Study: why the APOE4 gene enhances Alzheimer’s risk; choline reverses

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BrianR
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Study: why the APOE4 gene enhances Alzheimer’s risk; choline reverses

Post by BrianR »

Caveat: study done with yeast and brain cells in a dish.

Explainer article:
Study offers an explanation for why the APOE4 gene enhances Alzheimer’s risk
https://picower.mit.edu/news/study-offe ... imers-risk
The gene variant disrupts lipid metabolism, but in cell experiments the effects were reversed by choline supplements ...
Paywalled paper:
APOE4 disrupts intracellular lipid homeostasis in human iPSC-derived glia
https://stm.sciencemag.org/content/13/583/eaaz4564
Grzegorz Sienski, Priyanka Narayan, Julia Maeve Bonner, et al.
Science Translational Medicine 03 Mar 2021:
Vol. 13, Issue 583, eaaz4564
DOI: 10.1126/scitranslmed.aaz4564


Description and abstract. Emphasis mine.
APOE4 disrupts lipid homeostasis in glia:
APOE4 is a strong genetic risk factor for many diseases, most notably, late-onset Alzheimer’s disease. Sienski et al. now show that cultured human glia with an APOE4 genotype accumulated unsaturated triglycerides leading to a lipid imbalance. Using genetic screens in yeast, the authors discovered that promoting phospholipid synthesis through choline supplementation of culture medium restored a normal lipid state in APOE4-expressing yeast cells. The authors then demonstrated that choline supplementation also restored lipid homeostasis in human APOE4 astrocytes. These findings suggest that modulating glial metabolism could help to reduce APOE4-associated disease risk.

Abstract:
The E4 allele of the apolipoprotein E gene (APOE) has been established as a genetic risk factor for many diseases including cardiovascular diseases and Alzheimer’s disease (AD), yet its mechanism of action remains poorly understood. APOE is a lipid transport protein, and the dysregulation of lipids has recently emerged as a key feature of several neurodegenerative diseases including AD. However, it is unclear how APOE4 perturbs the intracellular lipid state. Here, we report that APOE4, but not APOE3, disrupted the cellular lipidomes of human induced pluripotent stem cell (iPSC)–derived astrocytes generated from fibroblasts of APOE4 or APOE3 carriers, and of yeast expressing human APOE isoforms. We combined lipidomics and unbiased genome-wide screens in yeast with functional and genetic characterization to demonstrate that human APOE4 induced altered lipid homeostasis. These changes resulted in increased unsaturation of fatty acids and accumulation of intracellular lipid droplets both in yeast and in APOE4-expressing human iPSC-derived astrocytes. We then identified genetic and chemical modulators of this lipid disruption. We showed that supplementation of the culture medium with choline (a soluble phospholipid precursor) restored the cellular lipidome to its basal state in APOE4-expressing human iPSC-derived astrocytes and in yeast expressing human APOE4. Our study illuminates key molecular disruptions in lipid metabolism that may contribute to the disease risk linked to the APOE4 genotype. Our study suggests that manipulating lipid metabolism could be a therapeutic approach to help alleviate the consequences of carrying the APOE4 allele.
Of course, this doesn't necessarily indicate that slamming down eggs and various flavors of choline supplements necessarily improves lipid balances in astrocytes in actual human brains functioning in the complicated federation of human and non-human cells that constitute our bodies.
circular
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Re: Study: why the APOE4 gene enhances Alzheimer’s risk; choline reverses

Post by circular »

BrianR wrote:Of course, this doesn't necessarily indicate that slamming down eggs and various flavors of choline supplements necessarily improves lipid balances in astrocytes in actual human brains functioning in the complicated federation of human and non-human cells that constitute our bodies.
Well put. I do hope they pursue this a long way to find out if there could be a simple and safe choline protocol that might help at least some who have apoe4.
ApoE 3/4 > Thanks in advance for any responses made to my posts.
Janpeter
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Re: Study: why the APOE4 gene enhances Alzheimer’s risk; choline reverses

Post by Janpeter »

circular wrote:
BrianR wrote:Of course, this doesn't necessarily indicate that slamming down eggs and various flavors of choline supplements necessarily improves lipid balances in astrocytes in actual human brains functioning in the complicated federation of human and non-human cells that constitute our bodies.
Well put. I do hope they pursue this a long way to find out if there could be a simple and safe choline protocol that might help at least some who have apoe4.
Does anyone know if the Bredeson supplement protocol Includes some form of choline ? I would think choline as such is of minimal negative risk and potentially of high importance.
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Re: Study: why the APOE4 gene enhances Alzheimer’s risk; choline reverses

Post by Quantifier »

Yes: CDP-choline (also known as citicholine) or alpha-GPC (also known as Alpha-glycerophosphocholine) - both can be converted to phosphatidylcholine.
NewRon
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Re: Study: why the APOE4 gene enhances Alzheimer’s risk; choline reverses

Post by NewRon »

This is SO eggciting!!!
Apo E4/E4, Male, Age 60
Jackooboy
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Re: Study: why the APOE4 gene enhances Alzheimer’s risk; choline reverses

Post by Jackooboy »

Hello, I am new to the board and saw this article from MIT about choline. I am E4/E4 and have high cholesterol, high triglycerides, fatty liver, etc... wonder if this choline would help with more than just AD risk.
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Lidaz
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Re: Study: why the APOE4 gene enhances Alzheimer’s risk; choline reverses

Post by Lidaz »

Jackooboy wrote:Hello, I am new to the board and saw this article from MIT about choline. I am E4/E4 and have high cholesterol, high triglycerides, fatty liver, etc... wonder if this choline would help with more than just AD risk.
Hello Jackooboy, welcome to the APOE4 site and thank you for contributing the Choline discussion.

As you are new the the site, you might find the following helpful in finding your way around.

There is an extensive Wiki encyclopedia section where you can search for particular topics and there is a useful How-To Guide on using the site.

We welcome all new users to introduce themselves and share their story on the Our Stories forum. If you would like to do this, you would select New Topic in the upper left side of your screen to make a new post there.

You seem very knowledgable on your APOE status but as a new user you might also find the Primer a useful general resource with information on diet and other lifestyle strategies.

We are so glad to have you join the community. If there is anything else you want to know and can't find it on the site, please don't hesitate to ask! :D

Warm regards,
Lisa
Lidaz
Functional Medicine Certified Health Coach
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