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At a Glance

Researchers found evidence that the Alzheimer’s-related gene APOE4 disrupts cholesterol management in the brain and weakens insulation around nerve fibers.

A drug that affects cholesterol led to improved learning and memory in mice with the gene, pointing to a potential new approach for treating dementia in Alzheimer’s disease.

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To build on these findings, the team conducted a multi-pronged study that assessed gene activity of all major cell types in post-mortem human brain tissue from 32 men and women who had one, two, or no copies of the APOE4 gene. Results were published in Nature on November 24, 2022.

The researchers found that APOE4 affected gene expression across all measured cell types. The team then took a closer look at genes related to cholesterol and other lipids. Cholesterol-manufacturing genes were overly expressed, and cholesterol-transporting genes dysregulated, in brain cells called oligodendrocytes with the APOE4 gene. Oligodendrocytes are found in the brain and spinal cord. They make and maintain a fatty substance called myelin that surrounds and insulates long nerve fibers. The abnormalities were more extreme in oligodendrocytes with two copies of APOE4 rather than one.

To better understand how APOE4 affects oligodendrocytes, the scientists created laboratory cultures of the cells with and without the APOE4 gene. Oligodendrocytes with APOE4 tended to accumulate abnormal amounts of cholesterol within their cells, rather than using it to make healthy myelin sheaths around nerve fibers. When the scientists examined post-mortem human brains, they noted that myelin sheaths tended to be fewer and thinner in brains that carried the APOE4 gene.

The scientists next used model systems to test whether APOE4-related abnormalities might be reversed via drugs that affect cholesterol processing. They found that a drug called cyclodextrin, which promotes cholesterol transport, reduced cholesterol buildup and improved myelin sheath formation in cultured oligodendrocytes. It did the same in mice with two copies of APOE4. The mice also performed slightly better in learning and memory tasks after treatment with the drug.

ApoE4 is five letters and should have been in the title.

Interesting, it seems to line up with the fact exercise and good diet, are linked to lower cholesterol levels are also linked to lower dementia risk/symptoms.

Exercise was more effective than all medicines tested.

>For the AD portrait, the top three scoring treatments for reversing AD expression with little effect on exacerbating AD expression were for exercise.

From <https://www.nature.com/articles/s41598-022-22179-z#Sec2>

Exercise is associated with lower dementia risk.

>These data suggest that aerobic exercise is associated with a reduced risk of cognitive impairment and dementia; it may slow dementing illness.
>
>https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3258000/

Diet is associated with lower levels of dementia.

>In this 20-year follow-up study, neither adherence to conventional dietary recommendations nor to modified Mediterranean diet were significantly associated with subsequent reduced risk for developing all-cause dementia, AD dementia, VaD or AD-pathology. https://n.neurology.org/content/early/2022/10/12/WNL.0000000000201336>

>MIND diet, a hybrid of the Mediterranean diet and the Dietary Approaches to Stop Hypertension diet, is associated with a slower cognitive decline and lower risk of Alzheimer’s disease (AD) dementia in older adults.
>
>https://content.iospress.com/articles/journal-of-alzheimers-disease/jad210107

Dementia or deaf?

https://www.frontiersin.org/articles/10.3389/fncel.2017.00355/full

Can you diet and exercise your way out of a gene that causes cholesterol management problems?

>Can you diet and exercise your way out of a gene that causes cholesterol management problems?

Diet and exercise are arguably even more important for people with these genes.

I mean, cells need cholesterol, that's mostly what our cell walls are made of. But it's hard to take in too much cholesterol from blood if there is only just enough cholesterol in the blood.

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If the issue is that cholesterol is not channeled where it can be made in myelin sheath then the problem isn’t too much cholesterol, its that the cholesterol is being sequestered in the wrong place. The effects of lifestyle changes will not eradicate that problem and an argument that diet and exercise are better than medication may be flawed. I’m a layman, just trying to understand the publication.

I as able to diet my way out, for now. Went from 190lb LDL=182 HDL=48 to 140lb LDL=90 HDL=75 in 1 year by going vegan +fish -fried (avoid hydrogenated and saturated oil) and try to limit sugar. Eggs did little the next year (LDL=92) but the last year I started eating "vegan meat" and was back to 160lb and LDL=116 HDL=60s. I am going to try staying around 150lb and cut out the "vegan meat" to see if that makes a difference.

My strength training exercise has stayed about the same but my ~20 miles a week 11min mile "running" basically stopped the first year so didn't make a huge difference, still walk around 10 miles a week though. I really need to get back to running though, made me feel much better.

