In part 1 of this look at Alzheimer's disease (AD), I introduced the concept of Alzheimer's as a metabolic condition. The primary driver of the disease pathology, and what's mainly responsible for the memory loss, cognitive impairment, personality changes and other signs and symptoms, is that neurons in affected regions of the brain become unable to effectively metabolize glucose.
Since, under normal circumstances, glucose is the brain's primary fuel, when neurons lose the ability to metabolize it, they essentially starve. And remember, the brain needs a large and constant supply of energy—even when you're just lying around watching TV or sleeping, when you think your brain isn't doing much, it's still using lots of energy.
I left off in part 1 emphasizing that the energy shortage in the brain is specific to glucose, and proposing that it would be possible to nourish these starving cells if there were some type of alternative fuel they could use. One of the bright spots in the darkness that is Alzheimer's disease is that these struggling, atrophied neurons can still metabolize ketones!
"When glucose utilization is impaired in neurodegenerative diseases, transport of KBs [ketone bodies] into the brain appears to be less affected and their utilization for energy by the brain mitochondria is not impeded by such factors as local insulin resistance that, by interfering with the neuronal fuel supply, may contribute to the progressive nerve cell damage observed in Alzheimer's disease" (1).
Ketones as Brain Fuel
Under certain circumstances, ketones can provide as much as 60% of the brain's energy (1). It may be that such a large portion of the brain's energy needs can only be met by ketones when ketone levels are relatively high—higher, perhaps, than most people would be able to achieve through a ketogenic diet alone.
But while the brain's use of glucose is compromised, it's not completely destroyed. Some glucose is still metabolized, so even if ketones only contribute a small amount of available energy, it's still a boost to cognitive function.
Do Ketone Levels Matter?
Uptake of ketones into the brain is directly proportional to the blood concentration of beta-hydroxybutyrate (βOHB) and acetoacetate: the higher the ketones, the more the brain will take them in.
During a prolonged fast, serum βOHB levels can reach 5-7 mmol/L (1). At a βOHB concentration of 1.5 mM, ketones supply about 18% of the brain's energy; 60% is achievable at 6 mM (2). However, people vary in the level of ketones they might respond to. Some people might notice improved cognition with relatively low ketones, while others will need to get their ketones elevated higher in order to experience a benefit for the brain.
Elevating Ketones is Beneficial for Alzheimer's
Elevated ketones clearly reduce the amount of glucose the brain requires. It would be difficult for an older individual to achieve a ketone level of 6 mM with a ketogenic diet alone, but a KD in conjunction with exogenous ketones or additional MCT oil could provide the brain with a substantial fuel supply.
Fortunately, we don't have to rely solely on mouse models and petri dish studies to assess whether ketones can be beneficial for people with AD or its precursor, mild cognitive impairment (MCI), although that evidence exists, and it's promising (3).
Several studies in human subjects with AD have shown that elevated ketones do lead to improved cognition. Many such studies have employed exogenous ketones, but some have used medium-chain triglyceride (MCT) oil or a ketogenic diet, and there's evidence that all three approaches can be effective.
The Ketogenic Diet without Ketone Supplementation
In a small study of adults with MCI, six weeks of following a ketogenic diet (~34g carbs per day) resulted in significant decreases in body weight waist circumference, fasting glucose, and fasting insulin. The reduced insulin had a small correlation with improved memory (4). The authors wrote:
"These findings indicate that very low carbohydrate consumption, even in the short-term, can improve memory function in older adults with increased risk for Alzheimer's disease. While this effect may be attributable in part to correction of hyperinsulinemia, other mechanisms associated with ketosis such as reduced inflammation and enhanced energy metabolism also may have contributed to improved neurocognitive function" (4).
In a different study of subjects with AD or MCI, subjects following a standard diet consumed a beverage containing emulsified MCTs, and then they completed some of the formal assessments for AD. In subjects without the ApoE4 gene, compared to placebo, the MCT drink resulted in improved scores on the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) (5). Subjects with the ApoE4 gene improved only in one test, for paragraph recall. (In all subjects, regardless of ApoE genotype, higher ketones correlated with better recall.)
As I explained in part 1, carriers of the E4 gene are likely the least suited to the modern high-carb diet. With this in mind, it may be that elevating their ketone levels via one-time MCT administration is not sufficient to improve cognition in an acute setting. We'll look at MCT oil and exogenous ketones in more detail in a bit. Before leaving this study, though, it's important to note that the MCT treatment resulted in a mean βOHB level of only 0.5 mmol/L. This isn't all that high.
According to well-known low carb researchers Stephen Phinney and Jeff Volek, 0.5 mM is the very bottom of the cutoff for nutritional ketosis (0.5-5.0 mM) (6), so it's possible that subjects would have had even better improvement in cognitive assessments if their ketone levels were higher.
