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Golden Seven

CR for those with two ApoE4 alleles?

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Greetings,

 

I recently found out via 23 and Me that I have two copies of the ApoE4 gene, which makes my risk for developing Alzheimer's disease much, much higher than average.

 

I'm 50, male, and, fortunately, I think, I've been on a mildish version of CRON for 15 years.

 

Do any of you know if there are studies looking at ApoE4 status and CRON, either in mouse models, or in humans? From what I know about CRON it's a reasonable guess that I should be somewhat protected against Alzheimer's, but I've been looking closely at some studies from Australia showing that people with TWO copies of the ApoE4 might not benefit from many of the things that benefit others, not moderate drinking, not even exercise (but the research is limited). Having two copies of ApoE4 is a very strange condition (though not extremely rare: 1.7 % of the population has it).

 

Anyway, I'm thinking about going on a more severe version of CRON (gradually, and carefully). But I'm just wondering whether the research supports it. See, for example:

 

http://www.brainhealthhacks.com/2011/02/16/alzheimer%E2%80%99s-disease-omega-3-and-exercise-the-complexity-of-treatment/

 

which suggests fish oil might help, but quotes a researcher saying exercise might actually be BAD!

 

Thanks,

Golden

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Thank you for your interesting and extremely important question. I have several friends who recently have been diagnosed with Alzheimer's (in all but one case caught very early), and there is some Alzheimer's in my family, so this topic is very important to me.

 

I will try to respond at length within a few days (struggling under a tight deadline right now), but, briefly, I'd say that Michaelson's research (in your link), and the research in Australia that suggests what's good for an ε4/ε3 is not at all necessarily good for an ε4/ε4, is worth keeping in mind, but none of these studies gives us solid answers. But they do raise serious questions about the standard advice about prevention: exercise, and moderate drinking. (According to one study -- reference coming in a few days -- 4/4s should drink ZERO alcohol, and exercise only minimally.)

 

When it comes to diet, however, my guess is that having been on mild CR is probably a huge factor in your favor, and taking it to a more restricted level, carefully, might not be a bad idea.

 

More as soon as possible,

Brian

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Sorry for the delay in returning to this. I had a work emergency.

 

Because of the work emergency, I couldn't do as much research as I wanted. But, what I do feel pretty confident about is that there isn't much information out there on homozygous ε4s! This is quite surprising, given that 4/4s are not all that rare (a bit less than 2% of the population).

 

I wrote to the researchers who've published studies looking at exercise on AD risk to see whether, when they say they differentiated between ε4-carriers and non-ε4-carriers, they also differentiated between ε4 heterozygotes and homozygotes. I'll report back when I hear from them.

 

Meanwhile, here's a fascinating article about the ApoE-ε4 genotype:

 

http://genes2brains2mind2me.com/2009/08/04/resting-state-networks-interact-with-apoe-genotype-to-reveal-risk-decades-before-alzheimers-degeneration/

 

Brian

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I recently found out via 23 and Me that I have two copies of the ApoE4 gene, which makes my risk for developing Alzheimer's disease much, much higher than average.


Do any of you know if there are studies looking at ApoE4 status and CRON, either in mouse models, or in humans?


Thanks to you and Brian for this extremely important discussion. When I was at Harvard Medical School a few years ago, I heard an impressive presentation by Lenny Guarente on CR, SIRT1 and Alzheimer's Disease. The abstract is now freely available: SIRT1 suppresses B-amyloid production. This tells me that generally CR in most people will likely be protective against Alzheimer's disease. Here's a link to 2 pages of studies that came up when I searched on calorie restriction and Alzheimer;s Disease: http://www.ncbi.nlm.nih.gov/pubmed?term=calorie%20restriction%20alzheimer%27s As you know the brain is one of the most energy sensitive organs. Finding out more about the brain's beneficial and neuroprotective adaptations in a low energy environment, motivated me to adopt a low glucose regimen in addition to CR. Here is a Society archive link that talks about it, when I first started such a regimen: http://arc.crsociety.org/read.php?2,166951,166951#msg-166951 It would seem to me that adopting a low glucose regimen would be beneficial.

