Changes in Brain Metabolism Induced by Metabolic Challenges and Their Beneficial Roles for Brain Aging

Abstract

Life expectancy has been increasing globally along with the risk of developing Alzheimer’s or other dementias. Diets high in saturated fats, refined sugars and a sedentary lifestyle are determining factors in the development of a metabolic syndrome. These factors induce energy imbalance and dysfunctional brain metabolism, hence increasing the risk of cognitive impairment and/or dementia. A cohort study with mild cognitive impairment found that it was found that the presence of three or more components of a metabolic syndrome increased the risk of Alzheimer’s. On the other hand, hyperglycemia induces glutamate excitotoxicity in neurons, β-amyloid accumulation, tau phosphorylation and oxidative stress. The present chapter will cover the dysregulation of brain metabolism during physiological and pathological aging, and how metabolic challenges such fasting, caloric restriction and ketogenic diet reverts many of the deleterious effects of brain aging, favoring energy balance and cognitive function.

1. Introduction

At the brain level, physiological aging is a natural process that can be associated with the cellular and functional impairment that precedes a decline in cognitive abilities. It is widely accepted that aging is the main contributing risk factor for the onset of dementia, such as Alzheimer’s disease (AD), Parkinson’s disease and Huntington’s disease that trigger pathological aging [1]. Studies suggest that brain aging has considerable interindividual variability [2]. Elucidating the possible genetic and/or environmental factors that can determine these differences seems to be a key point to understand why individuals may or may not trigger cognitive impairment and/or dementia. In 2015, the estimated number of people with dementia was 50 million, and the figure is projected to reach 82 million in 2030 [3]. The total cost of dementia worldwide was estimated at US$ 818 billion, which is equivalent to 1 .1% of world gross domestic product (GDP) [4], evolving into a relevant problem in global public health. A genetic analysis based on a cohort study suggested that about 75% has cognitive ability variations from childhood to old age due to environmental factors [5]. Nowadays, diets high in saturated fats, refined sugars and a sedentary lifestyle are determining factors in the development of a metabolic syndrome (MetS) such as obesity, hyperglycemia, dyslipidemia, type 2 diabetes and hypertension [6]. These factors induce an impact on various systems, including the central nervous system, thus increasing the risk of cognitive impairment and/or disorders associated with dementia [7].

Evidence shows the association between MetS and dementia, where subjects with MetS are 11.48 times more likely to develop AD compared to those without a metabolic syndrome [8]. A study carried out in China on a cohort with mild cognitive impairment found that the presence of three or more components of a metabolic syndrome increased fourfold the risk of Alzheimer’s and two times only with the presence of diabetes [9]. Similarly, several studies on patient cohorts have shown that other MetS components such as abdominal obesity, hypercholesterolemia and hypertension were risk predictors of cognitive impairment and AD [10].

An explanation about the connection between a metabolic syndrome and dementias can be found in some studies. For example, type 2 diabetes can trigger Alzheimer’s through hyperglycemia, which induces glutamate excitotoxicity in neurons; Furthermore, insulin resistance can contribute to β-amyloid accumulation, tau phosphorylation, oxidative stress, the formation of advanced glycation end products (AGEs) and apoptosis [11].

As life expectancy increases, the population is exposed to risk factors for longer periods of time, which may further increase the likelihood of developing dementia. In this regard, there is an increasing demand for strategies aimed at reversing the consequences of aging and its risk factors over cognitive impairment and/or dementia.

Glucose becomes the main energy demand for the brain during development. However, as time goes by, the risk of suffering from an altered energy metabolism due to the exclusive dependence on this substrate increases the pathophysiological context in the brain [12]. On the other hand, the existence of alternative energy substrates such as lactate [13] or ketone bodies [14, 15] may be beneficial for brain metabolism, thus reversing the consequences of cognitive impairment [16, 17, 18]. Lifestyles that include nutrition-based bioenergetic challenges such as caloric restriction, fasting, and ketogenic diet favor β-oxidation to produce ketone bodies that enhance synaptic plasticity, which correlates with the recovery of cognitive processes such as learning and memory [19, 20].

