Introduction
Alzheimer's disease (AD), a devastating neurodegenerative disorder, is becoming increasingly prevalent worldwide, affecting around 50 million people. Characterized by a progressive decline in memory, disorientation, and impaired self-care, AD poses a significant global health challenge. While the exact mechanisms underlying AD pathology remain under investigation, significant progress has been made in understanding the key features of the disease, including the deposition of amyloid-beta peptides (Aβ) in amyloid plaques, hyperphosphorylated tau protein in neurofibrillary tangles (NFTs), neuronal loss, and impaired glucose metabolism. The lack of effective prevention and treatment strategies has spurred interest in dietary and metabolic interventions, such as the ketogenic diet (KD), as potential therapeutic approaches.
Alzheimer's Disease: A Multifactorial Disorder
AD is a heterogeneous and multifactorial disorder characterized by cognitive impairment with a progressive decline in memory, disorientation, impaired self-care, and personality changes. The most common symptom present at the beginning of AD is associated with short term memory deficit, which affects daily activities. Cognitive deficits, resulting from the loss of neurons, are susceptible to neurofibrillary degeneration located in the limbic system, subcortical structures, archicortex and neocortex, and progressive synaptic dysfunction.
Neuropathological Hallmarks of AD
Pathologically, AD involves progressive deposition of amyloid β-peptide (Aβ) as amyloid plaques, hyperphosphorylated tau protein intracellularly as neurofibrillary tangles (NFTs) and neuronal loss in the hippocampus. Mitochondrial dysfunction and a decline in respiratory chain function alter amyloid precursor protein (APP) processing, which leads to the production of the pathogenic amyloid-β fragments. On the other hand, the reduced glucose uptake and inefficient glycolysis have been strongly associated with progressive cognitive deficiency, due to the downregulation of the glucose transporter GLUT1 in the brain of patients with AD.
The neuropathological features of the AD brain include extracellular diffuse and senile amyloid plaques and intracellular neurofibrillary tangles. Amyloid plaques contain amyloid β peptides consisting of 38 to 43 amino acids generated by cleavage of neuronal cell membrane glycoprotein (APP) by β- and γ-secretases. The main isoforms of Aβ have been distinguished: Aβ1-40 (90%) and Aβ1-42 (10%). β-secretase by cleaving the extracellular domain of APP and releasing the soluble N-terminal of APP into the extracellular space initiates the amyloidogenic pathway. Subsequently, the C-terminal of APP is cleaved by γ-secretase eventually yielding Aβ and APP intracellular domain (AICD). As a matter of fact, 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. The increase in the concentration of Aβ leads to neurotoxicity and neurons loss. Interestingly, Aβ at brain lower concentrations seems to promote neurogenesis and plasticity, exert neurotrophic functions, influence calcium homeostasis, antioxidative processes, and redox sequestration of metal ions. Elevated generation of Aβ accompanied by its reduced clearance clearly results in the accumulation of Aβ and its subsequent neurotoxicity.
NFTs are composed of abnormally hyperphosphorylated tau protein, located within neurons. The assembly and stabilization of microtubules requires tau protein, being crucial for cytoskeleton and transport of vesicles and organelles along the axons. Moreover, they play a role in the regulation of synaptic plasticity and synaptic function. Under physiologic conditions, phosphorylation of tau protein by kinases is balanced by dephosphorylation by phosphatases, but the change in structure is observed when tau protein is hyperphosphorylated. The development of paired helical filaments (PHFs) and/or NFTs, causing destabilization of microtubules, as well as synaptic and neuronal injury.
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Current Treatment Strategies and the Need for Novel Approaches
To date, there are only a few FDA approved drugs, such as acetylcholinesterase inhibitors and memantine. Drugs that regulate the activity of the neurotransmitters and partly ameliorate behavioral symptoms. Another treatment option includes active and passive immunization, anti-aggregation drugs, γ- and β-secretases inhibitors. Currently, there is no effective treatment to prevent the risk of AD development or modify its progress. Therefore, emerging results from preclinical and clinical studies show that change in dietary and lifestyle modifications may have a potential interest in the treatment of AD. These recommendations include minimizing the intake of trans fat and saturated fats, dairy products and increased consumptions of vegetables, fruits, legumes (beans, peas, and lentils), and whole grains.