You have said that certain interventions like exercise are not protective if one has two copies of ApoE4 . Can you explain any more about how that in addition to increased risk for Alzheimer's that ApoE4 and two copies of ApoE4 are manifested clinically. What can you test at your doctor's office that indicates that two copies of ApoE are at work? I began to search for answers and found studies like this:
http://www.molecularneurodegeneration.com/content/7/S1/L10. Although it provides hints, it is hardly an adequate answer to my question. I would think that establishing markers that can be easily tested would be a great help to you.

I am delighted that you and Brian started this discussion here because the forums lend themselves to ongoing dialogue and this subject certainly merits it.

Hoping to help,


Paul

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Paul, thanks for the reply. Golden, and others: I would recommend following the links in Paul's post. A lot of great info there!

 

The more I look into this the more I realize that carriers of the ε4 allele, especially homozygotes, should think less about this as a risk factor for Alzheimer's (specifically, late-onset Alzheimer's -- or LOAD) than as a particular genotype that carriers with it numerous risks, and, as you may have read, some benefits (on average, greater intelligence, as well as protection against certain diseases, though mostly those common in the developing world).

 

LOAD is indeed the primary concern of course. But understanding the problem you, and many others (possibly me: I haven't yet "unlocked" my ApoE results from 23andMe) as one of "ApoE4 pathology", as I call it, will help with the development of a good health protocol, one that reduces the risk of not just LOAD, but chronic herpes virus (including EWV, cytomegalovirus, etc.) infections, heart disease, and several other problems.

 

Many things that tend to work in reducing risk of LOAD don't work in ε4 carriers (even those who have just one copy). So looking at AD studies to see what works and doesn't work is probably the wrong approach. "Works", in any study, means there's statistical significance in the correlation of a particular intervention and an outcome, not that everyone in the experimental group had a better health outcome. It turns out that if you look closely at the subset of people for whom a given protocol had no effect, where otherwise there was a significant overall effect in the experimental cohort, they often turn out to be ε4-carriers, hetero- or homozygotes. Here's an example of this (in the context of a brief, very interesting speculative article about lifestyle and AD risk):

 

http://www.lmreview.com/articles/view/omega-3s-apoe-genotype-and-cognitive-decline/

 

But then, of course, there are cases where an intervention works for ε4s, but not others! Look at SNP . The G allele was protective for ε4s -- but not for non-ε4s -- in one study in Han Chinese.

 

Paul, your question about measurable outcomes is critical, since we want to be able to make changes and have some idea whether they work. The problem with ApoE4 pathology (note: the gene is ε4, the protein is Ε4) is that it's not obvious what the right biomarkers to look at are. That said, even though I've not yet seen (though I've only just begun learning about this) studies looking at CR in ε4-carriers, there are many reasons to believe that a CR practice that produced healthy, youthful glucose/insulin/IGF1 biomarkers would be extremely beneficial. Other standard measures of risk of diseases of aging, like cholesterol, are probably also useful, but there I'm less certain.

 

I have to run out, but I'll try to write more in the next couple days.

 

Brian

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But then, of course, there are cases where an intervention works for ε4s, but not others! Look at SNP . The G allele was protective for ε4s -- but not for non-ε4s -- in one study in Han Chinese.

 

 

Hm... the forum software doesn't like my Firefox SNP add-on (https://addons.mozilla.org/en-us/firefox/addon/snptips/ -- very useful). The SNP number was removed. It is rs number 2305421.

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Thank you so much for the detailed replies! Great reading. I'm a little over my head here, but I'm starting to think more severe CR is probably a very good idea for me (and for most people!).

 

I read the article about Sirt1 and Alzheimer's (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2911635/). Doesn't resveratrol upregulate Sirt1? Might that be a good thing to try for people genetically predisposed towards Alzheimher's?

