In my clinical practise, we periodically survey our clients on the health conditions or outcomes that most concern them. In the early years, we would consistently hear that the biggest concern was quite simply, weight… Now though, weight and body fat have fallen behind brain health and day-to-day energy as the major concerns for our clients. This is unsurprising given the rising incidence of neurodegenerative conditions Alzheimer’s, Parkinson’s, and other diseases that affect the brain and central nervous system.

What are ‘neurodegenerative disorders’?

Neurodegeneration is the progressive damage and destruction of neurons (brain and nervous systems cells) and/or components of those cells. This breakdown of cells results in age-related cognitive decline and in more serious cases the common neurodegenerative disorders; dementias such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (known as Lou Gehrig’s disease) and Huntington’s disease. According to Alzheimer’s Disease International, someone in the world develops dementia every 3 seconds. Additionally, over 50 million people now live with dementia worldwide and this number is expected to double every 20 years.^[1] The neurodegenerative disorders cause progressive disability, incurring a loss of cognition, memory, and physical function. Survival times are also typically short—for example, the average survival time post-diagnosis for Alzheimer’s disease is only 3-9 years.

Someone in the world develops dementia every 3 seconds

What causes cognitive decline?

Neurodegenerative disorders and age-related cognitive decline are both inherited (genetic) and also result from diet and lifestyle factors. These causes include head injuries, pesticide exposure (Parkinson’s), hypertension, lack of sleep, and a poor diet, along with additional risk factors of metabolic syndrome and diabetes, depression, excessive alcohol use, and tobacco use.¹

How can I improve my brain health and reduce my risk of cognitive decline?

Exercise the brain and the body

Lifestyle factors can reduce your risk of cognitive decline and even improve cognitive function. These include engaging in leisure and physical activities, playing a sport, listening to music, and doing brain-taxing activities (such as crosswords).^{1, 2}

Lifestyle factors can reduce your risk of cognitive decline

People who regularly and actively participate in a variety of social, cultural, and intellectual activities that challenge them, experience lesser cognitive decline, perform better on cognitive tests, and are less likely to develop neurodegenerative disorders.³ Physical activity shows a consistent, yet not always significant effect on cognitive decline and dementia,^4-6 and it’s likely that the effects of physical activity alone on cognitive decline are limited, and that the best effects come from a combination of physical activity, improved diet, and regularly challenging the brain with new activities.^{5, 6}

The best effects come from a combination of physical activity, improved diet, and regularly challenging the brain with new activities

Get enough sleep

Not sleeping enough, or poor sleep (i.e. insomnia, and lack of REM sleep) is a risk factor for cognitive decline and dementia.^{7, 8} It is recommended that people get between 7 and 9 hours of high-quality sleep per night.

Eat a healthy diet based on natural, unrefined foods

There is a relationship between diet and cognitive decline and it’s likely that eating a diet (such as the Mediterranean diet²) based mostly on natural, unrefined foods will reduce the risk of cognitive decline and dementia. In a review of studies, it was shown that following a Mediterranean diet was associated with up to a 48% reduced risk of dementia, and those with pre-existing Alzheimer’s disease had a 73% lower mortality risk than those who did not adhere to the diet.⁹

Increased fruits and vegetables

Increased intakes of fruit and vegetables are associated with both a lower risk of dementia and slowing rates of age-related cognitive decline.^{1, 10} However, subtype analysis has demonstrated that this effect is restricted to vegetables (and not fruit), with the strongest effects from cruciferous (like cabbage and broccoli) and green leafy vegetables.¹⁰ It has been further suggested that a minimum of 3 servings of vegetables should be consumed daily for this effect.¹⁰

The protective effect of fruits and vegetables is actually limited to vegetables…

Vitamin C

Maintaining healthy levels of vitamin C from nutrient-rich foods to avoid a deficiency (rather than mega-dosing) is also likely to have a protective function against age-related cognitive decline.¹¹

Omega 3 fats

The omega 3 fats EPA and especially DHA, play an important role in brain development and healthy functioning of the brain and central nervous system.¹² Omega-3 fats are linked to reduced mental fatigue,¹³ improved memory and cognition and reduced cognitive decline,^{1, 14, 15} reduced rates of depression and improved structural integrity of the brain.^{16, 17} Plausible mechanisms also exist to suggest a protective role for fish oil in neurodegeneration in Parkinson’s disease.¹⁸

Coffee and tea

Caffeine is a well-known cognitive enhancer. Evidence shows that caffeine improves attention, vigilance, reaction times, and problem-solving (especially in sleep-deprived people),^{19, 20} and improved mood and reduced fatigue even at low doses of caffeine-containing beverages (~ 1 cup of tea or coffee per day).^{20, 21}

Caffeine improves mood and reduces fatigue, even at low doses

In addition to its acute effect on mood and cognition, caffeine-containing beverages may be protective against cognitive decline and dementia,²² and coffee and tea are also associated with a reduced incidence of Parkinson’s disease.^{23, 24}

Multivitamin/Multimineral

Many people do not consume sufficient essential and secondary nutrients from diet alone.^{25, 26} Multinutrient supplements are suggested to help make up for this nutrient shortfall and have resulted in improved cognitive and memory performance in trials and reduced stress and anxiety.^{27, 28} It is likely that supporting the nutrient-sufficiency of the diet could improve long-term brain health and reduce cognitive decline.

