Food for thought: the emerging role of a ketogenic diet in Alzheimer’s disease management

KEYWORDS:

• Alzheimer disease
• dementia
• high fat diet
• ketogenic diet
• low carbohydrate diet
• medium-chain triglycerides
• nutrition

1. Introduction

Alzheimer disease (AD) is the leading cause of dementia in aging societies worldwide. A complex interaction of multiple mechanisms and neurodegenerative processes leads to the development of AD, and the initial pathological process may start as long as 20 years before its clinical manifestation. Currently, available therapies are still ineffective [1]. Therefore, the search for AD prevention and treatment methods also includes dietary modifications. Research indicates the potential importance of specific food components in preventing and managing AD, such as omega-3 fatty acids, vitamins B and E, choline, and uridine. However, clinical evidence on whether nutritional supplementation prevents AD onset or progression is still lacking. Thus, alternative strategies based on dietary patterns seem to be more valuable and promising than focusing on single food components. Recently, particular attention has been paid to the possible function of three dietary patterns in AD prevention: the Mediterranean diet, the Dietary Approaches to Stop Hypertension (DASH) diet, and the Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet. These dietary patterns have well-known anti-inflammatory and antioxidant properties, and their neuroprotective properties have been shown to be related to their high bioactive compound content. Further, based on animal models in AD studies, intermittent fasting and calorie restriction are emerging as new approaches that appear to lead to motor and cognitive improvements by promoting hippocampal neurogenesis, activating adaptive stress response systems, and enhancing neuronal plasticity [2].

Another dietary pattern has attracted increasing interest in AD prevention and treatment is a ketogenic diet (KD). KD allows imitating effects of fasting and induces physiological ketosis, owing to the diet’s extremely low amount of carbohydrates (usually < 50 g/day), through which fats become the body’s main energy source. After two to three days following KD, the body’s glucose resources (e.g. glycogen in the liver) are depleted and become insufficient for the normal course of fat oxidation and meeting the needs of the central nervous system (CNS). Ketone bodies (KBs), which are produced from fatty acids (ketogenesis) in the matrix of hepatic cells, become a new source of energy. During ketogenesis, the concentration of KBs (mainly beta-hydroxybutyrate) in the blood gradually increases, and when it reaches over 4 mmol/L, KBs become a source of energy for the CNS. In physiological ketosis, the concentration of KBs does not exceed 8 mmol/L, blood pH is maintained at a normal level, and glycemia, although decreasing, remains at its physiological concentration [3].

An increased level of KBs and a reduction in blood glucose concentration are vital factors for the therapeutic effects of KD. Impaired glucose metabolism and diabetes are related to AD, although the underlying pathophysiological mechanisms are unclear [4]. Reduced glucose uptake and inefficient glycolysis due to the downregulation of the glucose transporters GLUT1 and GLUT3 are observed in the brains of these patients [5]. Therefore, KBs could provide a supplementary energy supply for the CNS. They also have antioxidant action, increase glutathione and glutathione peroxidase activity, reduce the production of free radicals, inhibit apoptosis, and control the stabilization of nerve-cell synapse functions [3]. Another protective effect of KBs in AD may be their defense against the production of amyloid plaque and its neurotoxicity [6].

