Evidence continues to mount that a ketogenic diet may be an effective nutritional intervention for Alzheimer’s disease (AD) and its precursor, mild cognitive impairment (MCI).  For those familiar with the pathology of these conditions, using a ketogenic diet is an elegant and scientifically sound way to fuel the brain.  After all, the fundamental problem in this condition is that neurons in affected regions of the brain lose the capacity to harness sufficient energy from glucose.  In some individuals with AD, the brain may be metabolizing as much as 45% less glucose than the brain of a healthy person.  For this reason—and others related to peripheral and cerebral insulin resistance, Alzheimer’s disease is often referred to as “type 3 diabetes.”    

Alzheimer’s and Mild Cognitive Impairment are Energy Shortages in the Brain

MCI and AD can be thought of as “fuel shortages” or “energy crises” in the brain.  In people following a mixed macronutrient diet, or a “standard American diet,” which is typically high in carbohydrates, glucose is a primary fuel for the brain.  So, when affected neurons become unable to metabolize glucose, the logical outcome is precisely the kind of memory loss, confusion, personality changes, and behavioral disturbances seen in these conditions.  What is too often relegated to biochemistry textbooks and research laboratories, and not talked about enough in the offices of neurologists and geriatricians, is that in people following a ketogenic diet, ketones can provide as much as 60% of the brain’s energy supply.

It’s important to note that the energy shortage in these forms of cognitive decline is specific to glucose.  The brains of individuals with MCI or AD still take up and use ketones.  This is why dramatic improvements have been observed in individuals with Alzheimer’s or MCI who follow ketogenic diets or take exogenous ketone supplements (in the form of beta-hydroxybutyrate esters or salts).  Ketone entry into the brain, and then into neurons, is not impacted by alterations in insulin sensitivity and glucose transport that affect brain glucose uptake.   

Alzheimer’s researchers are well aware of the powerful potential for ketones to supply abundant energy to the starving, atrophying brain in MCI and AD:

“…two points are clear – (i) AD is at least in part exacerbated by (if not actually caused by) chronic, progressive brain fuel starvation due specifically to brain glucose deficit, and (ii) attempting to treat the cognitive deficit early in AD using ketogenic interventions in clinical trials is safe, ethical, and scientifically well-founded.” (Cunnane et al., 2016)

“…the deterioration in brain energy metabolism is specific to glucose. These results suggest that a ketogenic intervention to increase energy availability for the brain is warranted in an attempt to delay further cognitive decline by compensating for the brain glucose deficit in MCI and AD.” (Croteau et al., 2017)

Beyond fueling the brain: multiple beneficial effects of ketones & ketogenic diets

The ability of ketones to fuel a struggling brain would be enough of a reason for afflicted individuals to implement a trial of a ketogenic diet and/or experiment with exogenous ketones.  But the benefits of a ketogenic diet for brain health go beyond simply providing an alternative fuel to glucose. 

Beta-hydroxybutyrate (βOHB) has anti-inflammatory effects.  This molecule “holds promise in reducing the severity of multiple NLRP3 mediated chronic inflammatory diseases,” with the NLRP3 inflammasome being a key promoter of the release of caspase-1 and the inflammatory cytokines interleukin 1β and interleukin 18.  It’s currently unknown what, exactly, leads to the metabolic deficits that ultimately result in the cognitive decline observed in MCI and AD, but increased systemic and cerebral inflammation may contribute by altering or upregulating the immune response and potentially facilitating neuronal cell death.

When metabolized as a fuel source, βOHB produces more ATP than glucose does, while generating fewer damaging reactive oxygen species (ROS).  It’s a win-win: more energy with less damage.  If we were talking about cars, and not the human brain, this would be a slam dunk: more miles per gallon with less wear-and-tear on the engine. 

It must be noted, however, that while βOHB does have important effects of its own (including inhibition of histone deacetylase), the mere presence of this molecule doesn’t induce the multiple other beneficial changes observed in people following a ketogenic diet, such as lower insulin levels.  And considering that “insulin resistance is usually at or near the top of the list of known lifestyle-related factors heightening the risk of declining cognition in the elderly,” for the most “bang for the buck” with regard to brain health, it might not be sufficient to simply flood the body with ketones.  It may be better to generate those ketones endogenously, via a very low carb or ketogenic diet, which has dramatic effects on reducing insulin, as well as improving other parameters of metabolic and cardiovascular health, such as raising HDL, lowering triglycerides, and reducing fasting glucose, HbA1c, and CRP.

It’s time to stop feeling powerless in the face of Alzheimer’s disease.  Many unanswered questions remain, and certainly more research is needed, but we are not without actionable information now.  And considering that nearly every seemingly promising blockbuster drug for this frightening condition has failed to have any positive impact, it’s time to try a different tactic: one supported by multiple mechanisms and sound science.

By Amy Berger, MS, CNS