A separate study of an MCT oil preparation had similar but more promising findings. In subjects with mild-to-moderate Alzheimer's, compared to placebo, daily consumption of the MCTs for 90 days resulted in significant improvements in multiple cognitive assessments, with improvements being greatest in non-ApoE4s who were compliant with dosing (7). ApoE4 gene carriers showed no significant improvements.
The Limitations of Studies Involving Ketone Supplements
A major flaw of this study is that subjects were advised to mix the packets they were given (either the MCT or placebo) in 8 ounces of water, juice or milk. As if that weren't bad enough, to increase compliance and palatability, they were later recommended to mix them into Ensure™, which is notoriously loaded with sugar! Taking this into account, it's heartening they showed any cognitive improvement at all!
This is a major flaw of almost all studies involving MCTs and exogenous ketones, actually: these compounds are typically added to subjects' habitual diets, which are usually a standard Western or American diet, high in refined carbs and omega-6-rich seed oils.
That we see any improvement solely from slightly elevated ketones is encouraging. It shouldn't surprise us that some people with Alzheimer's don't show improvement with no other intervention besides elevated ketones; what should surprise us is that so many do.
Can Ketones Help ApoE4s?
It's true that most of the studies looking at MCTs for Alzheimer's show more favorable results for non-ApoE4s than for E4s. People with the E4 gene, however, do experience improved cognition under certain circumstances.
The most encouraging example of this was Mr. Steve Newport, husband of Mary Newport, MD, author of The Coconut Oil and Low-Carb Solution for Alzheimer's, Parkinson's, and Other Diseases (8). Mr. Newport was an ApoE4 carrier, and he experienced rapid and dramatic improvements in several aspects of cognitive function and performance of tasks for everyday living after being treated first with coconut oil and later with a ketone ester (9).
When Dr. Newport first became aware of the research on ketones for brain health and cognitive function, she added coconut oil to her husband's morning oatmeal. With just that small change—adding coconut oil to a high-carbohydrate diet-she noticed enough of an improvement to continue, increase the dose over time, and eventually progress to using a ketone ester, still in the context of a relatively high-carb diet. The ketone ester allowed Mr. Newport to experience βOHB levels as high as 7.0 mM (9).
The dramatic elevation of ketones resulted in him being able to perform tasks he had been unable to perform unaided for several months, such as shaving and showering. As improvements continued, he was able to perform more complex tasks, such as yardwork and other household chores, as well as "spontaneously discussing events that occurred up to a week earlier." Abstract thinking and his sense of humor returned, and he self-reported feeling well, having more energy, feeling happier, and finding it "easier to do things"-all of which Dr. Newport's observations corroborated (9).
Sadly, Mr. Newport lost his battle with Alzheimer's in January 2016, but his quality of life and that of his loved ones and caregivers were improved by his substantially improved cognitive function owing to their experiments with regularly elevated ketones. (You can watch Dr. Newport's fascinating account of her husband's remarkable improvement with ketone treatment here.)
ApoE4 May Need More Than Ketone Supplements
Recall from part 1 that people with the ApoE4 gene are believed to be the least suited for the modern high-carb diet. If this is true, then it's no surprise that most E4 carriers show little to no improvement from interventions that elevate ketones a single time in a laboratory, or even from interventions that elevate ketones for an extended period of time but do nothing else, especially when this happens in the context of the usual high-carb diet.
If the E4 gene is a product of the hunter-gatherer environment, then elevated ketones, by themselves, might not be enough to have a noticeable impact on cognition in E4s with Alzheimer's. It may be that E4s have to adopt several other changes that would help restore their metabolism and hormonal milieu to something more befitting them, including better quality and quantity of sleep, stress reduction, increased physical activity, fasting, and repletion of vitamins and minerals they may be deficient in.
"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." (10)
Individuals with the ApoE4 gene are having remarkable success using a mild ketogenic diet and multifactorial lifestyle intervention protocol created by Dale Bredesen, MD, and outlined in his book, The End of Alzheimer's (11).
Ketogenic Diet Versus Exogenous Ketones
Raising ketone levels via coconut oil, MCT oil, or exogenous ketones can be a gift to those suffering from Alzheimer's. Elevated ketones have clearly been shown to result in improved cognition; however, this is a short-term fix.
It's putting a band-aid on a sucking chest wound. Ketones are metabolized fairly rapidly; once they're gone from the bloodstream, so are their beneficial effects. For elderly people, or people with very advanced and severe dementia, exogenous ketones can still have a powerful acute effect. But contrast this with a ketogenic diet, which would have someone generating endogenous ketones all the time.
Not only would a ketogenic diet help someone have elevated ketones around the clock, instead of only after using exogenous ketones, but the KD also induces a host of other effects that exogenous ketones can't mimic.