Medium-chain triglycerides

Medium-chain triglycerides (MCT) are naturally occurring fats found in small amounts in dairy products and greater amounts in coconut oil. They are also commonly used as isolated supplement oils. MCT supplemented diets improve mental performance in those with Alzheimer’s Disease and age-related cognitive decline,^{29, 30} and a single dose of 20 g MCT has been shown to improve cognition.³¹

Lion’s Mane mushroom

Lion’s mane (Hericium erinaceus) is an edible and medicinal mushroom native to North America, Europe and Asia belonging to the tooth fungus group. Lion’s Mane has been shown to increase ‘Nerve Growth Factor’,³² which helps nerves and brain cells to grow and repair.^33-38 Because of this brain-repair effect, Lion’s Mane is being considered as one of the most promising preventatives for dementia and cognitive decline.^{39, 40} It’s also been demonstrated to significantly reduce depression and anxiety,³⁴ and to improve cognitive function.⁴¹

Other supplements indicated for cognitive decline

• Citicoline (an intermediate in the creation of phosphatidylcholine from choline) is likely to improve cognition in both dementia patients and healthy people.⁴²
• Acetyl-L-carnitine has been shown to reduce fatigue, anxiety and depression, and age-related cognitive defects.⁴²
• The traditional ayurvedic herb Brahmi (Bacopa monnieri) is likely to improve cognition, memory, and reaction times.^43-45
• The use of Ginkgo is controversial but recent reviews suggest a plausible role for ginkgo extracts to reduce cognitive decline (especially for patients with neuropsychiatric symptoms).⁴⁶
• Sage (Salvia officianalis) improves mood, alertness and attention, calmness, and overall cognition,^47-50 and is likely to improve brain health and reduce cognitive decline.
• Spearmint (Mentha spicata) is another common herb with purported cognitive effects. Spearmint extracts have resulted in improved cognitive scores in several studies.⁵¹ (Interestingly, one of the purported ‘active’ chemicals, rosmarinic acid, is also common in other herbs such as rosemary, for which it is named, and thyme).

Can a Keto diet improve cognition and prevent cognitive decline?

Ketogenic diets are low enough in carbohydrate and high enough in fat to encourage the creation of ketone bodies in higher than normal amounts (the body always produces a small amount of the ketone bodies). This ketonaemia (the presence of ketones in the blood) is called nutritional ketosis, which is typically just called ketosis. Very low carbohydrate ketogenic diets typically result in BOHB levels of ≥ 0.5 mmol/L,⁵² and this level is used as the threshold for achieving ketosis by nutrition researchers.^53-57

A ketogenic diet is simply a diet very low in carbohydrate, low-to-high in protein, and high in fat

Ketone Bodies

The ketone bodies are ‘brain-friendly’ fuels derived from fatty acids and some amino acids, especially leucine and lysine (which can only be converted to ketones, not to glucose). The ketone bodies are acetoacetate, ß-hydroxybutyric acid (BOHB) and acetone. While acetoacetate is the primary ketone body, BOHB functions as the main fuel ketone.^[2]

Ketogenic Diets, Ketosis and the Brain

The potential role of ketogenic diets for brain health has been hinted for over a century and keto-diets have been used to successfully treat childhood epilepsy since the 1920s.^58-61 It is now known that high carbohydrate diets play a role in the causation of Alzheimer’s Disease and cognitive decline, and ketogenic diets offer a potential treatment option.⁶² Both calorie-restricted diets and ketogenic diets are broadly neuroprotective,⁶³ probably due to reduced carbohydrate intake (i.e. reduced glucose-related damage to neurons) and due to the elevation of ketones and resultant reductions in oxidation and inflammation, reduced neuronal hyperexcitability, neuroprotection and neurogenesis, and improved fuel efficiency in the brain. ⁶⁴

In pilot studies, elevated ketones improve memory in adults with Alzheimer’s and reviews of the evidence show a positive role for the keto-diet in its treatment. Early research also suggests that keto can reduce Parkinson’s disease activity.^{65, 66}

Animal studies show benefits for reducing the plaque deposits that are part of the damage inflicted by Alzheimer’s,⁶⁷ along with improvements in motor function and improved neuronal fuelling.^{68, 69} In human studies the keto-diet has been easily tolerated by Alzheimer’s patients while improving cognition and memory performance vs a higher-carbohydrate control group.^{70, 71}

Ketogenic diets also reduce inflammatory damage in Parkinson’s disease.⁷² In rat models, a ketogenic diet protects dopamine-producing neurons of the substantia nigra. These neurons are cells damaged by endotoxicity in Parkinson’s, resulting in the loss of motor and other functions and so their protection is a key target of therapy,⁷³ and keto-diets improve motor function in rats with Parkinson’s.⁷⁴

In mouse studies, ketogenic diets reduce the loss of motor neurons on amyotrophic lateral sclerosis (ALS or ‘Lou Gehrig’s disease) and reduce muscle wasting.⁷⁵ Similarly, a ketogenic diet reduces wasting in Huntington’s disease.⁷⁶

Case study evidence is also beginning to show mood stabilising effects from the ketogenic diet used to treat type 2 bipolar disorder. ⁷⁷

Why do Ketones Have these Effects on the Brain?

