Ketones and Your Brain: How Keto Can Affect Brain Health

Ketones and Brain Health: How Ketones Fuel Your Brain

Your brain doesn’t run on glucose alone. It can also use ketones, an alternative fuel made by the liver from fat. Think of it a little like a hybrid car, able to draw on more than one source of energy.

Most of the time, your brain relies heavily on glucose. But when ketones are available, it can use these alongside glucose to help meet its considerable energy demands. Brain cells can use other fuels too, including lactate, but glucose and ketones are our focus here.

This ability to use different fuels is one reason ketones have become such an interesting area of brain research, particularly as we age. So what does science actually tell us about ketones and brain health? And can you raise your ketones without following a strict ketogenic diet?

Ketones and brain health: quick answers:

Are ketones good for the brain? Your brain prefers glucose but it can also use ketones, made in the liver during fasting, carbohydrate restriction or a ketogenic diet. As we age, and especially in the early stages of Alzheimer’s, the brain often gets worse at using glucose while its ability to use ketones holds up. That’s why researchers are investigating ketones as a way to support brain energy.

Is ketogenic diet good for brain health? Ketogenic diets have an established medical role in some forms of epilepsy. Early trials in mild cognitive impairment and Alzheimer’s disease are encouraging, but the evidence isn’t yet strong enough to say everyone should follow a strict ketogenic diet for better brain health.

What are ketones?

Ketones are an alternative source of energy for the brain, produced mainly by the liver when carbohydrate availability is low. Ketones, or ketone bodies, are small, fast fuel molecules that your liver makes from fat when glucose is in short supply. The two that matter for energy are beta-hydroxybutyrate (BHB) and acetoacetate. A third, acetone, is the one you breathe out, which is where “keto breath” comes from.

Brain cells, or neurons, are tightly packed and need instant fuel. They can’t burn fatty acids the way muscle cells can, so they rely on just two fuels: glucose or ketones. Support cells called astrocytes sit right next to the neurons and help supply them with fuel.[9]

You make some ketones every night while you sleep. Levels rise further the longer you go without food, the fewer carbohydrates you eat, and when you eat certain fats, especially the medium-chain fats in C8 oil.

Can your brain run on ketones?

Yes, to a large degree, though never completely.

On a typical carb-rich diet, glucose supplies around 90–95% of the brain’s energy and ketones only about 5–10%.[10] Much of the time the brain simply isn’t offered many ketones.

That changes when carbohydrates are scarce. In the classic study on this question, three people fasted for five to six weeks under medical supervision. By the end, ketones had overtaken glucose as their brain’s main fuel, supplying roughly two-thirds of its energy.[6] That’s an extreme situation, but it shows how much ketone fuel the brain can handle.

A few points follow from this:

The brain still needs some glucose. You don’t need to eat it, though. Your liver makes what’s required from protein and from the glycerol part of fat.

The more ketones in your blood, the more your brain uses. Cunnane’s team has shown that brain ketone uptake rises in step with blood ketone levels. This holds in people with Alzheimer’s just as it does in healthy young adults.[9,12]

Does the brain prefer ketones?

Patrick Holford, founder of Food for the Brain, argues in his book on Alzheimer’s prevention that when ketones are available, the brain will use them in preference, especially in people with age-related memory decline. It’s a view shared by many researchers in the field, though it isn’t fully settled. What is clear is that the brain uses ketones readily whenever they’re there.

Although it makes up only about 2% of body weight, the brain uses around 20% of the body’s energy.[11] For such a demanding organ, having a second fuel is a real advantage.

Ketones, Brain Energy and the Ageing Brain

What is the brain energy gap?

Having enough glucose in your blood doesn’t necessarily mean every part of your brain is using it well. Studies have found reduced glucose use in some brain regions in mild cognitive impairment and Alzheimer’s disease.

Why does this happen? There isn’t one simple answer. Metabolic health and insulin signalling may play a part, but it would be misleading to say that insulin resistance simply shuts glucose out of brain cells.

Could ketones help fill that energy gap?

That’s what researchers are testing.

Too much sugar, and particularly the fruit sugar fructose (half of table sugar and most of the high-fructose corn syrup in fizzy drinks and ultra-processed foods), drives insulin resistance. Insulin is the hormone that helps deliver glucose into brain cells. So the ironic end result of constantly eating too much sugar is glucose starvation in the brain.[16,17] That’s when you feel brain fog, struggle to concentrate and crave more sugar. Cunnane sums it up on one of his slides: more dietary sugar means less brain sugar.[10]

His brain-scanning research shows this is part of the Alzheimer’s story. In people with Alzheimer’s and Parkinson’s, the brain’s glucose uptake falls by around 15–30%.[10] In one study of mild Alzheimer’s, glucose uptake was about 13% lower than in healthy people of the same age, while ketone uptake was no different.[7] The problem is that the ketone supply doesn’t rise to make up the shortfall. The result is an energy gap, and it can appear in certain brain regions before any symptoms do.[9]

“People with cognitive decline have an energy gap. Probably due to insulin resistance, they are not able to make use of glucose. Providing a food source, C8 oil, from which the body can readily make ketones, fills that energy gap, brain cells come back to life and memory and brain function improve as a result. It reminds me of those announcements on the London Underground: ‘Mind the gap.'” Professor Stephen Cunnane, University of Sherbrooke, speaking to Patrick Holford for his book on Alzheimer’s prevention

Cunnane is a member of our Scientific Advisory Board and holds the Clinical Research Chair in Ketotherapeutics at the University of Sherbrooke in Canada. He is an expert on fatty acid metabolism in the brain.

