Researchers, clinicians, and patients have long experienced success with the ketogenic diet in treating epilepsy. However, the mechanisms and mediators that allow the ketogenic diet to act as an antidote for epilepsy are not entirely known. In the search for understanding, the ketogenic diet has been implicated as a possible therapy for other brain disorders including Alzheimer’s disease, Amyotrophic Lateral Sclerosis, brain cancer, depression, and Parkinson’s disease. The efficacy of the ketogenic diet in treating these brain disorders has recently been shown in cell culture, rodent, and human research studies.
Alzheimer’s disease, also referred to as Type III diabetes, is a type of dementia where symptoms of memory loss and intellectual difficulties develop and progress over time. Additionally, older adults with Alzheimer’s disease are at an increased risk of developing epilepsy (1). The development of the disease involves degeneration of neurons via the accumulation of extracellular plaques. This happens when amyloid protein and alterations in mitochondrial homeostasis, along with the decline in cerebral glucose metabolism, begin to malfunction (2,3). In other words, the progression of the disease is a result of the degeneration of nerve cells from the build-up of dysfunctional proteins (amyloids) which can alter the metabolism of the brain.
In the cell culture model, which is the study of cells isolated from animal or human tissues to investigate a specific occurrence, amyloid-β proteins (the dysfunctional proteins that characterize Alzheimer’s disease) were added to hippocampal neurons to induce toxicity and eventually promote cell-degeneration. However, when ketone body β –hydroxybutyrate (BHB) was applied to the contaminated cells, the neurons were protected from harm (4). In a mouse model, Alzheimer’s disease was imitated in transgenic mice that showed amyloid-β deposition by 3 months of age and brain plaques by 12 months of age in conjunction with behaviors of impaired memory. At 3 months, mice were fed either a standard diet (high carbohydrates/low fats) or a ketogenic diet (low carbohydrates/high fats) for 43 days. As compared to the standard-fed mice, the ketogenic-fed mice demonstrated lower body weights, increased ketone levels, and a reduction in brain amyloid-β deposition by 25%. However, the level of memory impairment between the two groups of rats was not significantly different (5). With the improvements in amyloid-β deposition after 1-2 months on the ketogenic diet, it is suggested that a longer-term ketogenic diet may be required to show improvements in memory behaviors (2). Another transgenic mouse model of Alzheimer’s disease demonstrated that a 7- week ketosis-inducing diet with 2-deoxy-D-glucose (a non-metabolized glucose analog that inhibits the use of glucose for energy) increased ketogenesis and ketone metabolism. This study went on to demonstrate an increase in mitochondrial bioenergetics capacity (mitochondrial metabolism), and neurotrophic growth factors (growth of nervous tissue: BDNF and NGF), reduced oxidative stress, and amyloid-β deposition in the brain (6).
With the positive cell culture and mouse data, the ketogenic diet and even ketone supplementation merit further investigations in humans with Alzheimer’s disease. Henderson et al. (7) wanted to see if there were other factors that could amplify the effects of a ketogenic diet, thus performed a study in patients with Alzheimer’s disease. After consuming a medium chain triglyceride-based ketogenic drink, the patients demonstrated cognitive improvements as measured by scores on the Alzheimer Disease Assessment Scale-Cognitive Subscale. However, these improvements only occurred in the patients negative for the APOε4 allele, which is the high-risk variant of the APO gene and is associated with increased risk for Alzheimer disease. For more information on possible benefits of MCTS and/or ketogenic dieting/exogenous ketones, see the work of Dr. Mary Newport and her experience with her husband.
Amyotrophic Lateral Sclerosis
ALS, also known as Lou Gehrig’s disease, is a progressive neurodegenerative disease that affects the brain and spinal cord cells leading to physical weakness caused by skeletal muscle atrophy (8). Death usually occurs within 3-5 years of symptom onset (9). The mechanism causing neuronal cell death is not yet known, but excitotoxicity (damaging or killing nerve cells by over-activation of receptors), mitochondrial dysfunction, and excessive oxidative free radicals are suggested as potential culprits (9). In a cell culture study, mitochondria from spinal cord cells of an ALS mouse model responded well to the consumption of β-hydroxybutyrate as it prevented the inhibition of mitochondrial complex I, but did not prevent the inhibition of complex II (9). Furthermore, in an ALS mouse model, a ketogenic diet was associated with improved motor function and an increased number of motor neurons in the spinal cord (9). These studies demonstrate potential benefits of a ketogenic diet and β-hydroxybutyrate aiding in the treatment of ALS as they promote ATP synthesis via bypassing ALS-associated inhibition of mitochondrial complex I (9).
