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

It’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!

About the Author

Mark Sisson is the founder of Mark’s Daily Apple, godfather to the Primal food and lifestyle movement, and the New York Times bestselling author of The Keto Reset Diet. His latest book is Keto for Life, where he discusses how he combines the keto diet with a Primal lifestyle for optimal health and longevity. Mark is the author of numerous other books as well, including The Primal Blueprint, which was credited with turbocharging the growth of the primal/paleo movement back in 2009. After spending three decades researching and educating folks on why food is the key component to achieving and maintaining optimal wellness, Mark launched Primal Kitchen, a real-food company that creates Primal/paleo, keto, and Whole30-friendly kitchen staples.

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