 

Thanks again for the interesting ideas,

Golden

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Paul, thanks for the reply. Golden, and others: I would recommend following the links in Paul's post. A lot of great info there!

The more I look into this the more I realize that carriers of the ε4 allele, especially homozygotes, should think less about this as a risk factor for Alzheimer's (specifically, late-onset Alzheimer's -- or LOAD) than as a particular genotype that carriers with it numerous risks, and, as you may have read, some benefits ...

 

I've not yet seen (though I've only just begun learning about this) studies looking at CR in ε4-carriers, there are many reasons to believe that a CR practice that produced healthy, youthful glucose/insulin/IGF1 biomarkers would be extremely beneficial. ...



Wonderful, tantalizing , and provocative response, Brian. We need to do a human CR study that looks at a whole lot of us and that begins by analyzing our heritable genome. I am going to to explore this.

Paul

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Thank you so much for the detailed replies! Great reading. I'm a little over my head here, but I'm starting to think more severe CR is probably a very good idea for me (and for most people!).

 

I read the article about Sirt1 and Alzheimer's (http://www.ncbi.nlm....les/PMC2911635/). Doesn't resveratrol upregulate Sirt1? Might that be a good thing to try for people genetically predisposed towards Alzheimher's?

 

Thanks again for the interesting ideas,

Golden

 

You are welcome, Golden. Be careful about CR that is "Severe." To most people that means extreme -- a lot of weight loss. I approach it very differently. I try to activate known Longevity pathways that are responsible for CR benefits. That means keeping insulin/IGF-1 on the low side , for example. Resveratrol may be helpful, but I have never been able to detect measurable benefits from it.

 

Paul

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Wonderful, tantalizing , and provocative response, Brian. We need to do a human CR study that looks at a whole lot of us and that begins by analyzing our heritable genome. I am going to to explore this.

 

Paul

 

Excellent Paul. I'm in touch with researchers who are aware that LOAD treatment and prevention needs to be tailored based on (among other things) ApoE status, and, critically, that the question isn't simply whether or not one is an "ε4-carrier" (as so many researchers write), but that all possible combinations of ApoE genes carry measurably different risks. Above all, ε4/4s seem to respond very, very differently than ε3/4s to some interventions.

 

People with a genetic risk for heart disease, type 2 diabetes, and many other conditions can be helped by CR, but, in many cases, also by other interventions (exercise, non-CR dietary changes, medication). They have many options (though CR is still probably the most effective option for most people, even if it might not be the easiest). But it may be that the people with the kind of risk that most calls for CR are ε4 homozygotes: the "drink or two per day" advice seems not to help, exercise may not help (we simply don't know yet), few medications have been shown to help much. For them, the aging process itself must be slowed.

 

There's the potential for a great study here, especially because, thanks to increasingly affordable personal genomics services [1], so many people are learning of their ApoE status before they develop symptoms. Let's take advantage of this research potential.

 

Brian

 

[1] 23 and Me is currently by far the cheapest, I believe. I don't have a lot of money, but $300 was well worth the investment. I've already learned many things that have altered my health regimen.

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Guest Dean Pomerleau

I agree that 23andMe offers a very useful service at a reasonable price. I recently "upgraded" my account ($99 - same price as signing up from scratch these days, although I originally paid $250...) to "unlock" my APoE genotype and was relieved to learn I don't have the e4 variant associated with elevated risk of Alzheimer's disease. Another data point for "citizen science".

 

--Dean

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Dean,

 

Congratulations on the good news!

 

One sixth or seventh or so of the general population is an ε4-carrier. If there's any (relatively) non-rare 23andMe result that would motivate someone to be on serious CR, it's being an ε4-carrier. The research on the effect of exercise, alcohol, dietary lipid composition, and much more, is extremely inconsistent when it comes to ε4-carriers. But initial epidemiological data suggests CR will help ε4-carriers. And we have, of course, tons of theoretical reasons to think CR will help ε4-carriers. (But we need to get CR researchers to start stratifying us by ε4 status!)

