brain

Apart from the well-documented benefits ketogenic diets provide—like weight loss¹, lower blood sugar and blood pressure², and improved cardiovascular risk factors³—people commonly report sharper thinking. Brain fog disappears, and it’s smooth sailing for cognitive function. Is this—no pun intended—all in people’s heads, or is keto genuinely good for the brain?

Your Brain on Glucose & Insulin

There isn’t much published scientific research specifically studying the effects of ketogenic diets on brain function in healthy humans outside the epilepsy world, so we can’t say for certain that keto is “good” for the brain. However, we do have a pretty good idea of what’s not good for the brain: chronically high blood sugar and insulin.

Type 2 diabetes and high blood pressure—two conditions rooted in high blood sugar and/or insulin—are among the risk factors for Alzheimer’s disease (AD). In fact, researchers now regularly call AD “type 3 diabetes,” and you might also come across the term “brain insulin resistance.”^4,5 The links between metabolic syndrome (driven by chronically elevated insulin) and cognitive impairment are so strong that researchers also use the phrase “metabolic-cognitive syndrome.”⁶

The reason AD is called “type 3 diabetes” is that the primary problem in the brain of someone with AD is that neurons in affected regions of the brain are no longer metabolizing glucose properly—that is, they cannot convert glucose into energy, so they’re basically starving for fuel. Calling AD “a brain form of diabetes”⁴ is helpful because it immediately makes a connection to problems with glucose, but it misses what might be an even more important factor in this energy shortage in the brain: chronically high insulin.

Millions of people have normal blood glucose (a.k.a. blood sugar) levels, but very high insulin, and having chronically high insulin—even when blood sugar is normal—is a major risk factor for AD. This is independent of family history or genetics: if you have high insulin most of the time, you have an increased risk for developing AD. According to one study, compared to people with normal insulin levels, those who had high insulin but who were not diabetic had double the risk of developing AD.⁷

What about when your blood sugar is just a little bit higher than normal? What if it’s slightly elevated but not so high that you’ve been diagnosed with diabetes? Here we also see some frightening data. One paper said it pretty clearly: “… even in the absence of manifest type 2 diabetes mellitus or impaired glucose tolerance, chronically higher blood glucose levels exert a negative influence on cognition, possibly mediated by structural changes in learning-relevant brain areas.”⁸ In plain English: people with higher blood glucose had worse cognition than people with lower glucose, and this was probably due to changes in the physical structure of the brain. This echoed earlier research which had similar findings—elevated average blood glucose may be a risk for dementia even at levels lower than the diabetic range.⁹

Alzheimer’s is only the most severe manifestation of the adverse effects of chronically high blood sugar and insulin on the brain. What about when things are in a much milder state? Could this be what we casually call brain fog? When your blood sugar fluctuates wildly throughout the day, it’ll reach some big highs and drop to some precipitous lows. Nervousness, anxiety, confusion, and difficulty speaking are some of the brain-related effects of acute hypoglycemia (low blood sugar).¹⁰

So if chronically high blood sugar has a negative influence on cognition¹¹, then it’s possible that keeping blood sugar within a healthy range could have a protective influence. We can’t say this for certain, but it’s a pretty safe bet that you’re better off having normal levels of blood sugar and insulin compared to chronically high levels of either.

Fueling the Brain

Well-meaning friends and family who tried to steer you away from keto may have peppered you with arguments about the brain “needing carbs,” or perhaps a medical or nutrition professional even warned you that your brain would starve on a low-carb diet because the brain needs 120 grams of glucose every day. Let’s set the record straight on this.

It’s true that your brain needs glucose. There’s no denying that. But a need for glucose doesn’t equate to a need for lots of sweet and starchy carbohydrates in your diet—or any carbs, for that matter. The human body is the ultimate reuse and recycle machine. It’s great at converting things into other things—moving and changing things here and there like some kind of wondrous biochemical Jenga game or Rubik’s cube. (Remember those?!) One of the things your body is great at making out of many different raw materials is glucose. You can make glucose from amino acids (from protein), glycerol (from fats), and from a few other starting points—no bagels, pasta, bread, rice, or cookies required!