2. Ketogenic diet characteristics

The traditional diet usually provides approximately 55%, 15%, and 30% energy from carbohydrates, proteins, and fats, respectively. The classic KD, as designed by Dr. Russell Wider in 1923, provides 90% energy from fat, 7% from protein, and only 3% from carbohydrates. Although a 4:1 ratio of fat to protein and carbohydrates is considered the gold standard for classic KD, a 3:1 ratio is also included in descriptions of this diet. A modified Atkins ketogenic diet (Atkins-KD) was proposed in 2003. In Atkins-KD, carbohydrates are restricted, providing 5% energy, while proteins and fats provide approximately 25% and 70%, respectively [7]. In recent years, the Mediterranean diet has also been adapted to adhere to KD guidelines. In the modified Mediterranean-ketogenic diet (Med-KD), carbohydrates, fat, and protein provide less than 10%, 60–65%, and 30–35% of energy, respectively [8]. Researchers from New Zealand have used another KD plan, which provides an average macronutrient ratio of 58% fat (26% saturated, 32% non-saturated), 29% protein, 7% fiber, and 6% net carbohydrates by weight [9]. The main fat sources in these ketogenic diets are long-chain fatty acids. Since the 1970s, the medium-chain triglyceride (MCT) ketogenic diet (MCT-KD) has been used. The macronutrients in MCT-KD provide 20%, 10%, and 70% energy from carbohydrates, proteins, and fats [7]. MCT supplementation allows ketosis to be achieved despite the higher proportion of carbohydrates in the diet, possibly because, after MCT hydrolyzation occurs in the gut, medium-chain fatty acids are rapidly absorbed into the bloodstream and reach the liver faster than long-chain fatty acids, in which the lymphatic system is involved in absorption and transport. It should be noted that medium-chain fatty acids are a good ketogenic substrate, as they do not need chylomicrons for transport or carnitine for mitochondria entry, and its β-oxidation in the liver is rapid because it does not need to be activated by coenzyme A [10].

3. Clinical studies

There are few randomized controlled trials focusing on the impact of ketogenic therapies on ameliorating cognitive function and delaying AD progression. The first study in which the feasibility and cognitive effects of KD in participants with AD were assessed was published by Taylor et al. in 2017 [11]. Fifteen enrolled participants with AD followed a medium-chain triglyceride-supplemented KD for three months, and the 10 completers achieved ketosis. Among the completers, the mean score of the Alzheimer’s Disease Assessment Scale-cognitive subscale improved significantly during the diet, and reverted to baseline after the one-month washout period. In 2020, Grammatikopoulou et al. [12] published a systematic review that identified only 10 studies assessing the effects of ketogenic therapy on mild cognitive impairment (MCI) or AD compared with placebo, usual diet, or meals lacking ketogenic agents. The authors concluded that the interventions were either heterogeneous, acute, or long-term (45–180 days), including adherence to KD, intake of ready-to-consume drinks, MCT powder for drink preparation, yogurt enriched with MCT, MCT capsules, and ketogenic formulas or meals. The participants were in the early stages of the disease, and the interventions effectively improved general cognition as well as episodic and secondary memory. However, psychological health, executive function, and attention did not show improvement. In all studies, increased blood ketone levels were observed, and the concentration correlated with neurocognitive improvement based on various tests. Cerebral ketone uptake and utilization were improved.

A few reports from randomized controlled trials have been published in the last two years. Nagpal et al. [13] compared the effects of Med-KD and AHAD on neuroimaging measures, cerebrospinal fluid AD biomarkers, peripheral metabolism, and cognition in older adults at risk for AD. Eleven participants with subjective memory complaints and nine with MCI completed both diets (six weeks separated by six-week washout periods). Med-KD was well-tolerated with good compliance. In addition, this KD was associated with improved metabolic indices and led to improvement in the AD cerebrospinal fluid biomarker profile and increased cerebral perfusion and ketone metabolism. Xu et al. [14] investigated the effects of MCT on cognitive ability in a randomized controlled trial with 53 patients with mild-to-moderate AD. Participants took either MCT jelly or placebo jelly by mouth three times daily for 30 days. This study showed that MCT supplementation leads to a significant reduction in Alzheimer’s Disease Assessment Scale-Cognitive scores. The authors concluded that these effects of MCT might be related to the metabolism of lysophosphatidylcholine, oleic acid, linoleic acid, and palmitic acid, in addition to the ketogenic effect.

