Links To And Excerpts From “A Potential Role for the Ketogenic Diet in Alzheimer’s Disease Treatment: Exploring Pre-Clinical and Clinical Evidence”

Today, I review, link to, and excerpt from A Potential Role for the Ketogenic Diet in Alzheimer’s Disease Treatment: Exploring Pre-Clinical and Clinical Evidence. [PubMed Abstract] [Full-Text HTML] [Full-Text PDF]. Tadeu P. D. Oliveira,1 Ana L. B. Morais,2 Pedro L. B. dos Reis,2 András Palotás,3,4,5 and Luciene B. Vieira2. Metabolites. 2024 Jan; 14(1): 25. Published online 2023 Dec 29. doi: 10.3390/metabo14010025

All that follows is from the above resource.


Given the remarkable progress in global health and overall quality of life, the significant rise in life expectancy has become intertwined with the surging occurrence of neurodegenerative disorders (NDs). This emerging trend is poised to pose a substantial challenge to the fields of medicine and public health in the years ahead. In this context, Alzheimer’s disease (AD) is regarded as an ND that causes recent memory loss, motor impairment and cognitive deficits. AD is the most common cause of dementia in the elderly and its development is linked to multifactorial interactions between the environment, genetics, aging and lifestyle. The pathological hallmarks in AD are the accumulation of β-amyloid peptide (Aβ), the hyperphosphorylation of tau protein, neurotoxic events and impaired glucose metabolism. Due to pharmacological limitations and in view of the prevailing glycemic hypometabolism, the ketogenic diet (KD) emerges as a promising non-pharmacological possibility for managing AD, an approach that has already demonstrated efficacy in addressing other disorders, notably epilepsy. The KD consists of a food regimen in which carbohydrate intake is discouraged at the expense of increased lipid consumption, inducing metabolic ketosis whereby the main source of energy becomes ketone bodies instead of glucose. Thus, under these dietary conditions, neuronal death via lack of energy would be decreased, inasmuch as the metabolism of lipids is not impaired in AD. In this way, the clinical picture of patients with AD would potentially improve via the slowing down of symptoms and delaying of the progression of the disease. Hence, this review aims to explore the rationale behind utilizing the KD in AD treatment while emphasizing the metabolic interplay between the KD and the improvement of AD indicators, drawing insights from both preclinical and clinical investigations. Via a comprehensive examination of the studies detailed in this review, it is evident that the KD emerges as a promising alternative for managing AD. Moreover, its efficacy is notably enhanced when dietary composition is modified, thereby opening up innovative avenues for decreasing the progression of AD.

Keywords: Alzheimer’s disease; ketogenic diet; ketone bodies; neurodegenerative diseases.

3. Risk Factors for AD

Despite 115 years having passed since Alois Alzheimer first described the disease, our understanding of AD remains incomplete. Consequently, researchers have explored genetic and environmental factors as potentially influential elements in the development of this condition [,]. Genetic risk factors for AD include mutations in amyloid precursor protein (APP), presenilin 1 (PSEN1), presenilin 2 (PSEN2) and apolipoprotein E4 (APOE4). Nonetheless, APOE4 stands as the most extensively established genetic risk factor for AD susceptibility beyond the age of 65 years [,,,]. It is linked to an elevated risk of NFT formation and a reduction in Aβ clearance, resulting in the accumulation of neurotoxic fragments [,]. Furthermore, while genes play a role in the risk of developing AD, they may account for only a modest portion of that risk [,]. It is important to highlight that the risk factors identified for AD share features and are not independent []. Notably, some of these factors encompass treatable medical conditions like stroke, hypertension and diabetes []. Epidemiologic studies revealed that the risk of AD is increased by 50–100% by type 2 diabetes mellitus (T2DM). A notable observation is that the APOE4 gene serves as a risk factor for the development of type 2 diabetes mellitus (T2DM), although it is important to recognize that not all individuals with T2DM possess the APOE4 gene. Additionally, this apolipoprotein has been linked to a reduction in glucose consumption by the brain []. Thus, T2DM is linked to an increased risk of developing late-onset AD (LOAD) [,]. Regarding modifiable environmental risks, numerous reviews have emphasized the substantial evidence associating smoking [], nutrition [] and obesity [], and such findings demonstrate that behavioral aspects can influence the onset of clinical manifestations of AD [,,].