The Ketogenic Diet: A Potential Therapeutic Intervention
The ketogenic diet was initially established in the 1920s to be used in refractory epilepsy therapy. To date, there are pieces of evidence showing that 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.
Metabolic Shift and Ketone Body Production
The ketogenic diet assumes a very high-fat and low-carbohydrate diet, reducing carbohydrate to ≤10% of consumed energy. This restriction triggers a systemic shift from glucose metabolism toward the metabolism of fatty acids (FAs) 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, which results 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.
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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. As already mentioned, 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. Bough et al. found that KD modulates the upregulation of hippocampal genes, which encode mitochondrial and energy metabolism enzymes. Consequently, therapeutic ketosis can be considered as a form of metabolic therapy by providing alternative energy substrates. Through these metabolic changes, brain metabolism is improved, and ATP production in mitochondria is restored. Moreover, decreased reactive oxygen species (ROS) production, antioxidant effects, lower inflammatory response, and increased activity of neurotrophic factors are observed. Another impact includes stabilization of the synaptic activity between neurons through increased levels of Krebs cycle intermediates, increased GABA-to-glutamate ratio, and activation of ATP-sensitive potassium channels.
Potential Mechanisms of Action in Alzheimer's Disease
The etiology of AD remains not fully explained, but both genetic and environmental risk factors have been proposed to be involved. Thus, the etiopathogenesis of AD has been linked to hypometabolism, mitochondrial dysfunction, inflammation, and oxidative stress. Some more cellular events associated with AD neuropathogenesis include impairment of calcium homeostasis and disturbed autophagy. On the brain tissue level, neurons loss, brain atrophy, and cerebral amyloid angiopathy have to be mentioned. In addition, the systems-level characteristic for AD involves the blood-brain barrier (BBB) abnormalities, brain arteries atherosclerosis, and brain hypoperfusion. Moreover, genome-wide association studies (GWAS) have revealed that more than 20 genetic loci may be implicated with the risk of AD development. The primary gene is the apolipoprotein E (ApoE), and the epsilon 4 (E4) variant of ApoE was found to increase the risk for AD generation.
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. Studies suggest that KD may affect neuropathological and biochemical changes observed in AD. 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.
Neuroinflammation and Oxidative Stress
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. It involves releasing proinflammatory cytokines, NO, and inhibition of neurotrophins, resulting in damage to surrounding tissues. 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 expr…
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Clinical Evidence and Ongoing Research
A new study from researchers at the University of California, Davis, shows a ketogenic diet significantly delays the early stages of Alzheimer’s-related memory loss in mice. This early memory loss is comparable to mild cognitive impairment in humans that precedes full-blown Alzheimer’s disease. The ketogenic diet is a low-carbohydrate, high fat and moderate protein diet, which shifts the body’s metabolism from using glucose as the main fuel source to burning fat and producing ketones for energy. The new study, which follows up on that research, found that the molecule beta-hydroxybutyrate, or BHB, plays a pivotal role in preventing early memory decline. It increases almost seven-fold on the ketogenic diet. “The data support the idea that the ketogenic diet in general, and BHB specifically, delays mild cognitive impairment and it may delay full blown Alzheimer’s disease,” said co-corresponding author Gino Cortopassi, a biochemist and pharmacologist with the UC Davis School of Veterinary Medicine. “We observed amazing abilities of BHB to improve the function of synapses, small structures that connect all nerve cells in the brain. When nerve cells are better connected, the memory problems in mild cognitive impairment are improved,” said co-corresponding author Izumi Maezawa, professor of pathology in the UC Davis School of Medicine. Cortopassi noted that BHB is also available as a supplement for humans. He said a BHB supplement could likely support memory in mice, but that hasn’t yet been shown. Researchers found that the ketogenic diet mice exhibited significant increases in the biochemical pathways related to memory formation. The study was funded by the National Institute on Aging, a unit of the National Institutes of Health.
