Marks Daily Apple
Serving up health and fitness insights (daily, of course) with a side of irreverence.
8 Apr

Dear Mark: ApoE4, Red Eye Recovery, TEDx Paleo Debunking, and Cough Drops

Night FlightIt’s Monday, which means it’s time for another edition of Dear Mark. This week, I’m covering four reader questions. First up is a really tricky one: ApoE4, the ancestral allele that’s classically associated with a host of maladies, like cardiovascular disease and Alzheimer’s. What’s the deal with it? We don’t have any concrete answers (yet), but I give my take on it. Next, I tell a reader who’s flying to Chile for vacation how I recover from travel-related sleep disturbances and realign my circadian rhythm. After that, I cover another paleo debunking that’s actually not much of a debunking, this time a TEDx video from Christina Warriner. And finally, I explore the eternal question of Halls cough drops, including whether or not any natural alternatives exist.

Let’s go.

Hi Mark and Worker Bees,

I read that APOE4 is the “ancestral” allele for the APOE genes. It is the risk factor for Alzheimer’s. I find it hard to believe that checking out mentally is in any way desirable. You linked a few months ago to an interesting article about high-carb seniors succumbing to cognitive impairment. Might you be able to think aloud about this topic?


ApoE is apolipoprotein E, the string of amino acids that attaches to lipoproteins and allows them to cross the blood-brain barrier and get into the brain to deliver nutrients and cholesterol and remove toxins. If a lipoprotein has the ApoE marker, it will be allowed into the brain to do its work. Different genetic variants of ApoE are better and worse at this task, however.

ApoE2, is associated with a lesser risk of Alzheimer’s and ApoE3 is “neutral.” Meanwhile, ApoE4 is associated with higher total cholesterol and a greater risk of Alzheimer’s. Thus, most people assume that the high cholesterol is also causing the Alzheimer’s and dementia. It’s not quite so simple, of course.

Brain is perhaps the richest source of cholesterol in all the land (or sea); just an ounce of raw lamb brain contains nearly 400 mg of cholesterol. In fact, brains – living ones – need plenty of cholesterol to work right. The synapses, or connections between neurons, are made of cholesterol. In case our brains aren’t getting enough cholesterol, the astrocytes – brain cells which supply nutrients to neurons – can even manufacture their own cholesterol.

That may explain why statins can hamper brain function, why high cholesterol late in life is associated with a reduced risk of dementia, and why Alzheimer’s patients have lower levels of cholesterol, phospholipids, and fat in their cerebrospinal fluid. Clearly, our brains need cholesterol.

So why is ApoE4 associated with high cholesterol and Alzheimer’s?

One hypothesis is that people with ApoE4 need higher baseline plasma lipids because ApoE4 makes the brain less efficient at taking up cholesterol. If that’s true, high cholesterol may be a protective mechanism designed to overcome this limitation. This would jibe with the observation that Alzheimer’s and dementia are often preceded by a big drop in cholesterol. That is, the early, asymptomatic stages of Alzheimer’s are associated with a decline in serum total cholesterol, not a rise. Interestingly, young ApoE4 carriers have better memory, better learning capacities, and more neural efficiency in general than non carriers, so it’s not all bad. Something goes wrong down the line.

My take is that ApoE4 carriers, being “ancestral,” are simply more susceptible to neolithic stressors like tobacco (yeah, yeah, I know it’s been smoked for a long time, but not in its current form), heavy metal toxicity, sedentary living, and chronic stress. Some evidence:

I’d also guess that a bit of intermittent fasting, or at least a movement away from the wholly modern grazing method of eating, would also be helpful. At any rate, closer adherence to a Primal way of life appears especially crucial for ApoE4 carriers.

Another view is that ApoE4 carriers are actually more sensitive to dietary fat, particularly saturated fat, as well as carbohydrate. William Davis MD has found that for these individuals, moderation of both fat and carbs is necessary to avoid elevations in the number of LDL particles, particularly small dense LDL. ApoE4s should probably at least monitor their lipids and spring for the more advanced tests to note how fat and SFA affect LDL-P, LDL-C, and small dense LDL – just to be safe.


