Alzheimer’s, Ketones, and Kidding Ourselves (Pt.3/3)

I concluded the previous post by introducing the idea that, when it comes to a body and brain being fueled by ketones, the absolute concentration of ketone bodies in the blood might be less important than the body’s ability to use those ketones. I expressed concern that placing the sum total of our faith in high β-OHB levels might take our eyes off the marker we should probably be more interested in: how well an AD patient is functioning. Maybe some AD patients do require ketones at upwards of 4-5mM. But maybe some others would do just great at lower levels.

Here’s my thinking on this...

Missing the cognitive function forest for the numerical trees

Let’s say someone has blood ketones of 4.0mM. That would be considered crazy good! But maybe that person isn’t experiencing the improvements in cognitive function we would expect from levels that high. And let’s say someone else measures ketones at 1.4mM. That’s quite a bit lower, but maybe their mind is sharp and they feel great. So it’s not necessarily what the numbers say, but rather, how someone is actually feeling, thinking, and processing information. It doesn't matter how high ketone levels are if the cells can’t use them effectively. (Think about nutritional supplements: you could take 1200mg of calcium in a form that’s not very well absorbed, or 400mg in a form that’s more bio-available. You might actually experience a greater benefit from the smaller dose, because the body is better able to use it. People who argue against using vitamin & mineral supplements say you’ll just end up with "expensive urine." So maybe it’s possible for people to end up with expensive blood, too. [Meaning, lots of ketones, but not using them to the best effect.]) 

The truth is, in most studies that employ exogenous ketones, higher ketone levels do tend to correlate with improved cognition. I don’t deny this. BUT: exogenous ketones must be administered every few hours, because the effects are transient. Like I said last time, when they wear off, they’re gone. Fin. Kaput! (And according to researchers, the half-life of elevated β-OHB in the blood induced by exogenous ketones is only about 1-1.5 hours. Not all that long.) 

But how might that compare to someone on a low-carb diet, doing a little fasting, lots of fat-fueled low-level physical activity, and maybe taking a couple spoonfuls of coconut oil here and there? This person would have elevated ketones all the time. (Maybe not 3-5mM, but certainly more than the 0.1-0.2mM typical of a “balanced” diet [i.e., high-carb].)

I keep going back to the LC versus KD thing, because I think it’s an important distinction to make, particularly when we have researchers making claims that boil down to, “It’s just too hard for people to change their diet, so that’s why we’re so excited about these ketone formulas.”

People might be more inclined to change their diets (or that of their loved ones) if they thought they could see some pretty good improvement by doing, say, a regular ol’ Atkins diet, rather than a 4:1 or 3:1-style medical ketogenic plan, where they’re living on avocados, macadamia nuts, cream cheese, butter, creamed spinach, and asparagus drenched in hollandaise sauce, and are about to puke from all the fat. Yes, when you need to restrict protein and get upwards of 80% of your calories from fat, a KD is difficult to maintain. You do almost have to arrange your life around the diet. But a regular ol’ low carb approach? Easy-peasy! (BTW: for those of you who don’t know, the real, true Atkins diet includes plenty of vegetables and even fruit, depending on one’s carbohydrate sensitivity. It is not all bunless bacon cheeseburgers. Please stop believing the stereotypes about this absolutely lifesaving nutritional plan.)

And the beauty of a more general low-carb approach is that it is completely workable in everyday real life. Millions of people have been doing it for years. As a low-carber myself, I’ve never found myself in a social situation or at a restaurant where I couldn’t find anything appropriate to eat. Eating on the go has never been a problem, and it’s really not difficult to stick to when you can eat (depending, of course, on individual carb tolerance) upwards of 75-100g of carbs a day. You don’t have to live on heavy cream and bacon. (Though that would be tasty!) You can enjoy strawberries, whole-milk yogurt, dark chocolate, and semi-massive piles of greens and other low-starch vegetables. (Even small amounts of carrots, beets and winter squash!) It’s not difficult. It’s easy to buy groceries, easy to prepare meals, easy to eat on the run, and you don’t have to drive yourself crazy about the macronutrient ratios and stress about limiting protein. I think this is where the researchers are missing the boat. They’re confusing “low carb” with a no-sh*t, crazy-strict ketogenic diet.