This chapter will study the changes in brain metabolism induced by substrates such as glucose, lactate, and ketone bodies in the context of physiological and pathological aging. Further discussion will focus on how nutritional interventions operate as metabolic modulators and neuroprotectors during physiological and pathological aging. The main interest of this section is to position the brain energy metabolism as an “energy switch” that determines the switch between physiological aging and pathological aging.

2. Brain energy metabolism: the key to the treatment of cognitive impairment and/or dementia

The human brain represents ~2% of total body mass and is the largest source of energy consumption, accounting for more than 20% of total oxygen metabolism [21], where neurons are estimated to consume between 75% and 80% of the energy produced in the brain [22]. This energy is primarily used at the synapse and a large proportion is spent on restoring neuronal membrane potentials after depolarization [23]. Therefore, normal brain function requires metabolic regulation from a single synapse level to a regional level. Neurons can use the following substrates as energy fuel: glucose, lactate, acetoacetate (AcAc) and β-hydroxybutyrate (βHB).

2.1 Cerebral glucose metabolism in physiological and pathological aging

Glucose uptake by the brain primarily starts at the blood-brain barrier (BBB). The BBB is made up of endothelial cells interconnected by tight junctions that inhibit the entry of water-soluble molecules. Passive diffusion is limited to gases and small nonpolar lipids. The rest of the nutrients need glucose transporters and monocarboxylate transporters [24, 25].

In neurons, glucose enters the cell via glucose transporter 3 (GLUT3), which is phosphorylated by hexokinase (HK) to glucose-6-phosphate (G6P) [26], which is then routed into the glycolytic pathway and the pentose phosphate pathway (PPP) [27]. The product of glycolysis is pyruvate that enters the mitochondria were metabolized through the tricarboxylic acid (TCA) cycle and oxidative phosphorylation in the electron transport chain (ETC), generating between 30 and 36 molecules of adenosine 5′-triphosphate (ATP). Pyruvate can also be generated from lactate dehydrogenase 1 (LDH1)-dependent conversion of lactate. In PPP, G6P is converted into 6-phosphogluconate (6PG) which is converted into ribulose-5-phosphate (R5P), with the production of reduced nicotinamide adenine dinucleotide phosphate (NADPH). NADPH is used to regenerate oxidized antioxidants such as glutathione (GSH) and thioredoxin. Neurons are unable to store glucose as glycogen due to constitutive degradation of glycogen synthase (GS) through glycogen synthase kinase 3 (GSK3) phosphorylation and ubiquitin-dependent proteasomal digestion mediated by the malin-laforin complex [28].

There is an astrocyte neuronal coupling where in astrocytes, glucose enters through glucose transporter 1 (GLUT1) and is preferentially stored as glycogen and metabolized through glycolysis. The generated pyruvate is converted into lactate by the expression of lactate dehydrogenase 5 (LDH5) and the inhibition of pyruvate dehydrogenase (PDH)-dependent pyruvate dehydrogenase kinase 4 (PDK4). The presence of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (Pfkfb3) allows astrocytes to generate fructose-2,6-bisphosphate (F2, 6P) which acts as an allosteric modulator of Phosphofructokinase (PKF1) thereby enhancing glycolysis [29].

Many factors likely contribute to age-dependent brain hypometabolism. Studies, for example, show that there is higher BBB permeability in seniors, which may induce a lower intake of nutrients to the neuron and a larger accumulation of proteins such as fibrinogen, immunoglobulins, albumin, thrombin, blood hemoglobin and immune cell infiltration that may produce inflammation [30, 31]. On the other hand, studies on humans and animals show a reduced expression of glucose transporters in the brain with aging [32], as well as changes in the expression of key enzymes involved in glycolysis and oxidative phosphorylation [33].