I’m leaving for a vacation to Chile later this week and I’m facing 2 overnight flights within 10 days of each other.

I’m about 6’2″, broad shouldered, and for the time being my pocketbook precludes me from sitting in the pointy end of the plane.

This upcoming flight has me wondering what tips and/or advice you have for people who are facing a situation with non-ideal sleeping conditions? What can be done in advance from an exercise/nutrition/supplementation standpoint to partially mitigate the effects of poor sleep?

Also, do you have any suggestions for things that can be done to promote better sleep in a tight spot (no pun intended!)?

Thanks for everything you do with this site. Look forward to your suggestions.


As a frequent traveler, I’ve figured out a perfect regimen for getting my clock aligned with wherever I’m staying. It may not work for you, but it certainly does for me and pretty much everyone else to whom I’ve suggested it.

On overnight flights going East, you’ll be experiencing what amounts to two “shortened days” as you erase multiple time zones from you diurnal rhythm overnight. Set your watch to your new intended time zone when you are in the air. Get as much sleep as you can on the plane. Typically you’ll arrive sometime later in the day at your destination, so you won’t have to work hard to stay awake, but do so. You got 4-6 hours on the plane maybe, but the new “day” will be several hours shorter. Adapt your mindset to the new time zone immediately. Do NOT nap. I usually go for a short walk to explore the city or I hit the gym and ride the bike a bit. As it gets close to the new bed time, try to take 3-5 mgs of melatonin an hour before your intended bedtime. By the time you hit the hay, it will have done a decent job resetting you internal clock and allowing to get some regular zzz’s. Repeat the melatonin ritual the next night and then cut in half the third night. From there you should be good to go.

Now, for Westbound flights that follow the daylight most or all of the way, you will be experiencing a very long single day and usually arriving towards the end of that day. In this case, same thing, set your watch on the plane to “get into” the new time zone. Stay awake as you see fit, but try to take a long nap maybe halfway through the flight. You will have rested, but not have had too much sleep that it throws your normal night off. When you arrive, same process, stay awake until it’s the local bedtime, find things to do, take a hike or work out, and do the same melatonin ritual.

Finally, for long night flights, just get as much sleep on the plane as you comfortably can, because you’ll have a long day at your destination. I try to do two naps with a few movies in between.

To sleep on the plane itself, I have a few suggestions:

Get a window seat. I know the aisle offers more legroom, but it’s hard to get comfortable when you have to worry about where to put your head. With a window seat, you can wedge yourself up against the side of the plane. Plus you won’t have people crawling over you to get to the bathroom.

Get an exit row. More legroom is always better.

Consult Seat Guru. Figure out what model plane you’ll be on and then check reader reviews to find the best seat in the house.

Bring a pillow if the airline doesn’t provide one. I like a super compact backpacking pillow, the kind you’ll find at REI. Barring that, a rolled up article of clothing works.

Hey Mark, big fan of this site.

Have you seen this TED talk by Christina who claims to debunk your theory and other Paleo like diets? She does a lot of fad calling, showing your books and movement a fad.

Check out the talk when you have the time and please, as your readers, we’d all like to see a post on your thoughts around this. She has left a lot unsaid and I’m wondering if she’s even read any of the books she’s talking about.


I have seen it. It was better than Paleofantasy, but it suffered from some of the same mistakes. Mainly, she didn’t really do her homework and ends up promoting a fairly Primal way of eating without actually realizing it. It’s just that the first five or six minutes are really rough.

She begins by saying that humans have no anatomical or physiological adaptation to eating meat, meaning (I assume) because we don’t have big scary claws and teeth and the ability to overpower and devour a bison barehanded, we aren’t “meant” to eat animals. On some level, this makes sense. Dogs, cats, lions, tigers, and other fearsome predators all come equipped with the physical, mechanical equipment to break down and consume a carcass. Humans do not. We do, however, have technology. We have spears, stone knives, bows, atlatls, slingshots, and, now, rifles, to kill and butcher our prey. We’ve harnessed fire to cook it. We’ve also harnessed fire to cook starch, which – unlike meat – we actually have to cook in order to really digest. Why no mention of that in the video?

