The Alzheimer's Enigma

by evilsimon • 12 years ago

61 39 12 years ago

bthornbury2• 12 years ago

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• 12 years ago

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

bthornbury2• 12 years ago

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

coldcode• 12 years ago

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.

biehl2• 12 years ago

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

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

mullingitover3• 12 years ago

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

djokkataja• 12 years ago

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...

davorak• 12 years ago

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.

pdq3• 12 years ago

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

robbiep3• 12 years ago

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• 12 years ago

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.

mrfusion2• 12 years ago

I think you mean apoe4.

voidlogic2• 12 years ago

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

tsmash• 12 years ago

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

mrfusion2• 12 years ago

Why do you say that?

sasoon2• 12 years ago

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

et2o• 12 years ago

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).

pcrh4• 12 years ago

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...

cariaso• 12 years ago

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.

jtmoulia2• 12 years ago

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...

irremediable• 12 years ago

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.

jtmoulia2• 12 years ago

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.

sasoon2• 12 years ago

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...

The Alzheimer's Enigma

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