Fortier et al. [15] assessed the influence of MCT supplementation on brain energy metabolism and cognition in 39 patients with MCI who received 30 g/day of MCT or placebo for six months. Brain KB metabolism increased by 230% in the MCT group, whereas brain glucose uptake remained unchanged. Measures of episodic memory, language, executive function, and processing speed improved in the MCT group compared to baseline. Increased brain KB uptake was positively related to several cognitive measures. In a subsequent study, the same research group [16] assessed cognitive changes in MCI patients (39 and 44 in the intervention and control groups, respectively). During the six-month intervention, participants received either an MCT supplement (15 g twice/day) or placebo. Improvements in executive function, memory, and language were observed in the MCT group. Higher levels of plasma KBs positively correlated with changes in cognitive tests. The plasma metabolic profile and ketone response remained unchanged after six months of MCT supplementation. The authors concluded that rescuing brain energy with an MCT drink could significantly improve cognitive outcomes in patients with MCI.

In a recently published randomized crossover trial, Phillips et al. [9] determine whether a 12-week modified KD improved cognition, daily function, or quality of life in a hospital clinic of AD patients. Patients achieved sustained physiological ketosis. The authors concluded that high rates of retention, adherence, and safety appeared to be achievable by for patients with AD by adhering to a 12-week modified KD. The patients showed improvements in daily function and quality of life, while changes in cardiovascular risk factors were mostly favorable, and adverse effects were mild (most commonly increased irritability).

Two earlier case studies are also worth noting in the context of using KD in AD therapy. In the first study [17], a 63-year-old man with younger-onset AD (diagnosed at age 51) received supplementation with ketone monoester (KME) thrice daily. Circulating beta-hydroxybutyrate levels were elevated after KME administration. During the 20-month study, improvements in behavior, cognitive function, and daily activity performance were observed. The physician-caregiver noted that performance seemed to track plasma KB concentration, with conversation and interaction declining as levels decreased toward baseline. Initially requiring almost constant supervision, the patient became much more self-sufficient. In the second case study [18], a 71-year old woman with mild AD was placed on a 10-week nutrition protocol with the aim of raising plasma KBs through KD, time-restricted eating, and physical/cognitive exercise. Her Montreal Cognitive Assessment score was 21/30 pre-intervention and increased to 28/30 post-intervention. This suggests that KD may serve to improve cognition in patients with mild AD.

4. Limitations and potential side effects of a ketogenic diet

Based on the limited clinical trials, KD has been associated with improved cognitive performance in elderly adults with MCI and AD. However, despite these studies’ promising findings, some limitations must be acknowledged. Previous clinical studies conducted with people with AD did not contain information regarding reliable biomarker evaluation of this disease. Biomarker evidence may increase the certainty in people who meet the core clinical criteria for probable AD dementia that the basis of the clinical dementia syndrome is the AD pathophysiological process [19]. Therefore, the results discussed above on the impact of KD on the symptoms of this disease apply to people with clinical AD. Moreover, these studies appear to be highly heterogeneous, differing in participant age, gender, and cognitive status and intervention type. All the randomized control trials aimed to measure acute or short-term changes (< 180 days) in cognition or brain metabolism. The observation period lasted longer than a year and a half in only one case study. In addition, the short follow-up durations and repeated cognitive assessments could have resulted in a retest effect in individuals with MCI, and patients with mild-to-moderate AD may not be able to observe benefits from the intervention. Furthermore, there is a lack of research with long-term follow-up to evaluate the persistence of cognitive changes after nutritional intervention completion. Although adherence to KD or MCT supplementation seems to produce good short-term effects, this must be carefully examined over a long-term period.

Patients can initially be motivated to follow KD; however, over time, they may demonstrate poor tolerance to a diet heavy in fat-rich foods and lacking carbohydrates. Moreover, monitoring potential adverse effects is mandatory. Although the above-cited studies reported good KD or MCT supplementation tolerance and no severe side effects, the long-term safety must be assessed. The reported short-term mild side effects included increased irritability, increased fatigue, sugar cravings, insomnia, muscle cramps, constipation, excessive hunger, nausea, headache, and diarrhea [9]. Particular attention should be paid to the influence of these dietary interventions on patients’ nutritional status. Neurodegenerative diseases cover a segment of the adult population that is at high risk of physiological age-related physical decline [20]. Moreover, the nutritional status of patients with cognitive decline is a severe predictor of rapid cognitive decline and functional limitations [21]. KD is commonly associated with weight loss due to reduced total energy intake [22]. On the one hand, the KD has an anorectic effect; on the other hand, the organoleptic attractiveness of this diet is low, especially after a long period of use. As a result, the amount of food a patient consumes may decrease. While such effects of KD are expected in obesity treatment [23], they are unfavorable in people at risk of malnutrition.