That said, despite the pretty obvious vegetarian bias (“paleo is for men,” “paleo is all about meat,” etc), the rest of the talk is good. She ends by acknowledging that we can learn a few things from paleolithic nutrition: eat fresh foods; eat whole foods; and eat high species diversity. Oh, and don’t eat refined sugary drinks. I agree with her on all these points. I think if she read through this blog she’d agree with most of mine.

Robb Wolf gave a good minute by minute summary (a Wolf’s Eye View) that I’d recommend reading. I agree with everything he says in it.

Dear Mark,

I have need for a cough drop for nighttime sleeping or when attending an event requiring quiet. I just looked at the ingredients in the 5 bags of Halls my hubby bought and it’s almost all sugar and junk. What would you recommend especially now that I’m on 21-day Sugar DeTox? Help!  :)
Currently, I have 2 cloves of clove in my mouth guessing this may help!  ??



I wasn’t really able to find any natural cough remedies with strong evidence. If natural methods aren’t working, a single Halls cough drop only has about 4 grams of sugar, mostly glucose (from glucose syrup). Unless you’re really wedded to this 21-day detox, I’d say just go ahead and take the cough drop. Besides, the 21-day sugar detox is more about avoiding sweets – elective junk food – than eliminating every trace molecule of sugar, which in this case is primarily glucose rather than fructose. One study even found that both menthol and a sweet taste are effective at suppressing coughs, so combining the two is likely more effective than either alone.

A bad night’s sleep is way, way more detrimental to your health than a tiny bit of sugar:

And those are just a few examples.

Both honey and chocolate may be effective against coughs, but, well, those aren’t exactly sugar-free.

That’s it for today, guys. Thanks for reading and be sure to chime in with your thoughts/opinions/suggestions in the comment section!

You want comments? We got comments:

Imagine you’re George Clooney. Take a moment to admire your grooming and wit. Okay, now imagine someone walks up to you and asks, “What’s your name?” You say, “I’m George Clooney.” Or maybe you say, “I’m the Clooninator!” You don’t say “I’m George of George Clooney Sells Movies Blog” and you certainly don’t say, “I’m Clooney Weight Loss Plan”. So while spam is technically meat, it ain’t anywhere near Primal. Please nickname yourself something your friends would call you.

  1. As the creator of the program I thought I’d chime in here for anyone interested in what I’d recommend on The 21-Day Sugar Detox for a cough issue, it would definitely be the following:

    1- herbal tea, specifically I like some from Traditional Medicinals like Throat Coat and Echinacea Plus

    2- a humidifier for sure – I like a warm air one personally, but it may depend on the season.

    I do wonder why this person “needs” cough drops, however. If it’s a matter of a cold, that’s one thing, but it almost sounds like a chronic issue. If that’s the case, I’d look at his/her overall hydration level as well as gut health and fatty acid digestion. It’s pretty common for skin and mucous membranes to feel more dry if these areas are not optimized.

    While on The 21DSD or otherwise, I wouldn’t recommend a commercial cough drop. I like some of the natural varieties that include slippery elm and possibly honey as ingredients. Glucose syrup may be derived from wheat, so I’d steer clear.

    Diane @ Balanced Bites, author and creator of The 21-Day Sugar Detox program

    Diane wrote on April 8th, 2013
  2. i was waiting for mark to tell the traveler to walk around barefoot to ease jetlag!

    jonasandpen wrote on April 8th, 2013
  3. Anyone worried about saturated fat in the diet, also Apo E4 carriers, may want to read this:

    Sabine wrote on April 9th, 2013
  4. I have had intense periods of intercontinental flights (all 5 continents and back) and have tried everything. As I see it, the biggest problem is that you are tired when you shouldn’t be. My advice is to sleep whenever you can for as long as you can (6 naps a day? Fine). You will be up at odd times and it will take a few days to get your schedule straight no matter what but you won’t be tired. And if you are not tired, you can work and enjoy yourself.

