Alzheimers and Genes

[August59]

Has this doctor been right all these years? Probably!

http://www.pri.org/stories/2015-04-30/do-we-all-have-alzhemers-completely-wrong-man-says-yes

 

[ahmo]

For participants deemed at high risk by the algorithm, the investigators are also testing whether a very low dose of a drug called pioglitazone can delay the onset of memory- and thinking-impairments. If a drug were available today that staves off dementia by five years, it would reduce the cost of patient care by $50 billion by 2020, the Alzheimer’s Association estimates. Rodent and human studies have already shown that low-dose pioglitazone improved mitochondrial function and enabled them to better metabolize energy sources.

“At a point in time when people are about to suffer from mitochondrial inadequacy in their brain, the aim of the study [with Takeda] is to double the number of mitochondria and increase their ability to metabolize glucose and oxygen," Roses says.

I happen to have several of the snps he's focusing on, ApoE and TOMM40.

 

[Thinktank]

@ahmo, is TOMM40 available in 23andme?
I carry one risk allele for ApoE4.

 

[ahmo]

Yes, 23andme. I found it via Promethease.

 

[Valentijn]

I happen to have several of the snps he's focusing on, ApoE and TOMM40.

Those are genes, and everyone has a great many SNPs on them. The revelant SNPs for the APOE4 haplotype are rs7412 C and rs429358 C. Just having one or two C alleles for one or the other means that you aren't APOE4 - it's necessary to have C alleles for both. CC for both would mean risk is the highest. CC for one and one C for the other would be one copy of the haplotype, and not as high-risk. If there's one C for each, there might be 1 copy of the halpotype or 0 copies of it - it can't be determined from 23andMe data in that case.

Increased incidence of some TOMM40 alleles might simply be due to those SNPs being in strong linkage disequilbrium with SNPs on APOE. Basically some SNPs get inherited together, or usually get inherited together, especially when they're close together on a chromosome. APOE and TOMM40 are close together, so the TOMM40 correlation might be solely due to those SNPs reflecting the presence of the risky APOE4 SNPs.

I also don't see any specific TOMM40 SNPs listed in that article, so it's hard to tell what he's talking about, and to check if the TOMM40 SNPs have identical prevalence rates compared to the APOE4 SNPs.

 

[ahmo]

Thanks @Valentijn. Mine are CC and CT. Frankly, I don't worry about Alzheimer's. I reckon that all the work I'm doing on my biochemistry now outweighs anything in my genetics.

 

[garcia]

Great article! A bigger question this article poses (beyond Alzheimer's disease) is that of how the scientific edifice works, or rather doesn't work. Medical science is often an accumulated collection of opinions, all based on previous opinions. What happens when one of these opinions (the amyloid hypothesis in this case) turns out to be false? You end up with the situation they have in Alzheimer's disease. Billions of dollars of research spent and almost nothing to show for it. This is one reason why the current medical paradigm is so poor at solving complex chronic diseases. Not only can they not answer the questions, they are not even asking the right questions. Everything is highly political. Step outside the existing paradigms and your research will not get funded, your papers won't get published. So orthodoxy prevails, even when orthodoxy is wrong (as it so often turns out to be). The entire algorithm is wrong.

P.S. Allen Roses is an interesting guy. Apparently in 2003 (as advisor to GSK) he admitted that "most prescription medicines do not work on most people who take them".
http://www.independent.co.uk/news/s...rugs-do-not-work-on-most-patients-575942.html

This is a slap in the face of the one-drug-to-cure-it-all paradigm that most medical research seems to adopt. Roses calls for individualized treatment in the article. Isn't that what Jay Goldstein did for decades? Sadly it is politically incorrect medicine.

 

[August59]

@garcia - Exactly

I feel sure that the amyloid hypothesis was deemed more lucrative for big pharma and therefore received all of hoopla and consequently clout and major funding.

 

[Wayne]

His hypothesis that Alzheimers is likely caused by a mitochondria disorder seems highly plausible to me...

Throughout his career, Duke University neurology professor Allen Roses has challenged what for decades has been the prevailing orthodoxy in Alzheimer’s research: Namely, the “amyloid hypothesis,” which suggests that a protein called beta-amyloid clogs up the brain, killing neurons and causing the dementia associated with Alzheimer’s disease.

“Beta-amyloid is the result [of Alzheimer’s], rather than a cause,” he says.

For more than 20 years, Roses, 72, has pursued a hunch that dementia in Alzheimer’s patients stems from an inability in the brain to metabolize energy sources, such as glucose and oxygen. The trigger, he argues, is variations in two genes — ApoE and TOMM40 — which ultimately inhibit mitochondria from supplying energy to neurons, causing them to die. A growing body of published literature supports his theory, Roses says, but by and large, he “has been totally ignored” by the field....​