 

Best,

Brian

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Guest Belindagannett

What about fatty acids, animal fat and the brain....I have greatly reduced my insulin levels by going grain and fruit free and increasing animal fat (tallow from grass fed animals).

 

The brain is 60% fat? We have reduced animal fat worldwide quite substantially because of the saturated fat correlation to heart disease, yet we did not see a decrease in heart disease. Am I correct about this? If I were to restrict my calories to 500 per day in candy I would not get the benefits of CR. I would be pretty sick.... So CR isn't the end all, right?

 

What do you think of this? Im an e3/e4. On my dad's side, high intelligence in grandmother and father (both developed LOAD) My aunt, however, developed EOAD. All dad's side of family were exposed to heavy metals through dentistry (mercury amalgams, my dad and his dad were dentists and grandmother worked in lab etc) . I read that amyloid plaques could signal a deficiency of some sort in the brain that the plaques are attempting to correct. This could be associated with high carb low animal fat diet.

 

Any info on this? Most geneticists will recommend low fat which I believe is a mistake for someone like me although I am 3/4 not 4/4. I have had great results from eliminating grains and fruit.

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What about fatty acids, animal fat and the brain....I have greatly reduced my insulin levels by going grain and fruit free and increasing animal fat (tallow from grass fed animals).

 

The brain is 60% fat? We have reduced animal fat worldwide quite substantially because of the saturated fat correlation to heart disease, yet we did not see a decrease in heart disease. Am I correct about this? If I were to restrict my calories to 500 per day in candy I would not get the benefits of CR. I would be pretty sick.... So CR isn't the end all, right?

The brain is indeed mostly fat, but that doesn't mean we need a high-fat diet to maintain it. We need an adequate-fat diet, and once fully developed that is far less than one might think. It's difficult to determine the historical intakes of nutrients and even more to correlate them with nutritional epidemiology. There is decent epidemiological and interventional evidence suggesting a reduction in saturated fats and cholesterol reduces cardiovascular disease risk factors and outcomes. Those studies that stratify results by ApoE show that this is especially true for E4. In fact, some studies show no significant impact on E2 or E3, but benefit for E4.

 

CR without ON is generally worse than even a standard diet. You are right in that CR isn't the end all, but CRON is very effective at offsetting neurodegeneration.

 

What do you think of this? Im an e3/e4. On my dad's side, high intelligence in grandmother and father (both developed LOAD) My aunt, however, developed EOAD. All dad's side of family were exposed to heavy metals through dentistry (mercury amalgams, my dad and his dad were dentists and grandmother worked in lab etc) . I read that amyloid plaques could signal a deficiency of some sort in the brain that the plaques are attempting to correct. This could be associated with high carb low animal fat diet.

ApoE4 reduces the ability to chelate and clear heavy metals, so any neurotoxic potential of metal exposure is magnified in this group. There's also data showing a reduced neuroregenerative capacity, so any neural insult is potentially magnified. Over time this could lead to Alzheimer's disease at an earlier age. The etiology and function of amyloid plaques are complex, but there is evidence that they are in part a compensatory mechanism to reduce oxidative damage and increase neuronal cholesterol influx. Unfortunately it does a lot of bad things too, including impairing insulin signaling and glucose metabolism. I'd imagine amyloid plaques are similar to arterial plaques in that they're an imperfect way to reduce further damage to the area, but continued insult (diet, injury, etc.) makes the plaque development progressive. Carbs are not damaging per se, but hyperglycemia is quite damaging to neurons, and more so in ApoE4.

Any info on this? Most geneticists will recommend low fat which I believe is a mistake for someone like me although I am 3/4 not 4/4. I have had great results from eliminating grains and fruit.