4. Pharmacological Treatment for AD

Currently, there is neither a cure for AD [] nor an effective drug for prevention or treatment that modifies the progression of the disease [,]. Given the severity of AD, advances in pharmacological treatments are progressing slowly [], as only a few drugs are approved. The drug therapy for AD is symptomatic or palliative and not effective for advanced stages of the disease [,,,]. Such pharmacological treatments are focused on improving cholinergic transmission, and they are divided by the mechanism of action into two classes: cholinesterase inhibitors (ChEIs), used for mild to moderate stages, and an NMDA receptor antagonist (N-Methyl-D-aspartate), Memantine [], used for moderate to severe stages or in cases of intolerance and contraindication [,,]. ChEIs have moderate symptomatic benefits regarding cognition, functionality and behavior [,,]. This class includes Donepezil, Galantamine and Rivastigmine []. Nevertheless, these drugs exhibit variations in certain pharmacological characteristics: Donepezil and Rivastigmine boast longer half-lives, but, in addition to acetylcholinesterase inhibition, Rivastigmine also deactivates butyrylcholinesterase. On the other hand, Galantamine demonstrates an additional enhancement in nicotinic receptor transmission [,]. As for the NMDA receptor antagonist, Memantine improves cognition, functionality and the management of agitation and aggression [,,]. Furthermore, combining Memantine with Donepezil can lead to improved patient outcomes [].

Additional treatment options are non-pharmacological, often more cost-effective and dependent on human effort []. This category encompasses numerous suggested approaches, including socialization [], cognitive training [], calorie restriction and exercise [,]. Among these alternatives, the ketogenic diet (KD) is currently under investigation as an adjuvant therapy [,,,].

5. Ketogenic Diet and Ketone Body Biosynthesis

The KD is a diet based on reducing carbohydrate consumption and increasing lipid intake [,]. This leads to a decrease in the use of glucose, which is no longer the main energy source, promoting the use of ketone bodies (ketones) from the breakdown of fatty acids (FAs) [,,]. The hepatic metabolism of FAs produces ketones commonly used as substrates for energy: acetoacetate, acetone and beta-hydroxybutyrate (BOHb) [,]. Normally, ketones are produced in starvation [], fasting [,], prolonged physical exercises [], pregnancy [] and in diets with high-fat and low-carbohydrate rates []. Thus, when glucose stores in the body are low, more FAs are made available to the liver for oxidation, leading to the consequent production of energy-rich molecules, mainly acetyl-CoA. Acetyl-CoA can enter the citric acid cycle in the liver or be used for the synthesis of ketones. Once in the liver cells, the fatty acid will be directed to the mitochondrial matrix by carnitine palmitoyltransferase (CPT1/2) where it initially undergoes a β-oxidation generating Acetyl-CoA that will undergo the process of ketogenesis []. In sequence in the process, the thiolase-2 enzyme acts in the conversion of two molecules of Acetyl-CoA to Acetoacetyl-CoA (AcAc-CoA) [,]. This molecule undergoes catalysis by the enzyme 3-Hydroxymethyl glutaryl-CoA synthase 2 (HMGCS2), resulting in the generation of hydroxymethylglutaryl-CoA (HMG-CoA) []. Subsequently, HMG-CoA is converted into acetoacetate and Acetyl-CoA via the catalytic action of HMG-CoA lyase []. Furthermore, acetoacetate can be reduced to D-β-hydroxybutyrate (D-βOHB) or decarboxylated to acetone []. After their formation, ketones are released from cells by monocarboxylate transporters (MCT1/2) and fall into the bloodstream to reach extrahepatic tissues for terminal oxidation []. Through the same MCT1/2 channels, ketone bodies enter the mitochondrial matrix of cells where they undergo the action of Succinyl-CoA: 3-ketoacid CoA transferase (SCOT) that transfers the CoA portion of succinyl-CoA to form Acetoacetyl-CoA []. The final part of the inverse process leads to the formation of Acetyl-CoA that is introduced into the TCA cycle for the formation of ATP that is used as an energy source in cases of glucose deprivation [] (Figure 1).

6. Types of KD

There are different types of KDs, listed as: classic long-chain triglyceride KD (LCT), medium-chain triglyceride KD (MCT), modified Atkins diet (MAD) and low glycemic index diet (LOGI) (Table 1) [,,,]. The four diets have the same original formula, characterized by a high rate of fat and low amount of carbohydrate in their composition. However, they have occasional variations in the composition weight and ingredient restrictions []. LCT offers around 90% of energy in the form of fat and 10% of carbohydrates and proteins []. The most recommended ratio is 4:1 to 3:1 (fats: proteins and carbohydrates), but the use of each diet can be evaluated based on the patient’s profile and the most appropriate type of diet []. The diet ratio represents the balance between fat and protein plus carbohydrate grams. For instance, a “1800 kcal 4:1 ratio classic KD” contains four times the grams of fat compared to protein. This ratio can be customized to enhance seizure management or to make it more accommodating for improved tolerance. In contrast to the standard KD, the MCTKD is not influenced by food ratios; instead, it depends on the proportion of calories derived from MCT oil as a crucial source of ketones [].