One thing is clear: the brain is an energy hog. Sources differ, but as a general ballpark, your brain represents only about 2% of your body weight, but it sucks up nearly 20% of your body’s energy.¹² But does all this energy have to come from glucose, or can the brain use some other fuel instead?

According to researchers, the brain metabolizes about 120 grams of glucose per day “under conditions of normal glucose availability.”¹² But what about under other conditions? What about in someone eating a very low-carb or ketogenic diet?

Well, as I mentioned, your body can make all the glucose it needs in-house. If your brain absolutely required a certain amount of glucose every day and your body couldn’t supply it, no one would ever survive more than a day or two of fasting. So either your body has no problem generating 120 grams of glucose in the total absence of dietary carbohydrate, or maybe your brain doesn’t need quite that much glucose if it’s being fueled by something else.

In addition to being great at recycling, your body—and brain—are like hybrid cars. They adapt to running on whatever fuel you give them. Most cells in your body can use glucose, fats, or ketones. Your brain can use glucose and just a small amount of fat, but it’s a champ at using ketones. Look at this breakdown of how much of your brain’s energy supply comes from ketones at different blood levels of beta-hydroxybutyrate (βOHB).

Data from reference 12.

Even people not on ketogenic diets could achieve a blood ketone level of 0.3–0.5 mM or higher if they do a hard workout and it’s been a few hours since their last meal. 1.5 mM is easily achievable when carbs are very low. The higher numbers in this table would likely only be seen in someone doing an extended fast, but levels in between—2.0–4.0 mM, for example—could provide a substantial amount of fuel for the brain and are not unheard of in people doing strict ketogenic diets.

Is it essential to be in ketosis, then? No. A few billion people all over the world who have a healthy cognitive function but who are not on ketogenic diets show us this implicitly. But based on the research we explored earlier, what probably is needed for healthy cognition throughout life is maintaining healthy blood sugar and insulin levels. Keto is certainly one way to do that, but everyone’s carb tolerance varies. Some people will have to stay ultra-low-carb most of the time; others can be more generous.

Exciting Research in Alzheimer’s and Traumatic Brain Injury

Getting back to the association between diabetes, metabolic syndrome (MetSyn), and cognitive impairment, some small-scale research suggests that ketogenic diets and other lifestyle interventions that help correct MetSyn may also improve cognitive function. Ketogenic diets combined with exercise, intermittent fasting, or brain training games were shown to reverse mild cognitive impairment (MCI, the precursor to Alzheimer’s) in three subjects, one with type 2 diabetes and two with MetSyn.^13,14,15 The diabetes and MetSyn were also greatly improved, and while we can’t say for certain that those improvements caused the reversal of cognitive impairment, it’s a plausible hypothesis.

Most of the research looking at ketones as an alternative brain fuel to glucose in Alzheimer’s disease have used exogenous ketones or MCT oil rather than ketogenic diets. This is disappointing but understandable. It can be difficult even for young, healthy, able-bodied people to adhere to strict ketogenic diets. Now imagine someone with cognitive impairment, who might also have limited mobility and capacity to cook. Caregivers already face heavy burdens in looking after their loved ones; trying to force them to make dietary changes they’re opposed to only makes things harder. Plus, by using exogenous ketones or MCT oil without changing someone’s diet, researchers narrow down confounding issues that might cloud the results. If a subject’s cognition improves when their ketone levels are elevated from MCT oil or exogenous ketones, then it’s more likely that it’s a direct result of the ketones and not something else, like weight loss, better blood sugar control, less inflammation, or other things we know keto typically leads to.