I don't think low-fat is necessary for all ApoE4. There are a number of other things contributing to Alzheimer's disease than may interact with ApoE, most notably LDL receptor functionality, though there are many. I'm E4/E4 and consume a fairly high-fat diet, probably 30-40%, though vegan and thus cholesterol-free, and my NMR lipid profile is phenomenal. Then again I'm athletic and quite lean, and I used to basically chug fat on a Paleo-esque diet and never had horrendous (though definitely not "good") lipid profiles. I've seen some studies showing that fat intake per-se isn't as important as cholesterol and saturated fat, with cholesterol being the primary offender, and good luck getting a meaningful amount of saturated fat on a cholesterol-free diet (coconut oil aside, though I was eating a lot of 100% chocolate when I had my last excellent NMR lipoprofile).

 

There are only three things that I'm aware of that have independently and repeatedly shown benefit for reducing cardiovascular and cognitive diseases in ApoE4: 1) very low cholesterol and saturated fat (vegan) diets, 2) CRON diets, and 3) gene therapy giving ApoE3 production to ApoE4 animals.

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Guest Nashua

I just discovered I'm E4/E4 and am also female, so I feel that the odds are stacked against me for developing AD. I'm ready to make some drastic changes in my diet if it could provide any preventative benefit. Do you have any suggestions on dietary changes or can you give me a typical daily menu for someone eating to decrease risk with homozygous E4. I would greatly appreciate. I have been reading thru all the numerous studies, but now feel even more overwhelmed and confused. Thanks

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I just discovered I'm E4/E4 and am also female, so I feel that the odds are stacked against me for developing AD. I'm ready to make some drastic changes in my diet if it could provide any preventative benefit. Do you have any suggestions on dietary changes or can you give me a typical daily menu for someone eating to decrease risk with homozygous E4. I would greatly appreciate. I have been reading thru all the numerous studies, but now feel even more overwhelmed and confused. Thanks


Welcome, Nashua! I have been thinking about your post and how best to answer it. I think the research suggests that in most cases a well thought out calorie restriction regimen provides protection against Alzheimer's disease. I am sure you have seen encouraging studies like this:

Calorie restriction attenuates Alzheimer's disease type brain amyloidosis in Squirrel monkeys (Saimiri sciureus).

J Alzheimers Dis. 2006 Dec;10(4):417-22.

Qin W, Chachich M, Lane M, Roth G, Bryant M, de Cabo R, Ottinger MA, Mattison J, Ingram D, Gandy S, Pasinetti GM.

Recent studies from our laboratories and others suggest that calorie restriction (CR) may benefit Alzheimer's disease (AD) by preventing amyloid-beta (Abeta) neuropathology in the mouse models of AD. Moreover, we found that promotion of the NAD+-dependent SIRT1 mediated deacetylase activity, a key regulator in CR extension of life span, may be a mechanism by which CR influences AD-type neuropathology. In this study we continued to explore the role of CR in AD-type brain amyloidosis in Squirrel monkeys (Saimiri sciureus). Monkeys were maintained on the normal and CR diets throughout the entire lifespan until they died of natural causes. We found that 30% CR resulted in reduced contents of Abeta1-40 and Abeta1-42 peptides in the temporal cortex of Squirrel monkeys, relative to control (CON) fed monkeys. The decreased contents of cortical Abeta peptide inversely correlated with SIRT1 protein concentrations in the same brain region; no detectable change in total full-length amyloid-beta protein precursor (AbetaPP) level was found. Most interestingly, we found that 30% CR resulted in a select elevation of alpha- but not beta- or gamma- secretase activity which coincided with decreased ROCK1 protein content in the same brain region, relative to CON group.

Collectively, the study suggests that investigation of the role of CR in non-human primates may provide a valuable approach for further clarifying the role of CR in AD.

PMID:17183154

It would be possible to fill a page with studies that show CR protects against Alzheimer's disease. The problem is that studies are lacking for homozygous E4. That will change. As I write this, I am working on the launch of cognitive workshops that, besides improving cognition overall, will raise funds for a long-term study to look at ways to reduce Alzheimer's risk. The study will be for human participants.