    Txomin wrote on April 9th, 2013
  5. That you for your post. It is great as usual. I have a good tip for you for coughing: put a warm compressor on your chest at least once a day and drink a cup of hot tea with herbs. This method always saves me from coughing.

    Melany D wrote on April 9th, 2013
  6. The second part of the TEDs video is very interesting. As for “seems to be targeted at men”, although I’m aware that more than 50% of Paleo adepts are women, the marketing materials and images on the paleo sites are indeed mostly men. This might be because the main Paleo sites and blogs are written by men, but it would be great to see more images of women or rather equal representation of women in the materials.

    Pov wrote on April 9th, 2013
    • Carrie’s new Primal Woman book ought to help with that bias too. I know there are lots of women from all kinds of ages and backgrounds who are finding their health turning around as they swap their no-fat, splenda-sweetened yogurt and low-fat cereal with skim milk for a plate of bacon and eggs. I know mine has!

      Rhonda the Red wrote on April 9th, 2013
  7. Mark, thank you for posting this on apoE4 and Alzheimer’s and especially all the links. It pulls together a lot of things that I can see happened in my father’s life in the couple of years before he was diagnosed with Alzheimer’s. I have no idea if he has the apoE4 allele but his basic diet used to be fairly basic meat and two veg, including an almost daily bone broth and very few sweet things. Then all around the same time, he became more sedentary – attempting to heal a detached retina – and his diet became more CW as my mother took over the shopping.

    I’m trying to move him back to a more primal diet now, as removing wheat (all grains in fact) has already made a noticeable improvement in his cognitive ability. Looks like getting him into walking again will be another good move. He only needs another 7 years now to get a telegram from the Queen!!

    awok677 wrote on April 9th, 2013
  8. “One hypothesis is that people with ApoE4 need higher baseline plasma lipids because ApoE4 makes the brain less efficient at taking up cholesterol. If that’s true, high cholesterol may be a protective mechanism designed to overcome this limitation.”

    I just recently found out I am ApoE3/ApoE4. This was my guess when I read the description of it, knowing how important cholesterol is to the brain. But even people with 2 copies may go on to never develop Alzheimer’s. And, even though we don’t hear about it – it’s not news unless it involves drugs – there is ongoing research using a high-fat, high-cholesterol diet to help Alzheimer’s patients – they have made progress. I haven’t seen the studies so I can’t link anything. This is info from the Alzheimer’s forums at 23andMe. I’m just so happy I figured it out.

    Heather wrote on April 9th, 2013
  9. Cough Drops.
    I frequently get spasmodic coughs. I use Thayers Slippery Elm Lozengers. They taste awful but work. The cherry flavor has .10 g(1/10) of dextrose/sucrose. I don’t know what the original flavor(none) contains.
    Natural or health food stores and some of the larger pharmavcy chains carrythese.

    Nancy wrote on April 9th, 2013
  10. I’d appreciate Mark’s take on the L-carnitine study mentioned in the above comments, too. Thanks.

    Ellen wrote on April 9th, 2013
  11. I think you should do a TED conference somday, maybe debunking “Debunking The Paleo Diet.”

    Anthony wrote on April 9th, 2013
  12. On the quelling coughs subject: I have a long history of colds or flus turning into bronchitis which results in uncontrollable asthmatic coughing fits. This winter I got the flu for the first time in years and it was the only time I’ve been able to stop the coughing. I had one very small coughing fit after which I took 2000 mgs of buffered Vitamin C (mineral ascorbates from calcium and magnesium) every hour for 36 hours except when I was sleeping. I had absolutely no more coughing! As far as I’m concerned, this was a miracle. I’ve been dropped to the floor and almost unconscious from coughing, torn rib muscles and been seriously sleep-deprived before from these coughing fits. No doctor has been able to help me with this except for suggesting inhalers which I was not going to do unless absolutely necessary! This time it was simply not an issue. No sugar necessary. :)

    Felicia wrote on April 9th, 2013
  13. Natural cough remedy that could work is to have some ginger and lime/or lemon mix. I would add some honey, but it is your choice.

    reza wrote on April 9th, 2013
  14. For something truly paleo, just get some calamus root, or what the Cree call “rat root”. It looks like a small twig. Just bite off a small junk (in private; otherwise people will think you’re eating wood!) and either suck on it or chew it slowly. If it’s from a good batch, it will have a noticeable menthol flavour. It’s my absolute go-to remedy for a sore throat, but it may also work for coughs.