So again, let me speculate: someone on a LC diet, with the fatty acid and ketone-using pathways ramped up and going 24/7—as opposed to someone following their same-old high-carb diet and insulin-resistance-inducing lifestyle, and just taking exogenous ketones every few hours—might (might) extract a bigger benefit from a lower level of ketones. (This being said, I certainly acknowledge that there are people who do need to follow a very strict ketogenic diet and get ketones up around 3-5mM in order to see benefits. I just think they might be in the minority. If nothing else, folks can start with a solid LC diet, see where that takes them, and refine the macronutrient ratio as necessary, over time.)

I wish there were more clinical trials looking at ketone supplements in conjunction with reduced CHO diets. There are currently very few, if any. They almost all employ only the ketone esters, but there are some more in the works, and we already have great indications that carbohydrate reduction combined with other lifestyle adjustments can have stunning impacts for AD and MCI.

Someone who is 70 years old, sedentary, and eats upward of 200g+ of CHO a day is probably not all that metabolically flexible. So we dose them with exogenous ketones, and maybe they get a small benefit. But would we see a much bigger (read: better/more effective) benefit in giving the same ketone dose to someone whose mitochondria are primed to be able to use that fuel properly? We tend to forget that we can't just shove certain compounds into our bodies and expect to automatically get the intended benefit. Certain physiological/biochemical mechanisms have to be in place in order to use them effectively. This is why I think the combination of outside ketones and a lower carb diet (and exercise, and anything else that improves insulin sensitivity and metabolic flexibility) would show much more promise than we’ve seen so far in studies where they administer ketones but require no other changes to diet or lifestyle.

The caveat I would give for a study looking at a LC diet for AD is that it would have to be a fairly long-term study, especially if the subjects are much older. The younger someone is, the more likely they can adapt quickly to a dietary change. For someone of advanced age, and advanced AD, it would probably take longer for them to bring the metabolic machinery up to speed. I would hate to have a clinical trial go for 6 weeks and it be determined that the approach is “ineffective,” when it might have been golden at 3 or 4 months.

Confounding factor: ApoE4

We need to talk about ApoE4.

Considering how long this post has already been, I won’t inundate you with the whys and wherefores of the ApoE4 genotype. Nutshell version: ApoE4 gene carriers (both hetero- and homozygous) have a markedly increased risk for developing AD. There are many reasons for this, but one of them seems to be related to lipid/lipoprotein processing. (E4s tend to have freaky high risks for cardiovascular disease, as well as Alzheimer's.)

The reason we need to talk about ApoE4 (which I’ll just call E4 from here on) is because, in studies where exogenous ketones have been used to improve cognitive function in AD patients, E4 people usually don’t show as profound an improvement as other genotypes, and sometimes they show no improvement at all. What gives?

This, my friends, is why I am so passionate about the importance of dietary and lifestyle changes. Study results showing that E4s don’t respond as well to ketone salts/esters as E2s and E3s typically employ the ketones with no other interventions. I understand that the ketone variable does need to be studied in isolation, to make sure it really is the ketones and not some confounding factor that is having the effect, but once it’s established that ketones do help—and this has already been established (at least, in non-E4s)—then it seems the right thing to do for the E4s isn’t to throw our hands up and give up, but rather, to ask why the E4s don’t get the same benefit as the other genotypes. My hunch—which is backed up by a significant body of research—is that the E4 genotype does not program anyone to develop AD. What it does is make its carriers the most susceptible to the detrimental effects of the modern diet and lifestyle. (Kind of like how the BRCA1 genes don’t cause breast cancer, but they increase susceptibility.)