It would be disingenuous for me to promise that any diet/meal plan will definitely protect you from Alzheimer's. On the other hand, following a regimen that can produce measurable improvement in cognitive performance, as well as extraordinary results at your annual physical, is a step in the right direction. I speak of the Daily Intermittent fasting plan that follow and write about here: Daily Intermittent Fasting. Let me hasten to add that this is only one approach. There are many ways to practice CR. Your job is to find the way that's right for you.


You mention that you are ready to make some drastic changes. Hold off approaches that are drastic, extreme, or severe. Take it slow and easy. CR is not about losing as much weight as you can stand. It's about activating longevity signaling. That is a joyous, energy-giving approach that should make every aspect of your life better. Have fun with it and I'll bet that soon you will look forward to every CR day and meal and you'll wonder how you could have ever lived any other way.

Regarding Alzheimer's Disease, take heart! Help is on the way. My guess is that within five years, definite ways to measure diet and lifestyle changes and how they protect against Alzheimer's will be in place. You may not have to worry about Alzheimer's and by adopting CR lifestyle now that you can naturally follow, you will likely have a longer disease-free life to enjoy.

Wishing you great success and much happiness with it,

Paul

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Dear Nashua,

 

Discovering one is an epsilon-4 carrier, let alone a homozygote, is shocking news. Fortunately, it's only part of the equation. There are many other genetic factors, some known, most still unknown, and then, of course, there are many environmental factors, including diet.

 

Because I know many epsilon-4 carriers -- including family members -- I've looked quite closely into what ε4s can do to minimize risk of dementia (and heart disease, and the other ε4-associated pathologies). There's a lot to say on the topic, but a few important things for now:

 

- The advice about moderate alcohol consumption in general being beneficial almost certainly does not apply to ε4-carriers. Zero alcohol appears to be best.

 

See http://apoe4.info/MWiki/index.php?title=Alcohol_consumption

 

- Exercise is particularly important.

 

- As for diet, I suspect CR is the best single thing you could do to minimize your risk, but not enough research has been done, of course.

 

Whatever you do, get as many "biomarkers" measured before you make changes to your diet or health regimen, so that it's easier to figure out what works and what doesn't. Even basic ones like fasting glucose and a lipid profile (cholesterol and triglycerides) would be useful, and fairly cheap and easy.

 

By the way, at apoe4.info there are a bunch of debates going on about diet and dementia and epsilon-4. Might be worth taking a look.

 

Best,

Brian

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Guest Doubtfully Dan

In Japan, e3s have a far lower incidence of LOAD than in the west. However, e4s seem to suffer it with the same frequency (in fact, the OR for e4/4 vs 3/3 is over 33 for Japanese people). This is despite the fact that much of the population is borderline CR, low on saturated fat, high vegetables, moderate drinkers, etc.

 

This should provide some evidence that diet (including CR) is probably not particularly beneficial for e4/4s.

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Doubtfully Dan- Thanks! Intriguing info. I'd looked for such data in the past and couldn't find any on industrialized populations. Of course, the project comparing African Americans in Indianapolis and Africans in Nigeria shows that lifestyle factors -- where it is presumed diet is a huge aspect -- do indeed make a difference among epsilon-4 carriers.

 

Can you point me to the source of the data on epsilon-4 carriers in Japan and LOAD?

 

Brian

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Thanks!

 

The original source of the data is the following meta-analysis, for anyone who wants to look it up:

 

http://www.ncbi.nlm.nih.gov/pubmed/9343467

 

JAMA. 1997 Oct 22-29;278(16):1349-56.

Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium.

 

I don't have access to the full article, nor to the three comments that appeared after its publication. But I'll try to get them.

 

As I said, intriguing, but I don't think it says much about CR. I'll write to the Wilcox team to see whether they have data on APOE-status for Okinawans, many of whom have indeed been on significant, though relatively mild CR for much of their lives.

 

Brian

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All,

 

APOE4 carriers just can't seem to catch a break, according to this new study [1] (popular press account): 

 

The gene variant ApoE4 is a major genetic risk factor for Alzheimer's disease, and it may interfere with memory formation by compromising memory playback.