Approximately 40% of healthy people over the age of 65 experience impairment in different cognitive domains such as working memory, spatial memory, episodic memory, and processing speed [34, 35], which is consistent with a gradual decrease in energy demand as aging progresses [36].

Functional neuroimaging studies have shown that glucose hypometabolism and mitochondrial dysfunction are early indicators of age-related functional changes during normal brain aging. Positron emission tomography (PET) analyzes with 2- [18F] fluoro-2-deoxy-D-glucose (FDG) in human subjects between the ages of 50-80 have revealed age-related decreases in glucose utilization in cortical and hippocampal regions [37]. This 14-year longitudinal study demonstrated that glucose hypometabolism can be observed decades before cognitive impairment becomes even more apparent. On the other hand, NAD levels are determinant of mitochondrial function and ATP production [38]. Studies on normal seniors show increased levels of NADH, with reduced levels of NAD and total NAD [39].

Thus, problems metabolizing glucose and impaired mitochondrial function may be a prelude to cognitive impairment and/or symptoms of dementia. Mouse model studies with reduced GLUT1 levels show an age-dependent decrease in brain capillary density, reduced cerebral blood flow and glucose uptake, and increased BBB leakage [40]. These metabolic and vascular impairments precede dendritic spine loss in hippocampal neurons and its associated behavioral alterations.

Moreover, women with AD have higher levels of amyloid plaques, neurofibrillary tangles, and higher cognitive impairment (at the same stages of the disease) than men. Recent studies show that these effects may be due to an impairment of mitochondrial complex I and an accumulation of glucose-6-phosphate (hexokinase inhibitor and rate-limiting metabolite of the PPP pathway) in AD. Furthermore, studies in mitochondria of astrocytes in the cortex and hippocampus show increased complex II-dependent respiration and increased cytochrome oxidase activity and expression of both nuclear and mitochondrial electron transport chain (ETC) subunits to compensate for metabolic disturbances in AD [41]. These data altogether show an increased female susceptibility to neuronal mitochondrial dysfunction and suggest a compensation to neuronal glucose hypometabolism through the donation of reducing equivalents via succinyl-CoA, thereby feeding succinate dehydrogenase (CII) for brain energy production inducing a neuroprotective mechanism.

Consistent with a deficit in glucose metabolism, G6P accumulation has been reported to affect the enzymatic activity of hexokinase (rate-limiting step of glucose metabolism) [42]. Furthermore, G6P is the rate-limiting substrate of the PPP which is critical for NADPH generation and subsequent detoxification of oxygen free radicals [43], thus connecting glucose hypometabolism and oxidative stress commonly observed in AD.

A recent positron emission tomography (PET) study found that the spatial distribution of aerobic glycolysis correlated with Aβ deposition in individuals with AD. This result suggests a possible link between regional aerobic glycolysis and the subsequent development of AD pathology [44, 45]. In APP/PS1 mice, glucose uptake becomes increased in the cortex and hippocampus compared to control mice. Particularly, an increase in glucose uptake is near plaques rather than in Aβ-free brain tissues, suggesting that glucose uptake may compensate for Aβ deposition [46]. Furthermore, it is presumed that weakened glucose metabolism might be a more accurate marker of neuronal atrophy than Aβ accumulation itself, since it precedes the onset of clinical symptoms in AD. In clinical studies, AD patients show early and progressive reductions in glucose metabolism in cortical and hippocampal regions. In contrast, increased glucose transport to neurons can rescue the neuronal toxicity of Aβ [47]. There actually is brain glucose deficit and hypometabolism in AD patients, which may further worsen energy insufficiency and accelerate Aβ-induced neurodegeneration.