Elevated ketones, by themselves, aren’t a slam dunk for radically improving Alzheimer’s or cognitive impairment. But let’s not dismiss even minor beneficial effects, especially considering that right now, there are no effective treatments for AD. Generally speaking, these studies show that at least some people have improved cognition when their ketone levels are elevated.^16-19 In MCI, the brain energy deficit is specific to glucose, and “at least partially correcting this deficit with ketones results in cognitive improvements.”¹⁶

Ketogenic diets and exogenous ketones also show potential in improving recovery from traumatic brain injury (TBI). Almost all the research in this area has been done in animals, but it’s encouraging and holds promise for people affected by these devastating injuries. TBI and AD have a surprising amount of overlap, first and foremost, a reduced capacity of the brain to convert glucose into energy.^20-22 TBI also results in increased free radicals, mitochondrial damage, an increased need for antioxidants, increased susceptibility to neuronal death, and other issues that ketones themselves or the collective effects of ketogenic diets can address.²³

Using ketogenic diets or exogenous ketones as therapy in TBI is in its infancy, but one thing that has been well known for a while is that higher blood sugar is associated with worse outcomes in TBI patients. So why not adopt a nutritional strategy that keeps blood sugar in a healthy range and gives neurons an alternative fuel to glucose? Research in animals and humans suggests that a switch to a ketogenic state might help to protect damaged neurons.^20,24

Spotlight on Vitamin B12 and Choline

Vitamin B12 is a crucial factor for anyone concerned about brain health and cognitive function. Outright B12 deficiency and milder subclinical insufficiency are common, particularly among older people who may be consuming fewer foods rich in B12, and whose digestive capacity may be waning, making them less able to absorb B12 from the foods they do consume. Inadequacy of this critical nutrient comes with a long list of signs and symptoms, including confusion, memory loss, dementia, dizziness, altered mental status, depression, apathy, paranoia, mania, delusions, psychosis, and hallucinations.²⁵ So yes, it’s fair to say that suboptimal B12 status could have a major impact on the brain.

With this in mind, it’s possible that raising B12 levels is another way keto may be beneficial for the brain, entirely separate from its influence on blood glucose, insulin, and ketones. An omnivorous ketogenic diet that includes red meat, eggs, pork, seafood or shellfish, provides plenty of B12. People may have been eating these foods all along, even before keto, but when sugary and starchy carbs are off the menu, replaced by fats and proteins, it’s possible people get more B12 than they did before.

Consuming foods rich in B12 doesn’t guarantee your blood levels will increase or be maintained at healthy levels, though. As we mentioned in a previous article, eating certain foods doesn’t automatically mean you’ll digest them effectively and absorb the nutrients they contain. So if you know you have compromised digestive function, consider getting your B12 level checked (it’s a simple blood test), and take supplements if warranted. B12 is found only in foods from the animal kingdom, so lacto-ovo vegetarians can get B12 from eggs and dairy products, but strict vegans must supplement.

Choline is another nutrient critical for brain health and neurological function. It’s an essential part of all cell membranes, and is a precursor to acetylcholine, a neurotransmitter that affects “memory, mood, muscle control, and other brain and nervous system functions.”²⁶ Patients with Alzheimer’s may have lower levels of acetylcholine compared to healthy people, and one class of drugs used to treat AD is designed to reduce the breakdown of this critical compound.²⁷

Your body synthesizes choline, but only in small amounts—not enough to meet the full demands, so you need to get some from your diet. Some of the richest sources of choline are the foods commonly consumed on ketogenic diets: eggs, red meat, pork, seafood, plus nuts and seeds, broccoli, and Brussels sprouts. Plant foods contain choline, but animal foods are more concentrated sources. To the extent that increased dietary choline may be providing more raw material for acetylcholine, this might be another way low-carb or ketogenic diets may be beneficial for the brain.

Conclusion

Ketogenic diets are impressive for helping people lose weight, banish acid reflux²⁸, reverse non-alcoholic fatty liver²⁹, improve hormone balance in PCOS^30,31, and for many other health issues. It stands to reason that this very low-carb way of eating would also be beneficial for the brain. So if you’re doing keto and you’ve noticed improved mental clarity and cognitive sharpness, it is in your head—and in the rest of your body, too.

Wondering how keto affects mental health? Stay tuned. We’ll cover that in a future article.

