Alzheimer's disease (AD) is a devastating neurodegenerative disorder affecting millions worldwide. As the prevalence of AD continues to rise, the need for effective prevention and treatment strategies becomes increasingly urgent. While the underlying mechanisms of AD pathology are not fully understood, significant progress has been made in recent years. This article explores the potential of the ketogenic diet as a therapeutic intervention for AD, examining the experimental and clinical data that support its neuroprotective properties.
Introduction: The Growing Threat of Alzheimer's Disease
Alzheimer's disease (AD) is the most significant cause of dementia, impacting around 50 million people globally. It is a heterogeneous and multifactorial disorder characterized by cognitive impairment, progressive memory decline, disorientation, impaired self-care, and personality changes. The most common initial symptom is short-term memory deficit, which affects daily activities. Cognitive deficits result from neuron loss, neurofibrillary degeneration in the limbic system, subcortical structures, archicortex, and neocortex, as well as progressive synaptic dysfunction.
Alzheimer's Disease: Etiology and Neuropathological Features
The etiology of AD remains incompletely explained, with both genetic and environmental risk factors implicated. The etiopathogenesis of AD has been linked to hypometabolism, mitochondrial dysfunction, inflammation, and oxidative stress. Cellular events associated with AD neuropathogenesis include impairment of calcium homeostasis and disturbed autophagy. On the brain tissue level, neuron loss, brain atrophy, and cerebral amyloid angiopathy are characteristic. Furthermore, systems-level characteristics involve blood-brain barrier (BBB) abnormalities, brain arteries atherosclerosis, and brain hypoperfusion.
Genome-wide association studies (GWAS) have identified over 20 genetic loci that may be implicated in AD risk. The primary gene is apolipoprotein E (ApoE), with the epsilon 4 (E4) variant increasing the risk of AD. Neuropathological hallmarks include extracellular diffuse and senile amyloid plaques and intracellular neurofibrillary tangles. Amyloid plaques contain amyloid β peptides (Aβ) consisting of 38 to 43 amino acids, generated by cleavage of neuronal cell membrane glycoprotein (APP) by β- and γ-secretases. The non-amyloidogenic processing does not result in the production of Aβ, due to the cleavage of APP by α-secretase, leading to the release into the extracellular space of a soluble neuroprotective protein-sAPPα. Finally, γ-secretase cleaves the remaining the C-terminal fragment C83, yielding P3 and AICD. Elevated generation of Aβ, coupled with reduced clearance, results in Aβ accumulation and subsequent neurotoxicity. NFTs are composed of abnormally hyperphosphorylated tau protein, located within neurons. They play a role in the regulation of synaptic plasticity and synaptic function. The development of paired helical filaments (PHFs) and/or NFTs causes destabilization of microtubules, as well as synaptic and neuronal injury.
Current Treatment Options and the Need for Novel Approaches
To date, only a few FDA-approved drugs, such as acetylcholinesterase inhibitors and memantine, are available. These drugs regulate neurotransmitter activity and partly ameliorate behavioral symptoms. Other treatment options include active and passive immunization, anti-aggregation drugs, and γ- and β-secretases inhibitors. However, there is currently no effective treatment to prevent AD development or modify its progress. Emerging results from preclinical and clinical studies suggest that dietary and lifestyle modifications may have potential interest in AD treatment. These recommendations include minimizing the intake of trans fat and saturated fats, dairy products, and increased consumption of vegetables, fruits, legumes (beans, peas, and lentils), and whole grains.
Read also: The Hoxsey Diet
The Ketogenic Diet: A Metabolic Shift Towards Neuroprotection
The ketogenic diet (KD) is a very high-fat, low-carbohydrate diet initially established in the 1920s for refractory epilepsy therapy. It has gained interest as a potential therapy for neurodegenerative disorders, such as AD, Parkinson’s disease, amyotrophic lateral sclerosis, and insulin resistance in type 2 diabetes. Moreover, because of altered glucose metabolism, it may have anti-tumor effects, as well as, for example, in glaucoma, or gastric cancer. The KD triggers a systemic shift from glucose metabolism toward fatty acid (FA) metabolism, yielding ketone bodies (KBs), such as acetoacetate (AcAc) and β-hydroxybutyrate (β-OHB), as substrates for energy.
