“In older people, brain glucose metabolism deteriorates regionally years before the onset of cognitive decline, but plasma glucose remains normal or somewhat elevated. Hence, during aging, hypoglycemia and hypoinsulinemia which are the normal stimuli for ketogenesis are less activated even though the brain is not receiving sufficient glucose, so it experiences a chronic metabolic demand that is unmet. Our present results suggest that a ketogenic intervention could, at least in principle, correct or bypass this brain glucose hypometabolism.” (Courchesne-Loyer et al, 2017)

It is taken for granted in the Alzheimer’s research world but less well appreciated among the general public that a primary hallmark of the Alzheimer’s brain is a dramatic reduction in cerebral glucose metabolism. This energy deficit is specific to glucose, and it’s been well-established that in mild cognitive impairment (MCI) and mild-to-moderate Alzheimer’s disease (AD), brain uptake and metabolism of ketones is not impaired. Since ketones can serve as an alternative fuel substrate to glucose in most body tissues but especially in the brain, and since the brain takes up ketones in direct proportion to their plasma level, it’s reasonable that interventions that raise plasma ketone levels may have a beneficial impact on cognitive function.

Ketogenic dieters and biohackers looking for a cognitive edge have been testing this for themselves for a while by adding coconut oil or medium chain triglyceride (MCT) oil to their coffee, tea, or other beverage or food. MCTs are triglyceride molecules consisting of medium chain fatty acids (MCFAs), which include caproic acid (C6), caprylic acid (C8), and capric acid (C10). Opinions differ on whether lauric acid (C12) should be classified as a MCFA; wherever one lands on this issue, lauric acid is the predominant fatty acid in coconut oil, which is known to raise ketone levels.

MCTs are uniquely suited for raising ketone levels because they’re metabolized differently than other fats. They don’t require emulsification with bile and are absorbed directly into the portal vein, rather than via the lymphatic system. The liver rapidly converts their constituent fatty acids to ketones and then exports these ketones for use by other tissues. And for tissues that use the MCFAs even when they’re not converted into ketones, MCFAs can enter mitochondria without using the carnitine transport system, making them a readily usable source of energy.

Regarding the effect of MCTs on cognitive function, specifically, it’s been shown in cultured mouse astrocytes that lauric acid is metabolized to ketones, and evidence indicates there’s an astrocyte-neuron ketone body shuttle in humans, whereby ketones produced in astrocytes are exported for use by neurons. This is important to keep in mind, because any ketogenesis localized within the brain itself is not measurable by home ketone monitoring methods, such as blood meters (which measure beta-hydroxybutyrate) or urine test strips (which measure acetoacetate). Brain ketone metabolism induced by MCTs could be an important factor in addressing the cerebral energy shortage in MCI and AD.

This is all well and good in theory, but what about in practice? Anecdotal reports from young, healthy Silicon Valley execs feeling a “brain boost” from putting MCT oil in their morning coffee are interesting, but what about real-world applications? What do studies tell us about the effect of MCTs on cognition in people where it matters most: those with some form of cognitive impairment or dementia? The good news is, MCT research is quite promising, especially compared to the list of Alzheimer’s drugs that have failed to have any beneficial impact, which is long and still growing, with at least one company waving the white flag and giving up entirely on research into new drugs for the condition.

MCT formulations raise plasma ketone levels and increase brain ketone metabolism; there’s no doubt about that. The next question is, does this increase in ketone levels lead to improved cognition in people with MCI or AD? The answer, in most cases, is yes, but the improvements aren’t quite enough to make headline news just yet. Generally speaking, in most studies, administration of MCT formulas results in significant improvements scores on AD assessments, such as the mini-mental state exam (MMSE) and MoCA (Montreal Cognitive Assessment), but the effects vary substantially among individual subjects, and multiple studies indicate that subjects who are not carriers of the ApoE4 allele show greater improvement than ApoE4-positive subjects. (The ApoE4 gene is currently the strongest known genetic risk factor for AD.)

A study published earlier this year showed that, compared to placebo, MCT oil dosed at 30g/day for 6 months “bypasses a significant part of the brain glucose deficit and improves several cognitive outcomes in MCI.” The MCT oil resulted in a 230% increase in total brain ketone metabolism (measured by PET scan). Cognitive scores in several tested domains improved in direct relation to the increase in plasma ketones and/or brain ketone uptake. The improvement is attributed to the presence of ketones because brain glucose metabolism was unchanged, so the energy deficit at the heart of MCI and AD can be at least partially mitigated through MCT-derived ketones.

Since there are a few different types of MCFAs that can be incorporated into an MCT oil or other MCT delivery system, and these individual fatty acids have unique properties, more research may point toward optimal ratios of different types of MCFAs for different purposes. For example, it was shown in healthy adults that tricaprylin (MCTs composed exclusively of C8) increased plasma ketones more than coconut oil or MCTs consisting of C8 and other MCFAs. One study showed that C8 increased ketogenesis in cultured human astrocytes while C10 did not, but C10 increased astrocyte glycolysis, with the resulting lactate exported to neurons for fuel. These are nuances that will need to be researched further in in vivo studies to determine if C8 is more effective not only for increasing ketone levels, but for improving cognition, which is the desired goal from raising ketones in the first place.

In studies employing MCT oil, there are typically no serious adverse events reported. The most common reason cited for noncompliance or for dropping out of such studies is GI distress. Diarrhea, loose stools, and nausea are frequently reported from MCT oil use. These can be ameliorated somewhat by taking the oil as part of a meal rather than in isolation, and by increasing the dose slowly over time.

In the interest of fairness, some trials employing MCT formulas have failed to show a cognitive benefit in AD patients, except for very mild improvement specifically in non-carriers of the ApoE4 allele. It may be that ketones alone, while helpful and effective for “statistically significant” improvement in some cases, may not be powerful enough to have a clinically relevant impact on cognition in AD patients. With growing recognition of the role of insulin resistance as a pathological factor in this illness (and even the phrase “type 3 diabetes” to describe it), there’s reason to suspect that a ketogenic diet may be a beneficial intervention for AD patients. Ketogenic diets would improve insulin sensitivity and glycemic regulation while inducing endogenous ketone synthesis, which could be augmented by MCT supplementation or use of exogenous ketone salts. Preliminary but promising research on ketogenic diets for AD is underway, with encouraging results so far.