Epigenetic signatures of methylated DNA cytosine in Alzheimer’s disease

[ru442]

This is way above my pay grade, but looks like promising work on detecting onset of AD. Maybe one of our science peeps can explain in laymen terms:

https://advances.sciencemag.org/content/5/8/eaaw2880

ETA: Ok this article dumbed it down enough for me to understand:

https://medicalxpress.com/news/2019-08- ... sease.html

[circular]

This is way above my pay grade, but looks like promising work on detecting onset of AD. Maybe one of our science peeps can explain in laymen terms:

https://advances.sciencemag.org/content/5/8/eaaw2880

ETA: Ok this article dumbed it down enough for me to understand:

https://medicalxpress.com/news/2019-08- ... sease.html

I only 'get' this on the most superficial level, but I think this is really important! While we see functional medicine become increasingly reductionist in some ways, where it's so easy to get lost in isolated biomarker and mechanism of action details -- and while that continues to fascinate me -- I suspect that the real deal, big player in AD prevention for most is the upstream lifestyle influence over epigenetic regulation.

Last night I was listening to an older, 2017 podcast interview with Dr. Kara Fitzgerald about this. I'm tempted to buy her ebook for clinicians, Methylation Diet and Lifestyle eBook, but again, can I implement what I need to without spending the money? It's on my possibly some day buy out of interest pile.

[Fiver]

Wow. That's a very interesting and VERY dense paper! I think I could spend all week reading this one to really understand it.

Basically, the researchers looked at cells with genes known to trigger early onset AD and other cells with the apoe4 genes contributing to late onset AD, comparing them to various controls. They first surveyed the overall amounts of methylation, which occurs when methyl groups bind to DNA - there are a few specific nucleotide sequences where this tends to happen, and they looked at several of these separately. Methylated nucleotides are sometimes called "epigenetic marks". The marks can control whether or not a specific gene is accessible to be expressed. After looking at overall levels of methylation in these cells types over time they got more specific. They looked at marks on specific genes, many known to be associated with AD, over time. They found differences in how the genes were marked, and how these marks changed over time, in the EOAD and LOAD cell types, compared to controls. THis is really cool. First, it suggests that these genes are indeed important. Second, it suggests that HOW AND WHEN THE GENES ARE EXPRESSED is controllable by epigenetics, e.g. methylation. This means that - in theory - even those will problematic genes may be able to control their expression in a way that makes them less problematic.

They say: "Collectively, our findings highlight the pivotal role of proper timing and landscape of the three DNA methylation states in regulation of AD-critical genes. Because the patterns of methylation of all states are disrupted in AD patient–derived lines at all differentiation stages, it is postulated that the dysregulation of 5mC, 5hmC, and 5fC/caC (these are the various sites on DNA that can be methylated) on these key AD genes may intrinsically and directly be linked to AD pathology."

The key, of course, is knowing whether or not one would want more or less methylation on specific genes, at specific times. And how to accomplish that. I'd have to read more to figure that out.

[SusanJ]

They found differences in how the genes were marked, and how these marks changed over time, in the EOAD and LOAD cell types, compared to controls. THis is really cool. First, it suggests that these genes are indeed important. Second, it suggests that HOW AND WHEN THE GENES ARE EXPRESSED is controllable by epigenetics, e.g. methylation. This means that - in theory - even those will problematic genes may be able to control their expression in a way that makes them less problematic.

Fiver, well said. This is how I read this paper, too. And it seems extra important that the changes they found are independent of age. At minimum, the excitement certainly lies in its potential to test to see who is really susceptible at an early age, allowing doctors to throw all the known helpful strategies at them.

The key, of course, is knowing whether or not one would want more or less methylation on specific genes, at specific times. And how to accomplish that. I'd have to read more to figure that out.

If I was in the trenches, I'd surely be looking at those genes as far as do the methylation changes represent gain or loss of function. And can that be manipulated somehow. Million dollar questions for sure.

[ru442]

Great analysis guys, thank you for taking the time to break this down!

[circular]

I'd surely be looking at those genes as far as do the methylation changes represent gain or loss of function. And can that be manipulated somehow. Million dollar questions for sure.

From listening to interview with Dr. Kara Fitzgerald on this (link above), my take is that the right broad lifestyle choices regulate hyper and hypomethylation in sweeping beneficial ways that would include the subject areas. For example she refers to the ability of plant polyphenols to regulate epigenetic expression, not allowing it to go too low or too high. She even suggests that such lifestyle approaches can mitigate or negate the need for supplements for some people with poor methylation SNPs, to be determined individually. I think, hope, that all we need to do is live in healthy ways and, subject to overall methylation genetics and functioning, our bodies will regulate epigenetics accordingly, rather than trying to tweak methylation specifically to a certain area of the genome, but we'll see Maybe I'm living in la-la land ... it wouldn't be the first time.

[Fiver]

I'd like to think that too! I am a big fan of plant polyphenols. I'd love it if they were a part of the solution.

I think it's going to take some time before we know for certain if we can alter methylation in a useful way with lifestyle. These techniques are pretty cutting-edge. I'm not aware that they are used in medicine to diagnose or monitor the progress of individual patients. Besides, it looks like they'd require actual patient brain cells. ouch.

The technology is really just amazing.