    I’ve never seen it in a health food store. I get it from a colleague who has connections to the local native community.

    Russ wrote on April 9th, 2013
  15. Great advice on long haul flights. I used to travel 100,000 miles plus a year when I worked for the big corporates. I would add to avoid alcohol, drink lots of water to keep hydrated, and make a point point of several walks up and down the cabin to keep your muscles loose.

    Also put on the eye mask and if you have an ipod put on some soothing music at low volume, it cuts out all the plane noise and I find it helps a lot.

    I always set my watch to the destination time as soon as I get on the plane, mentally I am then working my sleep patterns around that.

    Sally Jones wrote on April 10th, 2013
  16. Mark, I’ve always looked for a way to be able to balance sleep when I travel. Whenever I traveled, I would be very sleepy at my destination and also when I return home. I’m going to give your tips a shot. It makes much more sense to do it that way.

    I ALWAYS take the window seat, I can’t stand passengers that have to get up to go to the bathroom every hour on the hour.

    Chest Coach wrote on April 10th, 2013
  17. Sucrets cough drops work. The ingredients are similar to halls with DM. The menthol starts working quickly and the DM affects something in your brain that makes you cough.
    I’d go for a natural remedy if I were you though.
    Small amounts of mint oil, like a droplet, have worked for me for soothing my throat and slightly opening my airways. Even sniffing or inhaling over the bottle works a bit.

    Animanarchy wrote on April 12th, 2013
  18. I’m APO E4/E4, and I get a bit frustrated at the conflicting recommendations. I recently read that carbohydrate sensitivity is common with E4s, and that is definitely my experience. Considering that Alzheimer’s disease is sometimes referred to as diabetes of the brain, I figure the best strategy is to eat in a manner that maintains endocrine serenity, which for me is avoiding starch and the huge spikes of blood sugar and insulin that starch creates. My diet is low-ish carb, with carbs from fruits and veggies making up about 25-30% of calories. Fat is about 50-60% of calories. Also, my evening meal is eaten at around 5pm, and it’s usually a small, easily digested snack of fruit or vegetables such that I sleep on an empty stomach and basically fast for ~12 hours every day.

    Alex wrote on April 15th, 2013
    • I think you are wise to control your carbs. I follow the research, and am e-3/e-4 and wrote a tome below if you are interested, I could have continued – but don’t want to be totally boring to all with my agenda, but I’ll weigh in on any specific questions you have as I do try to keep up with the literature and am personally very interested in the topic :)

      Nancy Willcockson wrote on April 17th, 2013
  19. Thanks for sharing your thoughts about Mantle christmas.

