But first, let's look at the method used in this study, because that may be almost as important as a development. And for this, we will use a sports analogy.
Let's say there's an allele (an allele is a variant of a gene) that can boost your ability to play baseball. It really works. It causes an eye-hand coordination thing that improves batting, catching, and also affects your perception of movement in 3D space so you never miscalculate whether to throw or hold the ball or run vs. stay on base.
If you checked for this allele in professional baseball players, you might find that many have it, and even that there looks like there may be more copies of this allele in the overall genome of Major League Baseball, but perhaps at a statistically non-significant level. Yet, you are pretty sure this allele exists and has this effect.
Well, you really didn't want to test the hypothesis that this allele causes a person to be a professional baseball player. Rather, the allele causes this special hand-eye thing, which is a trait ... a phenotype ... that then would make a person a great baseball player. But there may be other ways to be a great baseball player, and there may be lots of things a person with this allele may end up doing.
So, you could re-do your statistical analysis by looking not for whether someone is an accomplished baseball player, but rather whether or not they have this hand-eye coordination trait. Then, you figure out a test for the trait, and a test for the gene, develop a sampling strategy that ignores one's involvement in baseball, and bingo, you've got a statistically significant result!
That is an increasing trend in genetic studies of traits (especially disease-related traits). The term that has emerged (but is not the only term used) is "endophenotype." The endophenotype in the fictional but plausible example I gave above is a super excellent genetically determined hand-eye coordination. In the study just released as you were reading the above paragraphs, it is something physical that seems to be related to the progression of Alzheimer's disease.
The endophenotype is a version of a protein found in cerebral spinal fluid, called CSF ptau181. If a cell was a house, microtubules would be the 2X4s and other pieces of wood. The house would be made of them, and some of them would be used for other purposes as well. Microtubules make up the cytoskelton of a cell and are involved in a lot of day to day cellular processes. Microtubules are therefore very important, and they are made up of tiny protein globs called tubulin. So, the exact structure of tubulin, which is mostly determined by the genetic code that specifies it, has important cascading effects. The tau genes code for "tau proteins" which interact with tubulin as it is being assembled into microtubules, in particular, in the Central Nervous System. Small variations in Tau DNA can cause variations in Tau proteins that could then affect microtubule formation or stability. Thus, the potential connection between certain Tau alleles and, in this case, Alzheimer's disease.
The current study looked at DNA variants in 846 patients and found a link between rapid progression of Alzheimer's and the suspect pTau protein.
"We have looked at data from three separate, international studies, and in all three, we found the same association. So we are confident that it is real and that this gene variant is associated with progression in Alzheimer's disease," said first author Carlos Cruchaga, PhD.
In particular, the researchers report the link between this slightly variant DNA (called rs1868402) and higher levels of the CSF ptau181 protein, and a faster rate of progression of the disease. This does not seem to be linked to the risk of having Alzheimer's or to the age of onset, which makes sense because increased levels of the protein levels is not associated with onset, nor does it occur prior to the clinical visibility of the disease.
Can this knowledge help? Probably. The researchers suggest that rs1868402 or some other variant ultimately causes a change in metabolic processes that lead to a pathological form of tau proteins, which would cause neurodegeneration. A similar metabolic glitch, if induced in mouse brains, affects neural function, supporting this idea. So there are two potential benefits: 1) Identifying those who are likely to have rapid degeneration among clinically new Alzheimer's patients; and 2) Developing a pharmaceutical intervention to fix the degeneration process now that it is (probably) better understood.
Cruchaga, Carlos, Kauwe, John, Mayo, Kevin, Spiegel, Noah, Bertelsen, Sarah, & Et.Al. (2010). SNPs Associated with Cerebrospinal Fluid Phospho-Tau Levels Influence Rate of Decline in Alzheimer's Disease
PLoS Genetics, 6 (9)
I don't think this technique is as useful as you think it is. The problem is that the âcomplex genetic diseasesâ (of which Alzheimer's is one), is that they are not âbugsâ, they are âfeaturesâ.
The whole paradigm that the genome researchers are working on is flawed. Yes, there are adverse effects like Alzheimer's. Is there any evidence that the gene pathways are not working âproperlyâ? By âproperlyâ, I mean the way they evolved to work.