My grandfather did a self triple bypass (as in his heart grew 3 bypasses naturally), was very active walker, ate mostly well when I knew him, and was not overweight. Over a couple years his mind had basically regressed to a kid (believing he was 5yo kid, asking for people that dies 50+ years ago, didn't recognize his wife who died 20 years earlier) when he died at the age of 92 years old. I am told I look and act a lot like him and my other parent has no cholesterol issues (but has diabetes) so I am guessing sooner or later I will need to give up grapefruit and pomegranate to get on statins (and hope I don't have some of the horrible side effects) then possibly go out the same way he did. If this is true though and I watch my cholesterol maybe I can increase my compression of mortality.

NOTE: I am not saying just diet going to be true for everyone, some can watch diet and exercise and still have dangerously high levels while others eat horrible stuff and still fine (well at least cholesterol). You asked the question so I was just giving one data point where diet helped me, for now.

I think your question contains a great teaching point about genetics. I prefer to think about genetics as a repertoire like a toolbox that a carpenter brings to a job. What tools are used is somewhat dictated by what’s in the box but if he is say sawing a plank of wood then he’s not going to reach for the hammer. The cell is trying to make similar contextual decisions all of the time. Diet and exercise may dramatically alter both gene expression and the effect of a product secreted into a vastly different environment.

You have this APOE4 gene? I understand lifestyle can affect all sorts of molecule levels throughout the body, but I’m curious if they are known to affect gene expression like the one this study identified.

> Diet and exercise may dramatically alter both gene expression and the effect of a product secreted into a vastly different environment.

This is the basic idea I’m interested in. So there is evidence that diet and exercise can affect the expression of genes like this? Maybe not for this specific gene but do you know of an example where a genetic defect is controlled or put in remission without other therapies?

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Could this be tied to Milenated (sp?) NEUROPATHY?

I mean it has been known for a long time APOE4 is associated with lipid and cholesterol metabolism, no?

I wonder (re abnormal nerve insulation) if there's a connection to Multiple Sclerosis.

Idk if I do sorry. I haven't gotten any gene testing done, maybe I should.

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A compound in sunflower seeds blocks an enzyme that causes blood vessels to constrict. As a result, it may help your blood vessels relax, lowering your blood pressure. The magnesium in sunflower seeds helps reduce blood pressure levels as well.

ELI5 please?

https://en.wikipedia.org/wiki/Epigenetics

https://en.wikipedia.org/wiki/Behavioral_epigenetics

https://en.wikipedia.org/wiki/Contribution_of_epigenetic_modifications_to_evolution

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Why are you on a science sub if you aren't familiar with reading scientific articles and studies.

A gene which people can have zero, one, or two of might be responsible for weirdness in the fatty layer which protects nerve cells like insulation on wires. When the gene is active (or more active if people have two), the nerve cells build up this fat poorly, making them behave poorly. A new drug, which helps cells collect and keep fat correctly, helps people with this gene from using the fat poorly, especially people with two of this gene.

Scientists think this poor protective layer on nerves in the brain might be responsible for Alzheimer's symptoms, and this gene's poor instructions might be what causes some of the symptoms of the disease, and this drug helps nerve cells not do what this gene tells them to do, making the nerves use fat more like how healthy nerves do.

r/gatekeeping

It’s not a matter of expression of the gene. ApoE transports and helps to dispose of cholesterol. The ApoE4 subtype is not good at transporting and disposing of cholesterol so cholesterol builds up where it shouldn’t be. Reducing cholesterol through diet and exercise means less cholesterol for ApoE to act on - the ApoE4 is still defective, but there is less cholesterol to gum up the works.

Cholesterol builds up where it shouldn’t AND does go where it is needed to make nerve sheath, if I’m reading correctly. So isn’t something still needed to redirect the cholesterol where it needs to go, not just to reduce overall cholesterol?

I wonder how this ties in with the Lean Mass Hyper-responders theory put out there by Dave Feldman of Cholesterol Code.

The LMHR theory seems to find that most people respond well to a keto diet in terms of blood biomarkers, but LMHR on a high fat diet have far greater increases in cholesterol.

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Wonderful, I vote for you to explain all the things please.

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It is a little complicated. ApoE transports cholesterol. The different isoforms have different abilities to bind cholesterol. ApoE2 is best, then ApoE3 with ApoE4 the worse but it still has some ability to bind and transport cholesterol. When cholesterol levels are low on the blood, ApoE4 might do an ok job but when cholesterol levels are higher, it can’t keep up. Also consider that there are heterozygotes (ApoE3/ApoE4) that fair better and homozygotes (ApoE4/ApoE4) that have the highest risk.

You understand it well. I am a little frustrated that others haven't read the article or bother to understand. To put it simply, bad gene means not enough cholesterol protecting the neuron's connections. Less cholesterol isn't the answer here, more is needed in the right place, as you say.