Moreover, KD can cause not only energy deficiency but also an insufficient protein supply. Therefore, a ketogenic approach could increase the risk of nutritional frailty, due to loss of weight and muscle strength. It should also be noted that KD may cause difficulties with achieving an adequate vitamin and mineral intake due to the drastic limitation of foods high in carbohydrates (e.g. cereals, carbohydrate-rich fruits, and vegetables). Currently, there is only one short-term study that describes the nutritional quality of KD used in therapies for patients with AD. Taylor et al. [24] reported that it is possible for KD to be nutritionally dense with a high intake of low-carbohydrate vegetables. In this three-month observation, micronutrient supply in KD achieved dietary reference intake for most nutrients. However, since using MCT supplements does not require such drastic dietary changes, it appears to be a safer way to obtain increased KB levels in the blood. Higher acceptable carbohydrate content in the diet of people taking MCT supplements allows for increased dietary diversity and long-term adherence. However, it should be noted that the use of MCT may also cause mild side effects, such as abdominal or stomach discomfort, reflux, diarrhea, nausea, bloating, headache, and constipation [15,16].

There is no long-term data regarding the use of KD in people with cognitive impairment or AD. The lack of this type of observation could be explained by the very nature of the ketogenic protocol, as it is restrictive in terms of both calories and carbohydrates and therefore predisposed to poor long-term adherence. The observations from prolonged KD adherence in other diseases have indicated that this type of diet might cause a reduction in mineral bone density, nephrolithiasis, impaired hepatic functions, hypoproteinemia, deficiencies in vitamin and mineral components, and anemia [3]. Some concerns about KD are related to its effects on the circulatory system. A high-fat, low-carbohydrate diet may increase low-density and very low-density lipoprotein concentration in the blood [23]. Cardiovascular diseases of unknown etiology have been reported in clinical trials of KD users [25]. Increased serum KB levels were independently associated with cardiovascular events and all-cause death in patients receiving hemodialysis [26]. A recently published study reported that prolonged KD exposure induces cardiac fibrosis [27]. In rats, KD or frequent deep fasting decreased mitochondrial biogenesis, reduced cell respiration, and increased cardiomyocyte apoptosis and cardiac fibrosis. A high-fat diet can also be dangerous to the brain. Holloway et al. [28] reported that in healthy young adults, a diet with a daily caloric intake that is 70% fat, 4% carbohydrates, and 26% protein reduced cognition (i.e. impaired attention, speed, and mood). Thus, it can be surmised that KD, apart from some possible benefits, may also be associated with health risks. Most early- and late-onset complications from KD are transient and can be successfully managed with careful follow‐up. Particular care should be taken when patients have comorbidities, and it is planned to use KD for a long time. Strategies should be implemented to prevent possible adverse long-term effects of KD.

5. Conclusions

Although limited in number, available clinical studies indicate the beneficial effects of KD or MCT supplementation on reducing AD symptoms. The studies included a small number of participants with MCI or various stages of AD, and the research protocols and intervention lengths differed. Ketogenic therapy improved memory and increased blood KB concentration, which is correlated with neurocognitive improvement. Over a short-term period, patients have demonstrated good adherence to this therapy. The observed side effects were mild and short term. The key to achieving the therapeutic effect of KD is to obtain a constant, elevated KB concentration in the blood over a long period of time. Therefore, the search for a well-tolerated dietary pattern following KD guidelines (including adequate MCT supplementation) seems crucial for future research on AD management. It should also be noted that possible positive effects of KD in AD patients were reported in few studies and need to be confirmed in larger studies with longer follow-up periods using biomarker-based stratification of participants.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.