study that demonstrated a
mechanistic link between these two factors (apart from Alzheimer's disease, of
course).

As a researcher in the field, I think this is one of the most intriguing
aspects.

Link to open access review on APOE in Alzheimer's disease:

[http://dx.doi.org/10.1016/j.neuron.2012.11.020](http://dx.doi.org/10.1016/j.neuron.2012.11.020)

Edit: For those interested in a reputable collection of recent reviews on the
biology of Alzheimer's disease:

[http://perspectivesinmedicine.cshlp.org/cgi/collection/the_b...](http://perspectivesinmedicine.cshlp.org/cgi/collection/the_biology_of_alzheimer_disease)

~~~
cariaso
I've never seen an explanation for why APOE1 is rare to non-existent. I feel
like understanding that may give useful clues to the larger Alzheimer's
question. Do you have any insight? While the population frequency of
heterozgosity for the 2 relevant SNPs

* [http://snpedia.com/index.php/Rs429358](http://snpedia.com/index.php/Rs429358)

* [http://snpedia.com/index.php/Rs7412](http://snpedia.com/index.php/Rs7412)

is low, but not low enough to justify the near total absence of E1/E1.

~~~
pcrh
A name is just a name. There are about 20 varieties of apoE, most of which are
extremely rare, i.e. found in only a handful of families.

ApoE1 is simply rare, and not really relevant to Alzheimer's disease, although
it does affect blood cholesterol levels.

[http://www.ncbi.nlm.nih.gov/pubmed/?term=22859420](http://www.ncbi.nlm.nih.gov/pubmed/?term=22859420)

------
sasoon
This completly focuses on finding the cure, but not much effort is spend on
finding the cause.

Crude example, should we focus on finding cures for consequences of lead
poisoning, instead removing the cause: lead in paint, cosmetics, fuels...

------
tsmash
We're cutting out cholesterol from the diet. Of course there's going to be an
Alzheimer's epidemic.

~~~
mrfusion
Why do you say that?

~~~
sasoon
The human brain is particularly rich in cholesterol: around 25 percent of all
body cholesterol is accounted for by the brain. Every cell and every structure
in the brain and the rest of our nervous system needs cholesterol, not only to
build itself but also to accomplish its many functions. The developing brain
and eyes of the fetus and a newborn infant require large amounts of
cholesterol. If the fetus doesn’t get enough cholesterol during development,
the child may be born with a congenital abnormality called cyclopean eye.

Human breast milk provides a lot of cholesterol. Not only that, mother’s milk
provides a specific enzyme to allow the baby’s digestive tract to absorb
almost 100 percent of that cholesterol, because the developing brain and eyes
of an infant require large amounts of it. Children deprived of cholesterol in
infancy may end up with poor eyesight and brain function. Manufacturers of
infant formulas are aware of this fact, but following the anti-cholesterol
dogma, they produce formulas with virtually no cholesterol in them.

One of the most abundant materials in the brain and the rest of our nervous
system is a fatty substance called myelin. Myelin coats every nerve cell and
every nerve fiber like the insulating cover around electric wires. Apart from
insulation, it provides nourishment and protection for every tiny structure in
our brain and the rest of the nervous system. People who start losing their
myelin develop a condition called multiple sclerosis. Well, 20 percent of
myelin is cholesterol. If you start interfering with the body’s ability to
produce cholesterol, you put the very structure of the brain and the rest of
the nervous system under threat.

Now, think about statins

~~~
pcrh
Recent genetic studies show no link between cholesterol and Alzheimer's
disease:

Genetic Predisposition to Increased Blood Cholesterol and Triglyceride Lipid
Levels and Risk of Alzheimer Disease: A Mendelian Randomization Analysis.
10.1371/journal.pmed.1001713