Are adverse effects like Alzheimer's inextricably coupled to beneficial effects that the same gene pathways that produce? An example I like to use is anaphylaxis. Anaphylaxis can make eating a peanut lethal. Is anaphylaxis a âbugâ, or a âfeatureâ? It is clearly a highly complex integrated series of pathways that are invoked and do things in seconds and minutes when the appropriate stimulus hits the trigger point.
Evolution didn't configure the immune system to stop all death, evolution configured evolution to minimize the sum of death and non-reproduction from all causes simultaneously. If bacteria get into your blood stream in âthe wildâ, the only thing that has a chance of saving your life is a massively ginormous immune system response; like anaphylaxis. If anaphylaxis causes 5% deaths, but prevents 25% then it is a fabulously advantageous feature.
It isn't that lethal anaphylaxis is good, but that an immune system that can support lethal anaphylaxis is superior to an immune system that can't. It is just like being able to run yourself to death while running from a bear. Running yourself to death is not good, but a control system that lets you run yourself to death will allow escape from more bears than a control system that doesn't.
In the context of Alzheimer's, the major symptom is reduced metabolic activity. Reduced glucose consumption, reduced ATP. Those changes are global, over the whole brain. The whole brain has reduced metabolic activity. Every cell in the brain is working âin syncâ to achieve the same (but reduced) metabolism. How many pathways are involved in that reduced metabolic activity? One, five, ten or hundreds? How can hundreds of pathways âgo badâ simultaneously in every cell in the brain? They can't.
I don't think that any pathways have âgone badâ. I see Alzheimer's as good regulation around a bad setpoint. Metabolic activity has been turned down by the normal pathways working as they evolved to work. They just have a bad setpoint. A setpoint that is controlled by nitric oxide.
Low NO leads to low ATP and triggers ischemic preconditioning. Ischemic preconditioning can only be a transient state. If it goes on for too long, the cells will eventually die. I think that is what Alzheimer's is. Ischemic preconditioning that has gone on for too long.
daedalus: clap, clap, clap
That may honestly be the first blog comment or posting I've seen that is actually interesting and thoughtful (much more so than the post here).
I hope you work in biology -- it would make me feel much less negative about my field.
Who'd think that biology selects over ensembles and not over unique cases? That a population wide healthy response does not imply that every, or even most, individuals have healthy responses?
Reminds me of a journal club where I asked what the Huntington protein is for -- other than to create Huntington's disease. Apparently no one in my department had ever considered the possibility that a protein exists because it has a function that is selected for... and that this might be of interest when looking at the pathological case...
frog, thank you. Huntington's is caused by low NO too. Pretty much all the neurodegenerative disorders are.
In Huntington's the polyglutamine ends agglomerate together because they are not kept apart by a high enough ATP level. That clogs things up which causes âstressâ and the generic stress response is to lower NO and ATP still more. That is what causes the hypometabolism observed in all neurodegenerative diseases. There can simultaneously be observations of hypermetabolism, but that is late stage.
Thank you for the explanation how to get statistically significant results, but apart from the fact that this proteinÂ´s function is understood a bit better, where is the problem?
If I had a gene that makes all neurodegenerative diseases shorter, I would relax!!
Knowing the function of the protein that is linked to disease is important, you don't want to disable something that is a component of another system. Similarly, if a gene variant confers resistance or reduced risk of a disease, you want to know why, because it could lead to possible intervention strategies for people who don't carry that gene variant.
Rune, making a fatal disease shorter is not the same as making a curable disease shorter.
@ Greg Laden:
O.K., a cure for the common cold working in 10 minutes would be perfect.
I did understand that AlzheimerÂ´s still would end with death having that gene, what I thought of was the time of suffering - provided I could not catch the outbreak at a time I am able to end my life.
I do have a living will, but I am not so sure that everything in it will be obeyed, therefore the usage of "relax".
I think this argues for biologists taking more formal courses in Causal Analysis, and using causal diagrams. Whether as you state : daedalus2u that NO is the cause of Alzheimers must be a complex question. That a decreased state of activity and hence Alzheimers is caused can putatively be caused by other synchronising events, and you might expect : age, immune system activity or insulin insensitivity.