Approximately 20% of basal metabolism for the adult brain is provided by the oxidation of 100-120 g of glucose over 24 h. The KD provides sufficient protein for growth and development, but insufficient amounts of carbohydrates for the metabolic requirements. Thus, energy is mostly derived from fat delivered in the diet and by the utilization of body fat. Within hours of starting the diet, changes in plasma KBs, glucose, insulin, glucagon, and FAs levels are observed, resulting in a drop in blood glucose concentration, as well as the insulin-to-glucagon ratio. An increased glucagon concentration is associated with the mobilization of glucose from its liver resources. Thus, the inhibition of glycogenesis and glucose reserves become insufficient for the fat oxidation process. After 2-3 days of fasting, the primary source of energy is KBs, produced in the mitochondrial matrix of hepatocytes. The higher level of KBs in the blood and their elimination via urine cause ketonemia and ketonuria. Under physiological conditions, the blood concentration of KBs ranges from <0.3 mM, compared to glucose concentration ~4 mM, to 6 mM during prolonged fasting. When KBs achieve concentrations above 4 mM, they become a source of energy for the CNS. The KD allows ~90% of total calorie income from fat and much lower from protein (6%) and carbohydrate (4%). This may be achieved, due to a macronutrient ratio of 4:1 (4 g fat to every 1 g protein and carbohydrates). Thus, it includes replacing carbohydrates by fats in daily meals.
The most common KD form contains mainly long-chain fatty acids, although KD requires changes in eating habits, which is challenging to maintain, especially from a long-term perspective. Therefore, a new form of KD was proposed. A diet based on medium-chain triglycerides (MCT) leads to similar effects by increasing the concentration of KBs in the blood, even if carbohydrates were present in the diet. Due to the restriction of glucose metabolism, KD requires to obtain energy from FAs of adipose tissue. Remarkably, the brain, due to its reduced ability to utilize FAs as an energy source, has to use KBs instead. KBs, through the mitochondrial β-oxidation of FAs yielding acetyl-CoA, are synthesized in the liver. Some acetyl-CoA molecules remaining may be utilized in the Krebs cycle or to produce AcAc, further being converted spontaneously to acetone or β-OHB by β-OHB dehydrogenase (BDH). Later on, KBs enter the bloodstream and are available for brain, muscle, and heart, where they generate energy for cells in mitochondria. β-OHB and AcAc can cross the BBB through proton-linked, monocarboxylic acid transporters, and provide an alternative substrate for the brain. Their expression is related to the level of ketosis. During the long period of starvation, KBs may provide up to 70% of cerebral energy requirements. Research studies evoked that KBs provide a more efficient energy source compared to glucose. They are metabolized faster than glucose and are able to bypass the glycolytic pathway by directly entering the Krebs cycle, whereas glucose needs to undergo glycolysis. Because it leads to fatty acid-mediated activation of peroxisome proliferator-activated receptor α (PPARα), the glycolysis and FA are inhibited. Thus, KBs reduce glycolytic ATP production and elevate ATP generation by mitochondrial oxidation, which enhances oxidative mitochondrial metabolism resulting in beneficial downstream metabolic changes. It includes the ketosis, higher serum fat levels, and lower serum glucose levels contributing to protection against neuronal loss by apoptosis and necrosis.
Potential Mechanisms of Action in Alzheimer's Disease
The ketogenic diet could alleviate the effects of impaired glucose metabolism by providing ketones as alternative metabolic substrates for the brain. Besides, this diet may help to reduce the deposition of amyloid plaques by reversing the Aβ(1-42) toxicity. Rodents treated with the KD, exogenous β-OHB, and MCT display reduced brain Aβ levels, protection from amyloid-β toxicity, and improved mitochondrial function. In the transgenic mice model of AD, it was observed that KD made soluble Aβ deposits level in their brain 25% less after only 40 days. Evidently, AD neuropathology is associated with aberrant hyperphosphorylation of tau protein. Mitochondrial dysfunction and decreased neuronal and glial mitochondrial metabolism follow in older people. The mitochondrial dysfunction results in diminished energy generation from the oxidation of glucose/pyruvate, and it can also increase Aβ accumulation and tau protein dysfunction. Consequently, the abnormal mitochondria could be characterized by an increased superoxide generation with subsequent oxidative injury, a decrease in oxidative phosphorylation, and finally resulting impairment of the mitochondrial electron transport chain.