Reduced inflammation

β-hydroxybutyrate directly reduces inflammation by suppressing activation of the NLRP3 inflammasome.⁷⁸ Interestingly, inflammatory messengers like tumour-necrosis factor alpha (TNF-α) might reduce the body’s ability to produce ketones,⁷⁹ and so, taking exogenous ketone supplements, or MCTs might help the body to reduce inflammation, while also allowing there to be a better internal environment for ketogenesis.

Reduced accumulation of malformed proteins and plaques

Proteins (like tau-protein) in the brain become distorted (mainly due to hyperphosphorylation) and accumulate in the brains of Alzheimer’s patients. These cause neuronal dysfunction and additional damage to neurons. These malformed and aggregated proteins are present in most people and can cause damage even if that person does not have Alzheimer’s. These proteins and plaques (β-amyloid) present in AD and other neurodegenerations are reduced by ketogenic diets/ketones.

Improved fuelling

Almost all cells, except those lacking mitochondria, such as red blood cells, can also utilise lipid-derived fatty acids (via β-oxidation) and most cell types (such as neurons and cardiac tissue) have a high affinity for ketone fuels. The entry of long-chain fats (the common dietary fats) into the brain and central nervous system tissue, is limited because the use of these fuels by neurons can cause hypoxia (lack of oxygen) and cell death. When the blood-brain barrier and cell membranes in the brain are damaged by trauma and injury though, or by endotoxicity and protein damage, long-chain fats can enter the brain and neurons, causing further injury. Interestingly astrocytes in the brain and CNS might ‘scavenge’ some of these fatty acids, to convert them to ketones for use as fuel, thus, preventing some of that damage.⁸⁰

Astrocytes in the brain and CNS ‘scavenge’ fatty acids to convert them to ketones for use as fuel

Glucose in excessive amounts is also undesirable, despite it being the main fuel for the brain. When glucose levels are consistently elevated, there is greater potential for glycation or damage to proteins caused when sugars ‘stick’ to proteins, which causes them to become dysfunctional. Ketones, on the other hand, are able to be used by neurons, without the raft of negative effects caused by long-chain fats and excessive carbohydrate intake.

Ketones are also protective against the effects of ischemia (loss of blood supply to tissue),^{81, 82} and cell damage caused by hypoglycaemia.⁸³

Ketones are also protective against the effects of ischemia (loss of blood supply to tissue) and cell damage caused by hypoglycaemia

Reduced excitotoxicity and neurotoxicity

Ketones improve the GABA to glutamate ratio. Gamma-aminobutyric acid (GABA) is a relaxing neurotransmitter, conversely, glutamate is an excitatory neurotransmitter. When there is an imbalance of these (too much glutamate, and too little GABA), excitotoxicity occurs. Excitotoxicity refers to the overstimulation of neurons, especially by glutamate. This causes an increase in calcium uptake into neurons which in turn, signals the activation of various enzymes which in excess, damage DNA, cell membrane, and other structures directly, and by damaging cell membranes, allow additional damage to those cells. This toxicity is implicated in Alzheimer’s, ALS, Parkinson’s, Huntington disease, brain injury and concussion, multiple sclerosis, alcoholism, and drug withdrawal. Excitotoxicity is reduced by ketones and a ketogenic diet, and worsened by excessive carbohydrate intake and rebound hypoglycaemia (low blood sugar, often caused by insulin resistance/pre-diabetes).⁸⁴

Neurogenesis

Ketones initially increase oxidative stress but a rapid adaptation, along with increased antioxidant activity and reduced excitotoxicity also results in increased brain-derived neurotrophic factor (BDNF).⁸⁵ This makes it highly likely that ketones can help the neurons of the brain to both survive, and to ‘regrow’ and repair.

Ketones can help the neurons of the brain to both survive, and to ‘regrow’ and repair.

What does this all mean?

Ketones provided by diet or supplements can help to support the healthy functioning of the brain and reduce damage to neurons. They provide fuel, reduce damage to neurons, and reduce the accumulation of plaques and proteins implicated in neurodegeneration. Furthermore, they help to reduce over-stimulation of the neurons and improve anxiety.

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[1] https://www.alz.co.uk/research/statistics

[2] Technically BOHB is not a ketone body as the ketone moiety has been reduced to a hydroxyl group