Risk factors such as MetS in adulthood are a risk indicator for impaired brain metabolism which trigger the same metabolic effects as in pre-asymptomatic patients risking Alzheimer’s. Analysis of 1H magnetic resonance spectroscopy scanning in the occipital lobe of 9 healthy participants; 10 obese nondiabetic participants; and 6 poorly controlled, insulin- and metformin-treated type 2 diabetes mellitus (T2DM) it was measured the change in intracerebral glucose levels during a 2-hour hyperglycemic clamp (glucose ~220 mg/dl). The change in intracerebral glucose was significantly different across groups. Individuals with obesity and those with T2DM had significantly reduced increments in brain glucose concentrations compared with controls (healthy 1.46 ± 0.1 mmol/l vs. obese 1.06 ± 0.06 mmol/l vs. T2DM 0.71 ± 0.1 mmol/l). Individuals with poorly controlled T2DM showed a further blunting of brain glucose levels compared with obese individuals 1.46 ± 0.1 mmol/l vs. obese 1.06 ± 0.06 mmol/l vs. T2DM 0.71 ± 0.1 mmol/l). Individuals with poorly controlled T2DM showed a further blunting of brain glucose levels compared with obese individuals [48].

2.2 Brain lactate metabolism in physiological and pathological aging

Lactate trafficking among astrocytes and neurons is mainly mediated by monocarboxylate transporter 2 (MCT2), which provides lactate uptake in neurons [49], and monocarboxylate transporter 4 (MCT4), which provides lactate release from astrocytes [49]. Both transporters serve vital functions necessary for memory formation and synaptic transmission in the hippocampus [50]. In an AD model, MCT2 and lactate levels were found to be reduced in the cerebral cortex and the hippocampus [51]. Hence, the alteration of these transporters could reduce lactate uptake into the neuron, further compromising energy metabolism and inducing cognitive impairment.

Glycogen is primarily stored in astrocytes, since its accumulation in neurons can induce apoptosis, thereby increasing the probability of suffering from dementia [52, 53]. Therefore, under physiological conditions, neurons inhibit their storage across the laforin-malin complex. Laforin is an enzyme that promotes glycogen storage but, in combination with malin, it stimulates proteasomal degradation of glycogen synthase. In the hippocampus of aged animals, Laforin becomes increased five-fold compared to adult mice and could induce increased glycogen synthesis in aged animals, which would be detrimental to neurons [54, 55].

In order to meet the energy demand of the brain, the system can generate more efficient compensatory mechanisms for quick energy production by either reducing the number of transporters in neurons or increasing the number of transporters in astrocytes.

In a study using proteomics, immunofluorescence, and qPCR in aged animals, glycogen phosphorylase (PYG), glycogen-degrading enzyme, was found to have increased its activity in hippocampal neurons, leading to a decrease in memory consolidation [56]. On the other hand, a decreased glycolytic capacity of astrocytes, along with a decrease in the number of suitable transporters for lactate secretion (MCT1) would balance the increased neuronal production of this compound, and the astrocytes would use the lactate produced by neurons to fuel. This could be a protective mechanism against neurodegeneration in the aged hippocampus.

Lactate is produced in neurons through neuronal lactate dehydrogenase (LDH) activity [57]. Native LDH consists of 4 LDHA or LDHB subunits assembled in all possible combinations, forming a variety of tetrameric LDH isoenzymes [57]. LDHA isoenzymes particularly favor anaerobic glycolysis, which may catalyze pyruvate to lactate, while LDHB isoenzymes mostly catalyze the conversion of lactate to pyruvate [58]. Studies shows that neuronal LDHA and LDHB are reduced, and that reduced levels of neuronal LDHB are more evident than neuronal LDHA in APP/PS1 mice. Meanwhile, the neuronal LDHA/LDHB ratio is increased in APP/PS1 mice compared to control mice.

On basis of these data, reduced expression of MCT2 and MCT4 is suggested to possibly prevent lactate transport from astrocytes to neurons. Consequently, neurons become lactate deficient. Also, reduced brain lactate levels further aggravate energy deficiency in neurons. Neurons can increase neuronal LDHA/LDHB ratio to favor lactate production and partially alleviate their lack of energy substrate. Nevertheless, this compensatory enzyme modification is still insufficient to compensate for energy deficiency in neurons.