Modified Mediterranean Ketogenic Diet (MMKD) and Lipidomic Changes
A randomized, single-site study involved 20 adults, nine diagnosed with mild cognitive impairment (MCI) and 11 with normal cognition. Researchers found that participants with MCI on the modified Mediterranean ketogenic diet had lower levels of gamma-aminobutyric acid (GABA) and of GABA-producing microbes. Participants on this diet also had higher levels of GABA-regulating bacteria. The study also showed that participants with MCI who had curcumin in their diets also had lower levels of BSH-containing bacteria. These bacteria regulate bile acids produced by the liver and gut. Lower levels suggest reduced gut motility, a phenomenon in which food and waste take longer to transit the gut. “These findings provide crucial insight into how diet may affect the microbiome and improve brain health,” Craft said. Craft and her team are currently conducting a follow-up study of the ketogenic diet in adults with MCI at Wake Forest University School of Medicine. The study was supported by the Wake Forest Alzheimer’s Disease Research Center P30-AG072947, the Hartman Family Foundation, Roena B.
Lipids are fundamental components of cellular structure and function, particularly in the brain, which is one of the most lipid-rich organs. Lipids are a major constituent of membranes and synapses, which are impaired and ultimately lost throughout the course of AD. Thus, studying lipids in the context of preclinical and early symptomatic AD (mild cognitive impairment or MCI) provides an important window into crucial lipid changes and how they may be modified by intervention prior to advanced neuropathologic changes.
Lipidomics is a powerful tool used to study the diversity of multiple lipid classes and species. A robust targeted lipidomics platform in which 784 species across 47 classes are measured to map the effect of a modified mediterranean ketogenic diet (MMKD) on the plasma lipidome in patients at risk for AD with and without cognitive impairment. The primary outcomes of this study have been previously reported. Substantial changes to the plasma lipidome with the modified ketogenic diet, and further identify that these changes were inversely related to a previously established signature of the AD lipidome.
Clinical Trial: Modified Ketogenic Diet in AD Patients
A randomized crossover trial was conducted to determine whether a 12-week modified ketogenic diet improved cognition, daily function, or quality of life in a hospital clinic of AD patients. Patients with clinically confirmed diagnoses of AD were randomly assigned to a modified ketogenic diet or usual diet supplemented with low-fat healthy-eating guidelines and enrolled them in a single-phase, assessor-blinded, two-period crossover trial (two 12-week treatment periods, separated by a 10-week washout period). Primary outcomes were mean within-individual changes in the Addenbrookes Cognitive Examination - III (ACE-III) scale, AD Cooperative Study - Activities of Daily Living (ADCS-ADL) inventory, and Quality of Life in AD (QOL-AD) questionnaire over 12 weeks. Secondary outcomes considered changes in cardiovascular risk factors and adverse effects.
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.
Ongoing Research and Future Directions
The KU Alzheimer’s Disease Research Center is conducting a study with participants randomly assigned to either the ketogenic eating pattern or the heart-healthy pattern known as the Therapeutic Lifestyles Changes diet. All participants are required to have a study partner. For three months, they will follow their assigned eating pattern. Participants receive a monthly stipend for groceries and compensation for study visits and will also regularly meet with, and have 24-hour access to, a registered dietitian for nutrition education and counseling.
The ketogenic eating pattern - a high-fat, low-carbohydrate diet with moderate amounts of protein - has the potential to improve brain health by providing the brain with an alternative energy source. In people with Alzheimer’s, the brain’s utilization of glucose, a critical source of energy, is decreased. When people are following a ketogenic diet, the diet’s high fat content is converted by the liver into ketone bodies, molecules that can help fuel the brain’s neurons and potentially improve cognition. Moreover, a small pilot study conducted by the KU Alzheimer’s Disease Research Center demonstrated that the ketogenic diet did improve cognitive test scores in people with Alzheimer’s disease after three months. The second eating pattern of the study is a heart-healthy plan called the Therapeutic Lifestyle Changes diet. This low-fat eating pattern limits saturated fat and sodium and emphasizes fiber intake with lots of fruits and vegetables and whole grains. The Therapeutic Lifestyle Changes eating pattern also increases insulin sensitivity, which enables the brain to better utilize glucose for energy.
Given the renewed emphasis on neuroinflammation as a pathogenic contributor to cognitive decline, and the decreased systemic inflammation observed with the ketogenic diet, it is plausible that this diet may delay, ameliorate, or prevent progression of cognitive decline. Several small human studies have shown benefit on cognition in dementia with a ketogenic diet intervention.