    forest frost wrote on April 16th, 2013
  20. Research has found that Alzheimer’s patients have decreased insulin sensitivity in the brain and diabetes is a major risk factor for the development of Alzheimer’s Disease – hence regulating your insulin response should be beneficial as in a primal diet. The brain is the second major source in the body to make cholesterol, after the liver, it is essential to neuronal cell walls and functioning, and the e4 is less efficient and slower at transporting lipids/cholesterol than are the other alleles. Heavy metals do cause oxidative stress, and in my opinion, anyone who isn’t anemic, shouldn’t be taking iron in their vitamin supplements – you get what you need from diet and the body is very efficient at storing iron. In fact research has found that women that have early hysterectomies have earlier onset of dementia – possibly due to increased iron stores from not menstruating. On that note, estrogen is brain protective, we have estrogen receptors throughout the brain, and hormone replacement immediately following menopause likely decreases risk of dementia and slows aging (recent research from Standford shows preservation of telomere length with hormone replacement in e-4’s but rapid telomere aging without) – of course caution if one has significant cancer risk factors. A delay in hormone replacement will increase risk of heart disease and stroke if instituted later though. Nicotine is brain positive – just not when inhaled with the rest of the pollutants in tobacco. Exercise is the one variable that consistently has been shown to decrease risk of dementia, regardless of your apo e status. Blood pressure control is also very important – even longstanding borderline hypertension increases risk for dementia. Interestingly, the e-4 allele is more susceptible to herpes simplex type 1 (fever blisters) and some research suggests that HSV1 may cause chronic inflammation and be a co-factor in the development of AD – there is increased HSV1 viral DNA in AD brains (so maybe anti-virals are good – I take them :) Also walking pneumonia, chlamydia pneumonia DNA is more common in the brains of AD patients, so chronic infection likely increases risk for AD. Some research shows e-4 brains to be different from birth, but the data on better memory doesn’t jive with the findings of smaller entorhinal cortices – so I don’t know about this discrepancy, but I do know of research that indicates higher IQ in e-4’s and some that doesn’t. I have read articles that showed that AD mice with a high fat, low carb diet have less Alzheimer’s pathology and better learning/memory, and the high carb diets having more Alzheimer’s pathology, but some of this research has been equivocal. I have also read research that reports lower incidence of Alzheimer’s Disease in hunter/gatherer societies, but longevity may have impacted the findings. On a discouraging note, I have also read an article that suggests that the e-4 is adaptive, would be genetically selected, in hunter/gatherers as around mid-age, one is not able to hunt or gather the calories needed to sustain oneself and as the brain is very caloric demanding, hence atrophy of “unneeded” functions can allow one to have preserved motor abilities and routine capacities, without the need for novel problem solving and memory, still contributing to the group and needing less resources for survival – bummer idea huh? I am an e-3/e-4 and a neuropsychologist who specializes in dementia. Unfortunitely my mother developed Alzheimer’s, which prompted my checking my own genetic status. On the positive, the e-4 is simply a risk factor, not a causal factor. Many people with e-2’s and double e-3’s also develop AD and many people with e-4 do not, so all you e-4’s don’t panic. I am primal because I believe it decreases my risk of manifesting Alzheimer’s Disease, based on the research, which I follow closely. Avoiding diabetes and insulin resistance is very important, controlling vascular risk factors, avoiding metals, pesticides, etc., and eating a diet high in anti-oxidants, healthy fats, and omega 3’s is important. Oh, and low levels of vitamin D are also associated with dementia – as well as many other things. Again, exercise – mental and physical – is preventative (not killer cardio – just regular exercise like walking), good social stimulation, good sleep, monitor your stress and cortisol (most of life is not so important as to stress about it), get therapy if you are depressed (depression is associated with earlier onset of dementia), avoid poisons, toxins, and excess metals, laugh, see the dentist regularly (poor oral health is associated with dementia), drink red wine and green tea, and eat dark chocolate (all decrease beta amyloid in the brain), take your omega 3’s and get sunshine or D3, and eat primal – and you may have a fighting chance, whether or not you are an e-4 carrier. Sorry this post is so long – there is so much to say about AD :)

    Nancy Willcockson wrote on April 17th, 2013
  21. Excellent post, Nancy.

    AND, I appreciate Mark’s summary of the status quo regarding fats and APOE4. There are most definitely two schools of thought out there: the high fat camp vs. the low fat camp.

    One camp (Masterjohn) has taken it further and even suggested that a higher LDL-P is GOOD for E4’s- in the absence of inflammation.

    This is personal for me. I am the dreaded homozygous E4. With 25% of the population carrying at least one E4- that leaves millions of us without definitive dietary advice.

    This Primal follower, and millions of others, would greatly appreciate if you could look into this further, Mark. I am in touch with other homozygotes. We are desperately searching for research (and willing to participate in such!) that will give us an answer.

    Julie wrote on April 20th, 2013
  22. The Berkeley Heart Lab offers a detailed and comprehensive panel of tests to assess the risk for cardiovascular disease for anyone interested.Genetic testing for ApoE as well as other genetic risk markers are included in the tests. Check it out! My physician is highly motivated to keep his patients stroke and heart disease free and he urged me to do it. The facts about Alzheimers disease became known to me after getting my lab results.

    Jules wrote on July 3rd, 2013

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