Inflammation and oxidative stress are two essential factors recognized in the neuropathology of AD, underlying neurotoxic mechanisms leading to neuronal loss, which is present in the brain regions responsible for memory and cognitive processes. Because a great proportion of cells in the immune system (e.g., macrophages or monocytes) express abundant GPR109A, KD may actually affect neuroinflammatory mechanisms. GPR109A, which was found in the brain tissue is, in fact, a G protein-coupled receptor known as hydroxy-carboxylic acid receptor 2 (HCA2). Moreover, the β-OHB may directly bind to HCA2, which is expressed on microglia, dendritic cells, and macrophages. Its activation induces the neuroprotective subset of macrophages, which depend on PGD2 production by COX1. KD has also been proved to exert effects on inflammatory processes by inhibiting the activation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB). It results in the downregulation of COX2, and inducible nitric oxide synthase expression.
Read also: Walnut Keto Guide
Clinical Evidence: A Randomized Crossover Trial
A randomized crossover trial investigated the impact of a 12-week modified ketogenic diet on cognition, daily function, and quality of life in AD patients. Patients were randomly assigned to a modified ketogenic diet or their usual diet supplemented with low-fat healthy-eating guidelines. The trial consisted of two 12-week treatment periods separated by a 10-week washout period.
The results showed that patients on the ketogenic diet achieved sustained physiological ketosis. Compared with the usual diet, patients on the ketogenic diet increased their mean within-individual ADCS-ADL and QOL-AD scores. The ACE-III also increased, but not significantly. Changes in cardiovascular risk factors were mostly favorable, and adverse effects were mild. This trial demonstrated that high rates of retention, adherence, and safety appear to be achievable in applying a 12-week modified ketogenic diet to AD patients. Compared with a usual diet supplemented with low-fat healthy-eating guidelines, patients on the ketogenic diet improved in daily function and quality of life, two factors of great importance to people living with dementia.
Modified Mediterranean Ketogenic Diet (MMKD)
A study included participants at risk for AD based on baseline cognitive dysfunction (MCI) diagnosed by expert physicians and neuropsychologists using National Institutes of Health - Alzheimer’s Association MCI criteria, or who had subjective memory complaints using the Alzheimer’s Disease Neuroimaging Initiative (ADNI) criteria. All had prediabetes as defined by American Diabetes Association guidelines, with a screening hemoglobin A1c of 5.7-6.4%. The experimental diet (MMKD) was a modified ketogenic diet, which has increasingly been utilized in medically intractable epilepsy due to its increased tolerability and similar efficacy to the traditional ketogenic diet. The target macronutrient composition (expressed as % of total calories) was 5-10% carbohydrate, 60-65% fat, and 30% protein. Daily carbohydrate consumption was targeted at <20 g/day. Participants were encouraged to avoid store-bought products marketed as “low-carbohydrate” and artificially sweetened beverages. Extra virgin olive oil was supplemented, and participants were encouraged to eat fish, lean meats, and nutrient-rich foods as the source of carbohydrates (i.e., green leafy vegetables, nuts, berries).
The control diet (AHAD) was adapted from the low-fat American Heart Association Diet. The target composition of the AHAD was 55-65% carbohydrates, 15-20% fat, and 20-30% protein. Daily fat intake was targeted at <40 g/day. Participants were encouraged to eat plentiful fruits, vegetables, and fiber-laden carbohydrates.
A registered dietitian developed daily meal plans for each participant based upon their food preferences and caloric needs as determined by a pre-study 3-day food diary, body composition, and activity level. Participants had weekly diet education visits (either in-person or by phone) starting one week prior to the start of each diet and continuing throughout the remainder of the intervention. Participants maintained a daily food record that was reviewed at these visits. Both diets were eucaloric and targeted to each participant’s baseline caloric needs with a goal of keeping weight neutral throughout the course of the study. Participants were asked to keep their exercise and physical activity level stable throughout the study.
Read also: Weight Loss with Low-FODMAP
Different Types of Ketogenic Diets
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). 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. 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.
tags: #Alzheimer's #disease #and #ketogenic #diet