MCT has a distinct composition, primarily comprising about 60% octanoic acid, an eight-carbon fatty acid, and roughly 40% decanoic acid, a ten-carbon fatty acid []. Unlike the conventional KD, which relies more on medium-chain fats for dietary energy, the MCT-based diet permits a broader inclusion of carbohydrates. Due to the swift metabolism of these shorter fatty acids, this distinction results in a more efficient synthesis of ketones []. The process starts with dietary triglycerides in the form of MCT supplements, undergoing breakdown in the gastrointestinal tract by specialized lipases with a preference for hydrolyzing medium-chain esters rather than long-chain esters. Consequently, MCTs are converted into medium-chain fatty acids, characterized by their carbon atom content ranging from six to twelve []. This unique property enables direct absorption through the intestinal wall, leading to swift transportation to the liver. Once in the liver, the medium-chain fatty acids, including decanoic acid and octanoic acid, undergo rapid metabolism via a process known as β-oxidation []. The integration of an MCT-rich diet with an elevated carbohydrate intake sets this approach apart from the conventional KD, offering a balanced and efficient means of achieving ketosis while harnessing the advantages of medium-chain fats [].

Due to the highly restrictive dietary regimen and concerning side effects associated with KDs, their implementation in pediatric patients is challenging. In this context, the modified Atkins diet (MAD)*emerges as a more balanced and easily applicable alternative dietary therapy. The advantages of increased tolerance and sustainable treatment approach could potentially position MAD as the preferred choice. Unlike the classic KD, MAD shares similar food choices but eliminates the need for precise ingredient weighing. It also deviates from a strict ketogenic ratio and lacks restrictions on protein, fluid and calories. MAD is used to treat some metabolic paroxysmal movement disorders, such as those observed in glucose transporter type 1 deficiency syndrome (GLUT1DS) [,,].

*Link is to The Modified Atkins Diet Manual from The Adult Epilepsy Diet Center of Johns Hopkins Medicine. Aug 2015.

Another type of diet that combines the principles of the Mediterranean diet with the macronutrient composition of a KD is the Mediterranean Ketogenic Diet (MKD). Inspired by the heart-healthy Mediterranean diet, the MKD incorporates high consumption of fruits, vegetables, whole grains and healthy fats, notably olive oil. Simultaneously, it aligns with the principles of a KD by emphasizing low carbohydrate intake and promoting a state of ketosis. The MKD includes the use of olive oil as a primary source of fat, moderate consumption of fish and poultry, and limited intake of red meat and processed foods. The MKD encompasses several common variations, including the Very Low-Calorie Ketogenic Diet (VLCKD) which is characterized by a low carbohydrate content (<50 g/day), 1–1.5 g of protein/kg of ideal body weight, 15–30 g of fat/day and a daily intake of about 500–800 calories []. In addition, the High-Fat Ketogenic Diet (HFKD) is based on a higher proportion of daily calories sourced from fat, typically ranging between 75–80%. In contrast to the traditional KD, the HFKD allows for a modestly increased protein intake, contributing to a more flexible nutritional profile [].

7. Possible Risks of KD

The benefits of ketones produced in the liver go beyond the energy supply of tissues such as the brain, skeletal muscle and heart []. Ketones antagonize inflammatory processes and oxidative stress [,], acting as signaling mediators []. Although the KD presents possible benefits to the organism [], its use can also promote adverse effects such as headache, gastrointestinal pain, constipation, nausea, fatty diarrhea, fatigue, vomiting and other gastrointestinal problems [,,]. These symptoms are usually associated with acute use of the KD as reported in studies with young and adult patients [,]. All the symptoms caused by the KD in the first few days are usually called “keto flu” []. It has been shown that the acute symptoms pass after a short period of time and patients who use the KD for more than one year can report different types of symptoms, as vitamin and mineral deficiencies, kidney stones, hyperuricemia, lethargy and infectious diseases, which can be harmful [].

In a study involving obese patients, the impact of a KD was assessed over a 24-week period. The findings demonstrated that the KD treatment yielded positive outcomes, including significant weight loss and improvements in the patients’ lipid profiles, with no notable adverse effects reported []. However, it is crucial to emphasize that individuals with a genetic predisposition to cholesterol metabolism dysregulation may experience an exaggerated rise in cholesterol levels when adhering to a KD. Moreover, there remain certain uncertainties surrounding the prolonged use of this diet, primarily due to the limited evidence available for durations exceeding one year. These uncertainties encompass concerns related to cardiovascular risks and disruptions in lipid metabolism as well as impacts on hormone regulation, such as insulin [,]. Although there is evidence supporting KD effectiveness in specific contexts, such as obesity, diabetes, non-alcoholic fatty liver disease (NAFLD) and kidney disease, it is crucial to recognize that individual responses to the KD can vary significantly [,].

This entry was posted in Alzheimer's Disease, Dementia, Ketogenic Diet, Memory Or Thinking Concerns, Mild Cognitive Impairment. Bookmark the permalink.