rs1129844 This story is so big... it deserves its own thread!

[Tincup]

None of those SNP's show up in my Sept 2014 version of 23andMe.

How did you get the Exome scan performed?

[J11]

Figure 4 in the article showed an enormous range of eotaxin-1 levels. Considering how potentially important eotaxin-1 might be for dementia it seems very worthwhile to ponder potential environmental factors that might be at play, aside from the genetic factors.

"No significant differences were found for any of the biomarkers, except chemokine eotaxin/CCL11, whose serum levels were higher in late-stage patients with BD when compared to controls (p=0.022; Mann-Whitney U test)."

http://www.ncbi.nlm.nih.gov/pubmed/25973785

[J11]

There's more!

It appears that Eotaxin-1 has relevance to asthma, allergies, cardiovascular disease, and GI disorders (e.g. colitis).
I am not clear whether having one of these disorders would necessary cause a body wide increase in eotaxin-1 levels.

A therapeutic antibody (Bertilimumab) that lowers eotaxin-1 levels is already in clinical trials.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4338813/
https://clinicaltrials.gov/ct2/results? ... rch=Search

[J11]

And more ...

A company is developing a diagnostic for Eotaxin-1.

http://www.immunepharma.com/wp-content/ ... _8-151.pdf

It appears that a chemical called synephrine which is used by dieters and is similar to adrenaline and is present in
green citrus plants can play a role in reducing Eotain-1 levels (though it is seems unclear whether it would be helpful given the recent research.)

http://www.mdpi.com/1420-3049/19/8/11883/htm

It would appear that there are a whole bunch of modifiers of Eotaxin-1 levels. It really might not matter what your genotype is. With the diagnostic kit and all these variables you might be able to move the number where ever you want to. Considering this might mean a difference of possibly 10 or more years in age of onset of AD, it could be very worthwhile to keep track of it.

[J11]

After carefully reading the article the results did not seem as persuasive. However, it is interesting that even in the much more diverse
LOAD population studied at UCSF the results still trended in the right direction. Supplementary Figure 5 showed that the AA genotype
appeared to have quite a delayed onset. It is disappointing that this was based on only 5 patients.

On further reading of the literature I found that eotaxin-1:
"In response to the presence of allergens, this protein directly promotes the accumulation of eosinophils,"
http://www.genecards.org/cgi-bin/carddisp.pl?gene=CCL11

Pigs suffering from salt intoxication due to water deprivation can develop an Alzheimer like disease within days.

Aust Vet J. 2010 Oct;88(10):405-7. doi: 10.1111/j.1751-0813.2010.00630.x.
Alzheimer type II astrocytes in the brains of pigs with salt poisoning (water deprivation/intoxication).
http://www.ncbi.nlm.nih.gov/pubmed/20854298

"It has been postulated that an elevated concentration of sodium ions in the brain induces eosinophilic infiltration of the meninges and perivascular spaces in the neuroparenchyma."

Wonder whether serum eosinophil levels have ever been associated with AD? Might simply bringing down these levels help in AD?
AD patients can also develop dehydration problems resulting in elevated salt. Might a similar response as happened with the pigs occur in people?


However, this article found otherwise.

http://www.ncbi.nlm.nih.gov/pubmed/23551244

[J11]

Here's an update on the genetics of AD.

Interesting that they are now using gene sets in AD. They are not quite ready for the clinic, though they seem to be improving.

"We investigated a GRS combining 22 AD susceptibility loci. The best model was a weighted GRS that took into account the different risk effects of APOE in different age groups.62,63 This model performed significantly better than APOE alone in discriminating AD patients from healthy elderly. Despite the fact that this model incorporated all reliable GWAS association signals reported thus far, as well as the established rare risk variant in TREM2, the model only achieved a sensitivity of 55% and a specificity of 78%, impeding use in clinical practice."

Reference 63 from the article: Sleegers K, Bettens K, De Roeck A, et al.; BELNEU consortium. A 22-single nucleotide polymorphism Alzheimer risk score correlates with family history, onset age, and cerebrospinal fluid Aβ42. Alzheimers Dement; e-pub ahead of print 15 June 2015.

(can't find it in pubmed)

http://www.nature.com/gim/journal/vaop/ ... 5117a.html

[J11]

Wanted everyone to know about ADSP. This is awesome!

After the big era of GWAS ended I was worried that no one would pick up the ball and run it into the end zone. It would make no sense with the technology now available not to finish the job.

Hopefully, this will make it so much easier for dementia families without a clear genetic cause to piece things together.
Our family was all ready to start our own AD family genomics project. It might have cost some money and some sleepless
nights, though at least we would finally be able to figure out how our 33 loved one has what appears to be a familial dominant
form of AD. With ADSP we can wait a bit to see what they find.

They probably should have called it the American Sequencing for Alzheimer's Project (ASAP).

"...the National Human Genome Research Institute to devote $25million, already committed to its large-scale sequencing centers, solely to
genomic studies of AD.The resulting Alzheimer’s Disease Sequencing Project (ADSP) has two objectives:

1) to identify new genomic variants contributing to increased risk of late-onset AD, and

2) to identify new genomic variants that are protective against late-onset AD.

The ADSP has two different studies designs: family-based and case-control.The family-based study will generate Whole-genome
sequencing data for 582 samples from 111 independent families, and the case-control study will include Whole-genome sequencing data
from 11,000 individuals of European ancestry."

With the ongoing decline in sequencing costs I wonder whether they could add in even more AD families.

http://www.ncbi.nlm.nih.gov/pubmed/26311074

[circular]

They already have a website https://www.niagads.org/adsp/content/home

[J11]

Yeah, I just noticed that.

It seems that the project is already pretty much finished.
They might be publishing these results soonish.

Sometimes it is great not to even know that Santa is already on the way: really cuts down on finger biting.

[J11]

I thought we should just let this one drift along, as I was not sure how important this really was after carefully reviewing the article.

Note: The below Nature Medicine result has not replicated with additional samples. This throws the importance of CCLs into doubt.

However, I have been reading around and found something interesting. The below article found 18 classifiers and predictors for AD in plasma.
The predictors did not include eotaxin-1 (CCL11), nor eotaxin-2 (CCL24) nor even eotaxin-3 (CCL26), though it did include CCL5, CCL7, CCL15, and CCL18!! Of these 4 only CCL18 had a d score greater than 0 in AD patients versus non-AD people. The nineteenth predictor was CCL22!

Many of the 18 predictors have immune functions: IL-3, IL- 1 alpha, IL-11, TNF-alpha, etc. . It is possible that Eotaxin-1 was not included in the list due to overlap with many of the other immune molecules that did make the list. It is quite impressive to see how central immunity, in general, and chemokines, in particular, appear to be with regards to classifying patients as AD or non-AD, and predicting those who will convert from MCTI to AD over the next few years as shown in this article. Given the findings of the below article the recent findings regarding eotaxin-1 appear more plausible. These CCLs appear very important in AD. Perhaps those on the thread might find it worthwhile to have this panel done and try to game it.

Nat Med. 2007 Nov;13(11):1359-62. Epub 2007 Oct 14.
Classification and prediction of clinical Alzheimer's diagnosis based on plasma signaling proteins

http://www.ncbi.nlm.nih.gov/pubmed/?ter ... e+Medicine