Studies in human brain cortex show that lactate could replace glucose to support respiration under basal conditions and during electrical stimulation [59]. Neurons in vitro prefer lactate over glucose when both substrates are provided [60]. In vivo studies demonstrate the existence of a metabolic coupling between astrocytes and neurons where a lactate gradient from astrocytes to neurons occurs [61]. Pharmacological inhibition of MCT2 irreversibly impairs long-term memory in mice [62]. Long-term memory impairment can be reversed by intrahippocampal administration of lactate—not glucose—in MCT4-deficient mice [63]. Additionally, heterozygous MCT1 knockout mice have impaired inhibitory avoidance memory [64]. All these results strongly suggest that neuronal lactate uptake is important for the recovery of long-term memories. The overall contribution of lactate to brain metabolism differs according to its availability. Studies in conscious humans have shown that, under resting conditions, lactate uptake by the brain provides about 8% of its energy needs. This percentage increases to 20% under high plasma lactate level conditions, such as during intense exercise [65]. Furthermore, under different exercise intensities, brain lactate metabolism is higher in trained subjects compared to controls. This suggests the possibility of adaptive mechanisms that allow the brain to respond to changes in substrate availability.

In a study, plasma samples were analyzed for fasting lactate to compare lean subjects, non-diabetic subjects with severe obesity, and metabolically impaired subjects. Fasting plasma lactate was elevated in obese subjects with the metabolic syndrome compared to healthy lean individuals. These data suggest that elevated lactate may be caused by an impairment in aerobic metabolism and may offer a focus assessing the severity of the metabolic syndrome [66].

2.3 Brain metabolism of ketone bodies in physiological and pathological aging

Ketone bodies such as β-hydroxybutyrate (BHB) and acetoacetate (AcAc) are recognized as essential energy substrates for the brain during development, delivering up to 30–70% of its energy requirements [67]. In the adult brain, ketone utilization is markedly reduced when being fed, but may increase under conditions of limited glucose availability, such as during fasting, starvation, low-carbohydrate/high-fat intake, and intense or prolonged exercise sessions. Under such conditions, the liver generates ketone bodies from the oxidation of fatty acids and ketogenic amino acids. Astrocytes can metabolize and deliver ketone bodies to neurons from fatty acid β-oxidation [68], however the rates of fatty acid transport are very low compared to those in the liver. In adults, the activity of ketone- metabolizing enzymes is high enough to easily allow a complete switch from glucose to ketones to meet the energy needs of the brain [69]. Because ketones are never produced in saturated concentrations, the brain’s rate of utilization is strictly regulated by their concentration in blood. In fact, brain glucose utilization during ketosis has been proven to decrease by approximately 10% per millimole of plasma ketones [70].

Whenever glucose availability declines due to fasting, starvation, exercise, caloric restriction or the ketogenic diet (KD), glycogen reserves in the liver become depleted and lipolysis of triacylglycerols or diacylglycerols in adipocytes generates free fatty acids (FFAs). The liver uses these fatty acids and ketogenic amino acids such as isoleucine, tryptophan, tyrosine, leucine, lysine, phenylalanine, and threonine. FFAs are metabolized by β-oxidation to AcetylCoA, which is used to generate ketone bodies such as AcAc, BHB and acetone (AC). AC is rapidly eliminated through urine and lungs, while BHB and AcAc cross the BBB into the neuron via monocarboxylic acid transporters (MCTs). In the anabolic pathway that takes place in the cytosol, acetoacetate is converted into acetoacetyl-CoA (AcAc-CoA) by the enzyme acetoacetyl-CoA synthase (AACS). AcAc-CoA can be synthesized into acetyl-CoA to generate sterol precursors, 3- hydroxy-3-methylglutaryl-CoA (HMG-CoA) by 3-hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS 1). Acetyl-CoA produced from AcAc-CoA by cytosolic β- ketothiolase (cBKD) or from citrate by ATP-citrate lyase (ACLY), can be converted into malonyl-CoA for fatty acid synthesis. The amino acid can be synthesized using TCA cycle intermediates. Ketone oxidation occurs in mitochondria where AcAc captured or generated directly from 3 HB by 3-β-hydroxybutyrate dehydrogenase (BDH) is converted into acetyl-CoA via succinyl-CoA-3-oxoacid CoA transferase (SCOT) and mitochondrial β-ketothiolase (mBKD). Complete oxidation of AcAc produces 23 ATP molecules, while 3 HB generates 26 ATP molecules. Additionally, astrocytes have an important local reserve of βHB for neurons [71].