References:

1. Staverosky T. Ketogenic Weight Loss: The Lowering of Insulin Levels Is the Sleeping Giant in Patient Care. J Med Pract Manage. 2016;32(1):63-66.
2. Westman EC, Tondt J, Maguire E, Yancy WS Jr. Implementing a low-carbohydrate, ketogenic diet to manage type 2 diabetes mellitus. Expert Rev Endocrinol Metab. 2018;13(5):263-272. doi:10.1080/17446651.2018.1523713.
3. Bhanpuri NH, Hallberg SJ, Williams PT, et al. Cardiovascular disease risk factor responses to a type 2 diabetes care model including nutritional ketosis induced by sustained carbohydrate restriction at 1 year: an open label, non-randomized, controlled study. Cardiovasc Diabetol. 2018;17(1):56. doi:10.1186/s12933-018-0698-8.
4. de la Monte SM. The Full Spectrum of Alzheimer’s Disease Is Rooted in Metabolic Derangements That Drive Type 3 Diabetes. Adv Exp Med Biol. 2019;1128:45-83. doi:10.1007/978-981-13-3540-2_4.
5. Frazier HN, Ghoweri AO, Anderson KL, Lin RL, Porter NM, Thibault O. Broadening the definition of brain insulin resistance in aging and Alzheimer’s disease. Exp Neurol. 2019;313:79-87. doi:10.1016/j.expneurol.2018.12.007.
6. Frisardi V, Solfrizzi V, Seripa D, et al. Metabolic-cognitive syndrome: a cross-talk between metabolic syndrome and Alzheimer’s disease. Ageing Res Rev. 2010;9(4):399-417. doi:10.1016/j.arr.2010.04.007.
7. Luchsinger JA, Tang MX, Shea S, Mayeux R. Hyperinsulinemia and risk of Alzheimer disease. Neurology. 2004;63(7):1187-1192. doi:10.1212/01.wnl.0000140292.04932.87.
8. Kerti L, Witte AV, Winkler A, Grittner U, Rujescu D, Flöel A. Higher glucose levels associated with lower memory and reduced hippocampal microstructure. Neurology. 2013;81(20):1746-1752. doi:10.1212/01.wnl.0000435561.00234.ee.
9. Crane PK, Walker R, Hubbard RA, et al. Glucose levels and risk of dementia. N Engl J Med. 2013;369(6):540-548. doi:10.1056/NEJMoa1215740.
10. Mayo Clinic. Diabetic Coma. Accessed Aug 31, 2020 from https://www.mayoclinic.org/diseases-conditions/diabetic-coma/symptoms-causes/syc-20371475.
11. Saedi E, Gheini MR, Faiz F, Arami MA. Diabetes mellitus and cognitive impairments. World J Diabetes. 2016;7(17):412-422. doi:10.4239/wjd.v7.i17.412.
12. Hashim SA, VanItallie TB. Ketone body therapy: from the ketogenic diet to the oral administration of ketone ester. J Lipid Res. 2014;55(9):1818-1826. doi:10.1194/jlr.R046599.
13. Stoykovich S, Gibas K. APOE ε4, the door to insulin-resistant dyslipidemia and brain fog? A case study. Alzheimers Dement (Amst). 2019;11:264-269. doi:10.1016/j.dadm.2019.01.009.
14. Dahlgren K, Gibas KJ. Ketogenic diet, high intensity interval training (HIIT) and memory training in the treatment of mild cognitive impairment: A case study. Diabetes Metab Syndr. 2018;12(5):819-822. doi:10.1016/j.dsx.2018.04.031.
15. Brown D, Gibas KJ. Metabolic syndrome marks early risk for cognitive decline with APOE4 gene variation: A case study. Diabetes Metab Syndr. 2018;12(5):823-827. doi:10.1016/j.dsx.2018.04.030.
16. Croteau E et al. A cross-sectional comparison of brain glucose and ketone metabolism in cognitively healthy older adults, mild cognitive impairment and early Alzheimer’s disease. Exp Gerontol. 2018 Jul 1;107:18-26.
