The Alzheimer's Enigma | Hacker News Reader

The Alzheimer's Enigma

mosaicscience.com

61 pointsevilsimon39 comments

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...

2. http://en.wikipedia.org/wiki/Type_3_diabetes

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

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.

A few years ago I watched "Sugar: The Bitter Truth" [1], by Dr Lustig of UCSF. It's a very interesting watch, which convinced me to change my diet away from most everything sugary, and put much more more fiber and fat into my diet.

[1] https://www.youtube.com/watch?v=dBnniua6-oM

My father developed alzheimer's in his early 60's. One thing I know didn't cause it was sugar because he rarely touched it.

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).

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.

I think you mean apoe4.

you're absolutely right, that is exactly what I meant. thanks for the correction

This is a must read for anyone interested in the possible connection: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2769828/

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.

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

http://www.helpguide.org/elder/alzheimers_prevention_slowing...

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

Anecdote does not trump data.

Agreed, my point was simply that even a textbook healthy diet isn't some silver bullet that protects you from dementia.

With little doubt, heredity does play a role. But, just because a non-smoker can still get lung cancer, should we smoke? Start with the population centers with low rates of Alzheimer's and dementia and work backwards. Even if some behaviors prove to be irrelevant, they may prove worth it for those with a genetic history of the disease.

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.

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.

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.

Unfortunately, the evidence with vegetarianism points towards the opposite. In addition, a healthy vegetarian diet includes grains, including rice and potatoes, to make complete proteins when paired with legumes. Sure, you can go overboard, but so can everyone else. Nuts are not a complete protein and still need paired: Avocados are a complete protein, but there isn't all that much in it. Sure, they are healthy and variety in diet is good, but more isn't necesarily needed.

I don't think those point address the question: "I've always wondered if what you do with your mind during your life has any actual influence on this disease."

From a brief reading of the hypothesized causes[1], the most straightforward behavioral thing you can do is to avoid smoking. The sibling's comment suggests generally healthy living. Other than that, don't worry about your behavior as regards Alzheimer's; the stress isn't going to make you any healthier.

1. https://en.wikipedia.org/wiki/Alzheimer%27s_disease#Other_hy...

> yet once someone has it deep it no longer matters to them.

Unfortunately, I think it is more accurate to say they are not longer the same person.

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...

2. http://www.nature.com/ncomms/journal/v3/n8/fig_tab/ncomms201...

> 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.

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.

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.

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

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

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 (Zhang et al. Cell 2013).

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

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...

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/Rs7412

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

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

By the way, I see you maintain SNPedia, thanks!

The apoE1 snp is Rs121918394

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...

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

Why do you say that?

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

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

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