Studies show that these metabolic challenges (fasting, exercise, caloric restriction, or ketogenic diet) should be intermittent as they increase insulin sensitivity and increase glucose reuptake and utilization by neurons. The incorporation of glucose stimulates the release of the hormone glucagon-like peptide 1 (GLP1), which crosses the BBB and has a direct action on neurons, hence improving cognitive function [72].

3. Metabolic challenges improve cognitive function when suffering from dementia

Whereas brain glucose metabolism declines with normal aging and more severely in AD, the ability to metabolize ketone bodies becomes another form of energy substrate for the brain and remains normal in older people and AD patients [73, 74]. Several clinical studies in aging with cognitive impairment or AD show how metabolic interventions can improve cognitive processing and possibly mitigate the effects of AD disease.

A cohort study in 70.1 (± 6.2) years patients and educational level 15.3 (± 2.8) years with cognitively impaired were given an additional 50% calories while another group consumed just 20 g of carbohydrates per day to maintain ketosis for 6 weeks. The group that held a lower caloric consumption had a higher intake of fat and protein (a typical KD). This group increased learning and memory, and their urine ketones increased by 5.4 mg/dl [75]. Researchers found that ketone concentrations had a significant correlation with memory performance.

A longitudinal study ran 2 caloric restriction diets to overweight and obese people for 1 year. A low-fat diet (46% carbohydrates and 30% total fat; <8% saturated fat) and a low-carbohydrate diet consisting of 20–40 g carbohydrates (4% energy) and a higher amount of fat (61% energy, 20% saturated). In addition to a reduction in weight, plasma glucose and serum insulin, working memory was significantly improved by KD intervention [76].

Several studies have suggested that ketogenic dietary interventions may slow functional cognitive impairment and the development of dementia; however, the benefit of KD-induced ketosis may be limited to those without the apolipoprotein E4 (ApoE4) variant [77]; a variant known to be associated with AD [78]. Nevertheless, a case study of a heterozygous ApoE4 71-year-old woman with metabolic syndrome and mild AD with progressive cognitive impairment showed significant improvement in memory measured by the Montreal Cognitive Assessment (MoCA) after 10 weeks of KD. The intervention was aimed at maintaining plasma ketones between 0.5 and 2.0 mg/dl while also doing physical and mental exercises [79]. Similarly, an obese heterozygous ApoE4 68-year-old man with mild AD and type 2 diabetes mellitus showed improvement on the MoCA scale, which represented an AD regression after 10 weeks of KD. In the latter case, a hybrid KD approach with time-restricted intermittent fasting (IF) was applied 3 days a week [80]. In both cases, improvements in various metabolic parameters such as glucose, glycosylated hemoglobin, insulin and lipid profile were documented [79, 80]. Even though multiple elements might have contributed to the cognitive improvements observed, these case studies have provided groundbreaking evidence of the potential to delay or reverse mild cognitive impairment from progressing to AD through ketogenic dietary interventions, even in ApoE4+ cases.

In view of pathological aging such as Alzheimer’s, mitochondria isolated from animal models and Alzheimer’s patients show reduced enzymatic activity of the cytochrome C oxidase complex (ETC IV) [81] at the cellular level, as well as decreased oxidative respiration and progressive accumulation of Aβ in the mitochondria of neurons [82]. Both metabolic dysfunction and mitochondrial Aβ accumulation appear to occur early in disease progression before the onset of amyloid plaque formation [83]. This suggests that early metabolic dysfunction is a key process in Alzheimer’s progression and a potential target for therapeutic intervention.