According to the people who eat, sleep, and breathe this stuff:

“The APOE Ɛ4 allele may not be inherently damaging but only in combination with a high-carbohydrate diet, which is damaging in itself and is likely to be a major contributor to the high risk of CAD [coronary artery disease], and possibly AD, in modern populations with or without the APOE Ɛ4 allele.” (Lane & Farlow, 2005)

“It should be noted that E4 is not an inherently damaging allele; it is only deleterious in combination with a HC [high-carb] diet (which is deleterious on its own).” (Henderson, 2004)

“A modified ‘Paleolithic prescription’ may prevent AD. The Paleolithic prescription proposes a change in diet and activity to a level more similar to our Late Paleolithic ancestors. […] Therefore, reducing dietary intake of high-glycemic carbohydrates and increasing protein, fiber and fat would be preferred. Similar diets appear to reduce the risk of AD. Since HC [high carb] diets are proposed to be the primary cause of AD regardless of apoE genotype, such a diet would generally reduce the risk of AD. However, this diet is predicted to be particularly beneficial to carriers of apoE4.” (Ibid)

From the study that inspired this post: (“the patient” is referring to Mr. Newport)

“Given the report by Henderson et al. indicating that the APOE ε4-positive subjects in their study failed to show statistically significant improvement in their ADAS-Cog scores in response to MCTG treatment, it is noteworthy that the patient, although APOE ε4-positive, exhibited clear cognitive and behavioral improvement while consuming equivalent or larger quantities of ketogenic MCFAs. The findings of Henderson et al. (which may have lacked the statistical power to detect a change in APOE ε4-positive subjects) do not rule out the possibility that carriers of the ε4 allele could show cognitive improvement if studied for longer periods of time and/or given higher doses of MCTG.”

You know what else the findings of Henderson et al. don’t rule out? How about the potential efficacy of smaller doses of ketones (or higher) combined with a freaking low-carb diet?!  (And maybe a little fasting here and there, some long walks, and good sleep.)

Maybe the exogenous ketones didn’t feed the starving neurons of the E4s because these folks were still eating pasta/bread/cookies/whatever, still not sleeping enough, and still being too sedentary, and there are only so many roadblocks outside ketones can overcome. What might happen to cognition in E4s when we provide some exogenous ketones, but their bodies are champing at the bit to use them, because the metabolic machinery is in place for them to do so, thanks to a low carb diet and whatever additional lifestyle modifications they are capable of? 

Another reason I wanted to address the E4 issue is that LC diets often—not always, but often—include high amounts of saturated fat. And since the E4s have exaggerated lipoprotein responses, they might need to adjust things a bit. I am not an expert on the ins and outs of E4. (But these folks are. Also here.) All I know is, with consumption of high amounts of saturated fat, E4s tend to have very elevated LDL cholesterol – and I mean very elevated, in both cholesterol content and particle number. They might also show unfavorable changes with high consumption of other types of fat, but saturated seems to have the biggest impact. (We in the LC/Paleo worlds generally don’t freak out about cholesterol like the mainstream medical world does, but there’s a lot that’s yet undetermined, and until we know anything for certain, it’s not unreasonable for these folks to be concerned.)

That being said, there’s no reason an E4 can’t construct a LC diet based on mono- and polyunsaturated fat. And, when combined with other lifestyle interventions that might help maintain/restore insulin sensitivity, it’s possible that they wouldn’t even require carbohydrate restriction to an extreme degree. I could see a place for 25-30% carbs in someone who’s got everything else in check, particularly if those carbs are coming from non-starchy vegetables, lower-glycemic fruits, and yes, maybe even small amounts of starchier foods. So it’s possible to have a lowER carb diet without it being super-heavy on fat, which seems like a prudent way for E4s to approach this. Some people might be able to get the cognitive benefits of a low-carb diet without being uber-ketogenic at all times.

My personal opinion is, getting ketones higher is probably a good thing for ALL people whose brain cells’ utilization of glucose has become compromised—regardless of genotype. But in order to balance long-term cardiovascular health and preservation (or restoration) of cognitive function, perhaps the E4s might do best on a ketone supplement combined with a low-ISH carb diet, rather than an ultra-low carb diet.

Either way, my purpose in writing these posts is this: if we think exogenous ketones alone will be some kind of miraculous silver bullet for Alzheimer’s disease, I think we’re kidding ourselves.

Remember: Amy Berger, M.S., NTP, is not a physician and Tuit Nutrition, LLC, is not a medical practice. The information contained on this site is not intended to diagnose, treat, cure, or prevent any medical condition.