 

Basically the researchers in [1] found that mice that carried the APOE4 allele had disrupted gamma oscillations in hippocampus during memory formation, interfering with memory consolidation.

 

From this other popular press account comes this helpful table of Alzheimer's risk as a function of APOE status:

 

TJIkFqM.png

Credit: Alzheimer's drug discovery foundation 

 

--Dean

 

----------

[1] Anna K. Gillespie et al, Apolipoprotein E4 Causes Age-Dependent Disruption of Slow Gamma Oscillations during Hippocampal Sharp-Wave Ripples, Neuron (2016). DOI: 10.1016/j.neuron.2016.04.009 

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All,

 

I've been on a mission lately pointing out how poorly the popular press covers new studies of diet and health. Here is another poster child example, this time in a Huffington Post article about a new study [1] on the benefits of fish consumption for preventing cognitive decline. Researchers followed about 1000 elderly folks for 5 years, asking them once per year to take cognitive tests and answer how often they ate fish.

 

Here is how the HuffPo summarizes the results of the study: 

 

People who reported eating fish at least once a week were less likely than less-frequent fish-eaters to have a decline in semantic memory and perceptual abilities. 

 

Notice anything missing from this statement? I'll give you a hint. You don't have to look past the %#^@#^$ title of the study to see what the HuffPo article fails to mention - "APOE ε4 and the associations of seafood and long-chain omega-3 fatty acids with

cognitive decline"
 
That's right, the study reports quite explicitly in the abstract that fish consumption was only beneficial for APO-ε4 carriers. Non-carriers did not benefit in terms of cognitive decline from consuming fish. So that's reasonably news for unfortunate APO-ε4 carriers (although it wasn't a randomized intervention trial, so the evidence is pretty weak even there). But it is another egregious example of very poor popular press reporting on a study. The HuffPo should have at least thrown in something like:
 

In people genetically prone to Alzheimer's disease, those who reported eating fish at least once a week were less likely than less-frequent fish-eaters to have a decline in semantic memory and perceptual abilities. 

 
--Dean

 

-----------

[1]  Neurology. 2016 May 4. pii: 10.1212/WNL.0000000000002719. [Epub ahead of print]

 
APOE ε4 and the associations of seafood and long-chain omega-3 fatty acids with
cognitive decline.
 
van de Rest O(1), Wang Y(2), Barnes LL(2), Tangney C(2), Bennett DA(2), Morris
MC(2).
 
Author information: 
(1)From the Division of Human Nutrition (O.v.d.R.), Wageningen University, the
Netherlands; and Department of Internal Medicine, Section on Nutrition and
Nutritional Epidemiology (Y.W., M.C.M.), Rush Alzheimer's Disease Center (L.L.B.,
D.A.B.), Department of Behavioral Sciences (L.L.B.), Department of Clinical
Nutrition (C.T.), and Department of Neurology (D.A.B.), Rush University Medical
Center, Chicago, IL. Ondine.vandeRest@wur.nl. (2)From the Division of Human
Nutrition (O.v.d.R.), Wageningen University, the Netherlands; and Department of
Internal Medicine, Section on Nutrition and Nutritional Epidemiology (Y.W.,
M.C.M.), Rush Alzheimer's Disease Center (L.L.B., D.A.B.), Department of
Behavioral Sciences (L.L.B.), Department of Clinical Nutrition (C.T.), and
Department of Neurology (D.A.B.), Rush University Medical Center, Chicago, IL.
 