Seyfried et al. (10) states, “The failure to recognize brain cancer as a disease of energy metabolism has contributed to the failure of management. As long as brain tumor cells have access to glucose and glutamine, the disease will progress.” When ketone levels are high and glucose levels are low, healthy neurons and glial cells in the brain use ketones in place of glucose for fuel (2). However, malignant brain cells show a reduced capability to transition from glucose to ketone utilization (10). Cancer cells produce energy by a high rate of glycolysis (glucose metabolism) followed by lactic acid fermentation as described by the Warburg effect and thus are sensitive to a lack of metabolic energy substrate (3,11).
Angiogenesis (new blood vessel formation), inflammation, and the ability to resist apoptosis (cell death) are all fundamental hallmarks of cancer. Under reduced glucose levels, as with the ketogenic diet, the attenuation in the progression of brain tumors may result from a lack of energy substrate. In this regard, a restricted ketogenic diet consumed by mice that exhibited malignant brain cancer was found to possess anti-angiogenic, anti-inflammatory, and pro-apoptotic characteristics in the brain (11). Also, a case report of advanced brain cancer (astrocytoma) in two girls revealed that an 8-week ketogenic diet composed of 60% medium chain triglyceride oil reduced glucose uptake by the malignant brain cells by 21.8%. Moreover, the girls improved by the end of the study and the brain tumor did not progress (12). According to the literature, the ketogenic diet in combination with glucose- and glutamine-reducing drugs serves as a viable, effective, non-toxic therapeutic option for brain cancer (11).
The ketogenic diet may have anti-depressant properties as it has been suggested to act as a mood stabilizer (13). This was observed in rats that were subjected to the Porsolt test, also known as the behavior despair test. The Porsolt test forces the rats to swim in an inescapable glass cylinder in order to survive. The rat is likely exhibiting behavior despair or depression when they become immobile and stop swimming. Anti-depressants have shown to reduce immobility time in the Porsolt test as did the ketogenic diet in this study. The data suggests that a ketogenic diet reduces depressed-like symptoms similar to anti-depression medication (13).
Parkinson’s disease develops from the death of dopamine-secreting neurons in the midbrain area with associated symptoms that include physical tremors and abnormalities in movement and cognition. An impairment in the activity of mitochondrial complex I has been hypothesized to lead to a loss of the dopaminergic neurons (1,2). The use of ketones as fuel may reduce the degeneration of these neurons by providing substrate that can by-pass mitochondrial complex I, thereby providing an alternative source of energy (3). To examine this hypothesis, in-vitro (outside the body) and in-vivo studies (inside the body) have been performed.
In a Parkinson’s disease cell culture model, a substance (MPP+) that inhibits mitochondrial energy production and increases the risk of death was applied to dopaminergic neurons secured from the midbrain. The addition of D-β-hydroxybutryate protected these at-risk neuronal cells and they survived (4). In a mouse study, Parkinson’s disease was imitated with the use of a neurotoxin (MPTP) which induces dopaminergic neurodegeneration, mitochondrial deficits, and motor impairments. The infusion of D-β-hydroxybutryate provided partial protection against the dopaminergic neurodegeneration and associated symptoms (14). VanItallie et al. (15) placed 5 patients with Parkinson’s disease on a ketogenic diet for 28 days. The Unified Parkinson Disease Rating Scale (UPDRS), a tool used to follow the longitudinal course of Parkinson disease, was completed and scored weekly. The Parkinson’s patients demonstrated a decrease in the mean UPDRS score of 43.4%
The safety and holistic nature of the ketogenic diet and exogenous ketones as treatment options warrants future exploration in clinical populations that exhibit these brain disorders. The scientific and clinical communities should continue to work together in order to provide reliable support for ketosis through mechanistic cell culture and animal models, as well as more applicable human studies. More studies are needed to build the scientific support for the utilization of this diet as a collectively agreed-upon form of treatment.