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)