OBJECTIVE: To examine the association between consumption of seafood and
long-chain n-3 fatty acids with change in 5 cognitive domains over an average of 
4.9 years.
METHODS: From an ongoing longitudinal, community-based epidemiologic study of
aging and dementia (the Rush Memory and Aging Project), we included 915
participants (age 81.4 ± 7.2 years, 25% men) who had completed at least one
follow-up cognitive assessment and dietary data. Diet was assessed by
semiquantitative food frequency questionnaire. Scores for global cognitive
function and 5 cognitive domains (episodic, semantic, and working memory,
perceptual speed, and visuospatial ability) were assessed using 19 cognitive
tests. Mixed models adjusted for multiple risk factors of cognitive change were
used to assess the associations.
RESULTS: Consumption of seafood was associated with slower decline in semantic
memory (β = 0.024; p = 0.03) and perceptual speed (β = 0.020; p = 0.05) in
separate models adjusted for age, sex, education, participation in cognitive
activities, physical activity, alcohol consumption, smoking, and total energy
intake. In secondary analyses, APOE ε4 carriers demonstrated slower rates of
decline in global cognition and in multiple cognitive domains with weekly seafood
consumption and with moderate to high long-chain n-3 fatty acid intake from food.
These associations were not present in APOE ε4 noncarriers. Higher intake levels 
of α-linolenic acid were associated with slower global cognitive decline, but
also only in APOE ε4 carriers.
CONCLUSIONS: These results suggest protective relations of one meal per week of
seafood and long-chain n-3 fatty acids against decline in multiple cognitive
domains. The role of APOE ε4 in this association needs further study.
 
© 2016 American Academy of Neurology.
 
PMID: 27164694

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Thanks, Dean.

 

It looks like those same authors published a similar paper a few months earlier, but autopsied brains to assess Alzheimer's pathology vs. testing cognitive tests in the more recent study.

 

http://www.ncbi.nlm.nih.gov/pubmed/26836731

Association of Seafood Consumption, Brain Mercury Level, and APOE ε4 Status With Brain Neuropathology in Older Adults.

 

Higher intake levels of α-linolenic acid (18:3 n-3) were correlated with lower odds of cerebral macroinfarctions (odds ratio for tertiles 3 vs 1, 0.51 [95% CI, 0.27 to 0.94]). Fish oil supplementation had no statistically significant correlation with any neuropathologic marker. Higher brain concentrations of mercury were not significantly correlated with increased levels of brain neuropathology.

 

 

 
I wish they tested the tissue levels of omega-3. Other studies have shown no benefit from omega-3 supplements in ApoE4 carriers, so either there's something unique about fish oil omega-3 bioavailabilty (there is, but I'm not sure it matters based on other evidence) or it's a lifestyle issue or similar confounder.
 
On a lighter note, am I the only one wondering about the accuracy of annual food frequency questionnaires in demented patients? :-)
Dietary omega 3 polyunsaturated fatty acids and Alzheimer's disease: interaction with apolipoprotein E genotype
 

 

3.1.1. Dietary studies

The Cardiovascular Health Cognition Study was the first to evidence an interaction with borderline significance between consumption of fatty fish and presence of the ApoE4 allele on the risk for AD [75]. Fatty fish appeared to have little or no association with risk for AD in those with the ApoE4 but was associated with significantly lower risk in those without the ApoE4 allele. Similar results were observed in the French Three-City (3C) study which reported a significant protective effect of fish consumption against all-cause dementia only in ApoE4 non-carriers [10]. However, there was no statistical interaction between fish consumption and ApoE genotype on the risk for AD. Moreover, the same study showed a deleterious effect of n-6 rich oils (sunflower or grape seed oil) when their consumption was not counterbalanced by consumption of n-3 rich foods (oils or fish) among ApoE4 non-carriers. This detrimental effect was not observed in ApoE4 carriers.

 

This is an excellent review, and the section "4. Putative mechanisms underlying this interaction" explains a lot of why I doubt the results of the most recent study you posted, Dean, at least for a direct effect of omega-3 fatty acids.

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Possible already existing drug that may help ApoE4 carriers:

 

"The analysis showed that those who had the genetic risk and took bumetanide had a ~35% to 75% lower prevalence of Alzheimer's disease compared to those not taking the drug."

 

Precision medicine data dive shows diuretic pill may be viable to test as Alzheimer's treatment

 

https://www.sciencedaily.com/releases/2021/10/211011110815.htm

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