We received a question recently from a gentleman who purchased a custom nutrition plan and wondered about the results. His diet type was Villager, which due to issues with fat metabolism is a largely plant-based diet, but he’d heard that a ketogenic diet was an effective way to reduce risk for Alzheimer’s, and as a carrier of APOE4, he was particularly concerned about which path to take.
We wrote this blog as a reference for future use in case the issue comes up again.
For a deeper dive, check out our first podcast episode titled: Ketogenic diets: the good, the bad and the genetic.
What is APOE4?
The role of the APOE gene in the development of Alzheimer’s disease is something we’ve covered previously on the blog, and the basic information about the various risks associated with the various ε2-4 isoforms is discussed in depth there.
The take-home message is that if you carry two copies of the ε4 isoform of APOE then your risk of developing Alzheimer’s is nineteen times greater. But we should also state that carrying ε4 , even two copies, does not mean you will develop Alzheimer’s. While the association is well established it is not routinely used in clinical diagnoses.
However, in this post, I’m going to try and drill down on one particular issue, namely should ε4 carriers follow or avoid a ketogenic diet. For those of you who aren’t familiar, a ketogenic diet involves eating large amounts of fat in an attempt to transition the body from burning its preferred fuel source, which is glucose, and instead making it rely on ketones (which are a source of energy produced when the body burns fat, as it does during a fast).
Alzheimer’s and glucose metabolism in the brain
The science behind the idea comes from the hypothesis that the development of Alzheimer’s is driven by a dysregulation of glucose metabolism in the brain. Numerous studies have reported that the glucose metabolism is slowed in individuals with Alzheimer’s. There is a lot of evidence demonstrating this association, but in a chicken and egg situation the order of effect isn’t entirely understood yet, i.e. does Alzheimer’s lead to a reduced requirement for glucose in the brain, or does a reduction in glucose metabolism lead to the development of Alzheimer’s?
Some studies provide some evidence for the latter, but the exact impact remains unclear (R).
If a lack of glucose metabolism can indeed lead to Alzheimer’s then attempts to bypass this limitation are very desirable; enter the ketogenic diet.
As we mention above, ketogenic diets are typically very high in fat, very low in carbohydrates with a small amount of protein since the body can actually turn protein into glucose. The aim is to induce the body to use fats rather than the preferred carbohydrates as its energy source by converting fatty acids into ketone bodies.
The hypothesis follows that, as the brain is no longer reliant on glucose for energy, its altered metabolism won’t impact on health.
This idea isn’t actually as far out as it sounds. In fact, epilepsy was often treated with a high-fat low-carb diet until the development of anticonvulsant drugs. Its use as a therapy or co-therapy has even begun to increase again in recent years as the ketogenic diet becomes more mainstream and people want to move away from medication (R). However, just because the ketogenic diet works in epilepsy does not necessarily mean it works in those at greater risk for Alzheimer’s.
Testing the glucose hypothesis
There are actually quite a few studies looking at the effect of ketogenic diets in various Alzheimer models which are covered in detail in this article (R). I’ll briefly go through a few here just to show the effects reported.
By way of background, substances called amyloid plaques, which form in the brain, are thought to be responsible for the development of Alzheimer’s. In a cell culture model, ketone bodies were shown to have a protective effect against a fragment of the amyloid precursor protein (which is toxic to neuronal cells and implicated in the pathology of Alzheimer disease), and even promoted neuronal growth (R).
A similar positive effect has been observed in several mouse models of Alzheimer’s. The most interesting study demonstrated that mice fed a ketone body precursors showed significantly less amyloid and tau deposition in the brain, and also improved learning and memory responses, compared to those on a more traditional carbohydrate based diet (R).
In humans, several small clinical trials have been carried out in individuals with Alzheimer’s or similar disorders. An MCT supplement was able to increase plasma ketone bodies in patients with Alzheimer’s, which correlated with an improved cognitive score. Interestingly this effect was only seen for ε4 negative patients, those who were ε4 saw no positive effect (R). A similar effect was seen when the a specific ketogenic drug was administered, whereby those who were ε4 negative saw an effect but ε4 positive individuals did not (R).
So, based on this evidence, it would appear that a ketogenic diet can have benefits for those with Alzheimer’s, but, and this is a big but for purposes of this blog post, those with APOE4 don’t get the benefits.
Can a ketogenic diet prevent development of Alzheimer’s?
The mouse work and early human studies are certainly positive, and there are in fact several clinical trials ongoing (no data reported yet) looking into this effect (R, R, R, R, R, R). Of these studies two are particularly interesting as they could potentially answer the impact of a ketogenic diet in those at risk, but who currently don’t have Alzheimers (R, R).
So what’s stopping everyone jumping on board the ketogenic diet, especially those who are ε4 positive?
Well firstly, the lack of response in ε4 positive individuals is quite striking. The simple answer may be that the dietary interventions described didn’t last long enough to see an effect in this population, another potential is that the symptoms are more severe in these individuals and so cannot be rescued by a ketogenic diet.
We simply don’t know at this point.
There are also a few other potential issues most notably the fact that elevated LDL cholesterol (and lowered HDL) and other blood lipids may be associated with an increased risk of developing Alzhemiers or associated disorders in later life (R, R, R, R), although this is in itself unclear as trials targeting LDL through statin intake were inconclusive (R, R). This is alongside the other potential health effects associated with high-fat low-carb diets. The bottom line here is that, for some, the ketogenic diet could do some bad things to their lipid markers which would appear to put them at increased risk.
So at the moment it’s a bit of a mixed picture. Based on John’s excellent series of posts about LDL and cholesterol hyper-responders/producers I would predict that there will be a significant variation in response.
People who deal well with a ketogenic diet may in effect nullify their APOE type, whereas those who don’t deal well with such a diet may actually end up increasing their risk. The way to differentiate would appear to be to know how your body metabolizes fat. In other words, are you someone who sees a big spike in metrics like LDL-P when on a high fat diet? If so, the ketogenic diet is more likely to be dangerous, especially in APOE4 carriers where the ketone benefits aren’t established. If however, you can handle a higher fat diet and keep your LDL-P in range, the ketogenic diet may offer some protective effects. From a genetic standpoint, the response to a high fat diet is one of the things we try to gauge with our custom nutrition plan product. Our higher fat diet types, like Urban Grazer and Mosaic, or even California Keto, may stand to benefit from a ketogenic diet in some cases, whereas the Villager, Wyoan and Okinawan diet types would likely be at increased risk.
So it’s a very interesting cutting edge piece of research, we just have to wait for those clinical trials to start reporting and see if we can dive into the data. If you’re looking for some key takeaways / rules, what follows is a good outline to keep in mind:
- A ketogenic diet appears to be beneficial for those with Alzheimer’s (or similar diseases) who do not carry ε4.
- For those with Alzheimer’s, who also carry ε4, no beneficial effect was seen (but this may be due to small sample size).
- For those without Alzheimer’s, elevated LDL cholesterol and APOE-ε4 infer an increased risk for developing dementia, so know your numbers. A poor lipid profile is also a marker for developing Alzheimer’s.
- There is currently no information about how a ketogenic diet will impact those at increased risk, the issue really comes down to the latest science on heart health. if you’re on a ketogenic diet and your LDL-P spikes, you’re not helping yourself.
If we had to end the post with one overarching rule for APOE4 carriers, it would be this: once Alzheimer’s is already present, APOE4 carriers may benefit from a ketogenic diet. However, a ketogenic diet, especially one that is high in saturated fat, is likely a poor strategy for preventing Alzheimer’s disease in APOE4 carriers.