Ketogenic diets are anti-inflammatory, they reduce glucose and insulin levels, reduce formation of reactive oxygen species ("free radicals"), may help increase mitochondrial biogenesis (making new mitochondria), enhance glutathione levels in the brain, and more (12,13,14).
By providing βOHB to fuel languishing neurons, exogenous ketones help make up for the glucose fuel deficit, and we shouldn't downplay the significance of this, but they don't result in any of the other long-term benefits of the KD. For the purpose of improving cognitive function in AD, elevating ketones is probably the most important step, but it's not the only one. The diet has several effects that can't be mimicked solely by exogenous ketones or ketones induced via MCT oil. It would be a major blockbuster, but as of yet, there is no "ketogenic diet in a pill" (14).
Bottom line: exogenous ketones are an adjunct to, not a substitute for, a ketogenic diet. But for those of very advanced age or with severe impairment, who can't or won't change their diet, exogenous ketones are worth trying.
Special Considerations on the Ketogenic Diet for Alzheimer's
In order to help a loved one implement a ketogenic diet, you have to have complete control over their diet. It will be virtually impossible if the afflicted individual lives in a care facility where their food is provided for them. In situations where supportive family members and friends can help with food shopping and meal preparation, the younger someone is, and the more mild their degree of cognitive impairment, the more likely they are to experience improvements from a ketogenic diet, and the easier it will be to implement one.
The older an individual, and the more severe their impairment, the more difficult it will be to change their diet. People with advanced Alzheimer's may be belligerent and uncooperative, making it almost impossible to have them adhere to a KD. Big changes in diet can be difficult enough when we want to change; forcing a change upon someone who does not want it is an exercise in frustration and futility.
Alzheimer's disease is striking people at ever younger ages, but it still primarily strikes those who are older. With that in mind, here are some things to consider when implementing a KD for improving cognitive function:
Digestive Fire Naturally Decreases with Age
The increase in fat, and, for some people, protein, might take some getting used to for someone accustomed to living on cereal, pasta, bread, and fruit. In order to get the best benefits from a KD, older people may need digestive support in the form of supplemental HCl (betaine HCl), ox bile, or digestive enzymes, all of which are available online or at health food stores.
Many Older Individuals are Underweight
For those in this category, be sure they're getting enough calories. Protein should not be restricted in the underweight, and fasting is not recommended. Higher ketones can be achieved with liberal intake of coconut or MCT oil, rather than with fasting or limiting protein.
Some Drugs May Hinder Progress
Certain pharmaceutical drugs common among older people may hinder progress. Statin drugs and prescription antacids are two of the most common. Work with a physician to see if it is prudent to continue the medication or if they can be discontinued. (Remember: 25% of all the body's cholesterol is in the brain! You cannot have healthy cognitive function without adequate cholesterol. Regarding antacids, what's the point of someone eating a nutrient-dense, cognition-supporting diet if they also take a drug that impairs healthy digestion and absorption of those nutrients?)
Emotional Support is Crucial
People of all ages can benefit from having a "diet buddy" - someone else in the same household who will follow a ketogenic diet along with them, or perhaps do a slightly more liberal variation of a low-carb diet.
Don't underestimate the importance of emotional support and solidarity; this can make adhering to the diet easier. Considering the myriad issues these ways of eating are beneficial for, the whole family can be involved. Even for those with no known health issues and who are not overweight, no one's health ever got worse from eliminating refined sugar and processed food from their diet.
Take Home Message: There is Hope
The ketogenic diet is not a slam dunk for Alzheimer's. There are still unanswered questions, and much research remains to be done. But considering there are no effective pharmaceuticals and no effective alternatives for people living with AD, keto may be worth trying.
That people with mild cognitive impairment and Alzheimer's Disease do show improved cognition when ketones are elevated is proof that their withering, atrophied neurons aren't dead; they're hibernating. It's as if they're in "powersave mode," downregulating non-essential functions to conserve energy until they receive enough fuel to bring everything back online. According to Alzheimer's researcher Stephen Cunnane and colleagues:
The brain energy deficit in Alzheimer's "can at least in part be bypassed by ketogenic treatments. A core element of this interpretation is that brain cells and/or networks that were previously dysfunctional can start to function more normally again once they are provided with more fuel, i.e., they were starving or exhausting but not dead; otherwise this cognitive improvement would not be possible" (15).
If the primary pathological feature of Alzheimer's disease is reduced glucose usage in the brain, then the logical first step is to provide the brain with an alternative fuel, in the form of ketones.
If you'd like to learn more about Alzheimer's disease as "type 3 diabetes" and the potential therapeutic use of ketones and the ketogenic diet, consider exploring my book, The Alzheimer's Antidote: Using a Low-Carb, High-Fat Diet to Fight Alzheimer's Disease, Memory Loss, and Cognitive Decline.
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- Amy Berger, MS, CNS, NTP
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