An interesting nutritional strategy would be to improve the quality of fatty acids with medium chain fatty acids (LCFA) that are directly absorbed into the portal vein instead of the lymphatic system. Caprylic acid (C8) and capric acid (C10), medium chain fatty acids (MCFAs), are most ketogenic, which can be found in coconut oil and palm kernel oil [84]. Nevertheless, the concentration of these lipids is relatively low in coconut oil interventions, as they only raise levels of ketones slightly ~0.6 mM [84, 85].

Another alternative to the ketogenic diet is the ingestion of exogenous ketone esters and salts, which significantly increase ketone levels to >1 mM after ingestion, where ketone ester is the most potent in increasing circulating ketones even while consuming regular meals [86, 87]. Ketone salts often consist of a mixture of BHB D and L isoforms, although the metabolic contribution of L isoform is poorly understood. All three approaches (ketogenic diet, MCFA and exogenous ketone bodies) have been used in studies of neurodegenerative diseases, where MCFA becomes the most employed one. It is worth mentioning that MCFAs may have neuroprotective effects that are unrelated to ketonemia, as MCFAs can cross the blood-brain barrier (BBB) and work as substrates for energy metabolism [88]. Studies also establish that MCFA, capric acid, may have the ability to improve mitochondrial function and reduce neuronal hyperactivity, which is often observed in AD [88].

A study on 39 subjects 63-year-old with mild cognitive impairment were supplemented twice daily for 6 months with 15 g of MCFA. Participants showed an improvement in different cognitive domains, including episodic memory and executive function compared to 44 subjects with a non-ketogenic placebo. A marked increase in plasma ketones was observed only in those assigned MCFA, and this increase was directly and significantly correlated with cognitive improvements.

Another study on subjects with cognitive impairment were given 56 g of MCFA oil or a placebo (canola oil) for 6 months. Study subjects assigned to placebo reflected no changes in BHB levels or cognitive functions. Nevertheless, subjects who were administered MCFA oil as well as, one subject lacking the ApoE4 gene, showed an increase in BHB levels compared to baseline, which decreased over the following weeks. This was different from the other subject who had the ApoE gene, as he maintained this BHB increase throughout the study period. As for cognition, both subjects showed improvements in this sense, as measured by the Alzheimer’s Disease Assessment Cognitive Subscale (ADAS-Cog); however, the ApoE4- negative subject showed a greater improvement.

A study on people with very mild, mild, and moderate AD showed cognitive improvement in the Mini-Mental State Examination Scale (MMSE) and ADAS-Cog after 3 months of being supplemented with an MCFA. However, this improvement in cognitive function did not persist after the dietary intervention ended. These findings suggest that efficacy depends on administration time. In another study on AD subjects, they were given 20 g of MCFA for 3 months, which led to improvements in working memory, short-term memory, and processing speed.

4. Conclusion and future directions

Brain hypometabolism of glucose and lactate to be altered long before the onset of Alzheimer’s disease. Moreover, risk factors such as MetS in adulthood are a risk indicator for impaired brain metabolism which trigger the same metabolic effects as in pre-asymptomatic patients risking Alzheimer’s. Therefore, providing more ketones to the aging brain can help it overcome progressive deficit in glucose absorption and metabolism, which delays brain energy depletion and decreases the risk of cognitive impairment and/or Alzheimer’s disease.

Future challenges lie in elucidating the cellular and molecular mechanisms of nutritional therapies based on intermittent ketosis that account for the increase in synaptic plasticity, cognitive function, and resistance to neurodegeneration.

Understanding these mechanisms will contribute to the awareness of the pathophysiology of dementias and a more effective approach to their treatments.

Acknowledgments

This project was supported by ANID Grant Number SA77210016.

Conflict of interest

The author declares no conflicts of interest.