14 years and still no good genes!

I am preparing a talk for the Connecticut Geriatric Society and I am just can't get over it. We haven't found good genes for Late Onset Alzheimer's Disease since 1994. Sure we have SORL1, GALP and MAPT from the sexy Genome Wide Studies....but nothing increases risk like APOE Epsilon4.

In fact when you look at all the other genetic risks, NONE top an Odds Ratio of 1.5. Why do a I always harp on Odds Ratios? It's simple. If you can't beat the family history risk increase (300-500%) for a first generation relative, then you can't have much clinical significance, unless you have a multiple gene panel that does.

Why is clinical utility so important? Why not just test everyone with everything. I see several problems with this.

1. False Reassurances, patients are led to believe they won't get some devastating disease and thus fail to plan appropriately. And in some cases take preventative measure...This is called Harm to Patient and it is malpractice.

2. Inappropriate Action, there are several modifiable risk factors in many diseases. This often is argued as the reason FOR testing everyone. But this only assumes that modifying behaviors are actually good things. But, did you know some things like vitamins can actually be bad and promote things like cancers? So you mega dose on Folate and end up promoting breast or colon cancer because you found out that you "Process Folate poorly" on a Nutrigenomics test. And that is just Folate, what about preventative medications? Even more dangerous!

3. Exposure to Discrimination, as I stated in previous posts GINA has passed, but will not go into effect until 2009. In addition, GINA does not cover disability, life, or long term care insurance. Nor does it cover any form of discrimination outside of workplace or health insurance. Medical records can be subpoenaed. However, in most states it is illegal to ask for health records without good cause. Unlike corporate information, which can be bought and sold without YOUR permission! This includes identifying factors Ladies and Gentleman!!! This is why this testing should be done in the realm of healthcare protection.

These are merely 3 of the many reasons I see that we should not be applying SNP scans to everyone. There has to be some clinical significance for actions. If you want consumer enabled research, then you have to protect the consumer. Just as if they were a subject under the protections of an Institutional Review Board.

The Sherpa Says: I could go on a diatribe about this forever. But I have a talk to prepare. Imagine this 80% heritability and only 1 gene for Late Onset Alzhemiers....we must not be looking in the right place.

Why Watson Didn't Want His ApoE4 Results.

Alzheimer's disease (AD) afflicts about 10% of persons over 65 and almost half of those over 85.

When Jim Watson had his genome sequenced he asked not to have his ApoE4 status revealed. Why??

Dr Watson did not want to know his genotype status because although twin studies suggest that there are several susceptibility genes which, along with the APOE 4 allele, contribute to up to 80% of LOAD (Late Onset Alzheimer's Disease) cases, the story is nowhere near being finished. Not everyone with APOE4 gets Alzheimer's. In fact, the majority do not......

But the picture for those predisposed is getting clearer.

This last week a study was released by the team at TGen (Translational Genomics) in the journal Neuron. According to the study:

"...suggests that the gene - called GAB2 - modifies an individual's risk when associated with other genes, including APOE4. The study results appear in the June 7 issue of the prestigious peer-reviewed journal, Neuron."

"The team screened the DNA from 1,400 individuals who had been clinically assessed with Alzheimer's prior death, and simultaneously examined more than 500,000 SNPs or genetic variations to characterize and confirm additional LOAD susceptibility genes. The search revealed GAB2."

The polymoprhism is known as SNP rs2373115 . It interacts with APO epsilon 4 to prevent neurofibrillary tangles. This protein is over expressed normally in APOE4 afflicted brain cells.

So what does this mean? GAB2 normally acts like your mother. Remember when you made a mess of your room? If you were lucky, your mother cleaned up the mess. You kept making more of a mess and she kept cleaning up. If your mother didn't clean up, then your room was a constant mess. Even worse, you couldn't find anything in your room that you needed. Much like the way an Alzheimers patient can't find their memories.

In the end a Non-cleaning mother and a really messy kid led to a very dirty room. Just like the combination of GAB2's SNP and APOE4 lead to an odds risk of 4.06 a 400% increased risk.

The Sherpa Says: I agree with Jim. ApoE4 testing can often be uninformative with only 25% of those with the gene polymorphisms going on to get Alzheimers. I think family history will have to lead the way. At least until we have a GAB2/ApoE-4/new gene panel that puts together the picture much more clearly.