17. Fortier M, Castellano CA, Croteau E et al. A ketogenic drink improves brain energy and some measures of cognition in mild cognitive impairment. Alzheimers Dement. 2019 May;15(5):625-634.
18. Cunnane SC, Courchesne-Loyer A, Vandenberghe C, et al. Can Ketones Help Rescue Brain Fuel Supply in Later Life? Implications for Cognitive Health during Aging and the Treatment of Alzheimer’s Disease. Front Mol Neurosci. 2016;9:53. doi:10.3389/fnmol.2016.00053.
19. Cunnane SC, Courchesne-Loyer A, St-Pierre V, et al. Can ketones compensate for deteriorating brain glucose uptake during aging? Implications for the risk and treatment of Alzheimer’s disease. Ann N Y Acad Sci. 2016;1367(1):12-20. doi:10.1111/nyas.12999.
20. Prins M. Diet, ketones, and neurotrauma. Epilepsia. 2008;49 Suppl 8(Suppl 8):111-113. doi:10.1111/j.1528-1167.2008.01852.x
21. Bernini A, Masoodi M, Solari D, et al. Modulation of cerebral ketone metabolism following traumatic brain injury in humans. J Cereb Blood Flow Metab. 2020;40(1):177-186. doi:10.1177/0271678X18808947.
22. Prins ML, Matsumoto JH. The collective therapeutic potential of cerebral ketone metabolism in traumatic brain injury. J Lipid Res. 2014;55(12):2450-2457. doi:10.1194/jlr.R046706.
23. Greco T, Glenn TC, Hovda DA, Prins ML. Ketogenic diet decreases oxidative stress and improves mitochondrial respiratory complex activity. J Cereb Blood Flow Metab. 2016;36(9):1603-1613. doi:10.1177/0271678X15610584.
24. Miller VJ, Villamena FA, Volek JS. Nutritional Ketosis and Mitohormesis: Potential Implications for Mitochondrial Function and Human Health. J Nutr Metab. 2018;2018:5157645. doi:10.1155/2018/5157645.
25. Pacholok, S and Stuart J. Could It Be B12? An Epidemic of Misdiagnoses. Quill Driver Books, Linden Publishing, Inc. Fresno, CA, 2011.
26. S. Department of Health and Human Services. National Institutes of Health, Office of Dietary Supplements. Choline Fact Sheet for Health Professionals. Updated July 2020. Accessed Aug 31, 2020 from https://ods.od.nih.gov/factsheets/Choline-HealthProfessional/.
27. Oregon State University. Linus Pauling Institute Micronutrient Information Center. Choline. Updated Jan 2015, accessed Aug 31, 2020 from https://lpi.oregonstate.edu/mic/other-nutrients/choline.
28. Pointer SD, Rickstrew J, Slaughter JC, Vaezi MF, Silver HJ. Dietary carbohydrate intake, insulin resistance and gastro-oesophageal reflux disease: a pilot study in European- and African-American obese women. Aliment Pharmacol Ther. 2016;44(9):976-988. doi:10.1111/apt.13784.
29. Luukkonen PK, Dufour S, Lyu K, et al. Effect of a ketogenic diet on hepatic steatosis and hepatic mitochondrial metabolism in nonalcoholic fatty liver disease. Proc Natl Acad Sci U S A. 2020;117(13):7347-7354. doi:10.1073/pnas.1922344117.
30. Mavropoulos JC, Yancy WS, Hepburn J, Westman EC. The effects of a low-carbohydrate, ketogenic diet on the polycystic ovary syndrome: a pilot study. Nutr Metab (Lond). 2005;2:35. doi:10.1186/1743-7075-2-35.
31. Paoli A, Mancin L, Giacona MC, Bianco A, Caprio M. Effects of a ketogenic diet in overweight women with polycystic ovary syndrome. J Transl Med. 2020;18(1):104. doi:10.1186/s12967-020-02277-0.