Learn more about how excess fructose may contribute to insulin resistance, brain fog and dementia risk.

Ketones, memory and Alzheimer’s disease

If the ketone supply line still works, can topping it up help? What happens when researchers put this idea to the test? Here are three examples, looking at brain energy, memory and everyday function. 

Brain energy. Cunnane’s team gave people with mild to moderate Alzheimer’s 30g a day of ketogenic MCT oil for a month. Their brain’s ketone uptake roughly doubled, while its use of glucose stayed the same, so the brain’s total energy supply went up.[12]

Memory and thinking. In a six-month randomised controlled trial led by Dr Melanie Fortier and Cunnane, 122 people with mild cognitive impairment took either a ketogenic MCT drink (15g twice a day) or a placebo.[8] The MCT group did better than the placebo group on tests of memory, verbal fluency, naming and attention/processing, and the bigger their rise in brain ketones, the bigger the improvement. The study enrolled 122 people, and 83 completed it. Some cognitive test results improved compared with placebo, but the dropouts matter when judging how practical and reliable the approach may be.

Diet. In New Zealand, 26 people with Alzheimer’s followed a modified ketogenic diet and a healthy low-fat diet, each for 12 weeks. Of those, 21 completed both.[13] On the ketogenic diet, their ability to manage daily activities and their quality of life both improved, which is striking at that stage of the disease. Cognitive scores also went up, but not by enough to be statistically significant.

These are small or early trials, and quite a few participants dropped out, mainly because of digestive side effects from the MCT oil. Together they suggest that ketones can help support a brain that’s struggling with energy. They don’t show that ketones prevent or reverse Alzheimer’s.

That’s why we see ketones as one part of a bigger prevention picture. Disturbed glucose balance is one of “four biological horsemen” that together drive risk, alongside low omega-3, low B vitamins (shown by raised homocysteine) and low antioxidants. Activity, sleep, stress and social connection matter too. Even for people who carry the ApoE4 gene variant, eating a low-GL or more ketogenic Mediterranean-style diet could help.[14]

Is a keto diet good for brain health?

A ketogenic diet is very low in carbohydrate and high in fat, strict enough to keep the body making ketones continuously. Beyond Alzheimer’s, there are three other areas of evidence for the brain.

Epilepsy. The ketogenic diet has been used under specialist medical supervision for drug-resistant epilepsy since the 1920s, in both children and adults. For some people it markedly reduces how often seizures happen.[1] This is the most established medical use of the diet, and it’s always done with a specialist team.

Parkinson’s disease. In a small eight-week trial, 38 people with Parkinson’s completed either a low-fat or a ketogenic diet.[2] Both groups improved to a similar degree on motor symptoms such as tremor and stiffness. The keto group, however, improved far more on non-motor symptoms: 41% compared with 11%. These included fatigue, daytime sleepiness, pain, urinary problems and cognitive symptoms.

Fatigue and mood. It has been proposed that ketones could help in chronic fatigue syndrome, through the same energy-supply logic.[3] Low-carb, ketogenic diets are also being studied in mental health conditions. Both are early-stage areas.

So is keto good for your brain? Honestly, it depends on the health issues are facing. For most people, they can get the benefits of ketones without living on a strict ketogenic diet. Either through ketone supplementation or by having a ‘hybrid diet’ where you have periods of time eating in a ketogenic way (outlined in one of Patrick’s books the Hybrid Diet)

How to Increase Ketones Naturally

Your body makes more ketones when carbohydrate availability falls. Fasting, a ketogenic diet and MCT oil can all increase ketone availability, but they work differently. Raising ketones is one thing. Showing a benefit for brain health is another.

1. Cut back on sugar and refined carbs.

Every time you eat sugar or starchy carbs, insulin rises and ketone production switches off. Food for the Brain’s Alzheimer’s prevention advice is simple:

Avoid “the white stuff”: sugar, white flour and white rice.

Avoid ultra-processed foods.

Eat your fruit rather than drinking it as juice.

Keep grains and potatoes to one or two servings a day.

Cunnane’s team found that cutting carbohydrate intake by 30% in a retirement home for two months lowered blood sugar by 11% and increased ketones.[10]

2. Stretch your overnight fast.

It takes only about 12 hours to start running low on stored glucose and begin switching towards ketones. An 18:6 pattern goes further: you don’t eat between dinner at 6 or 7pm and lunch at 12 or 1pm the next day. Holford recommends doing this a couple of days a week, with a Hybrid Latté in the morning (see below). “My brain stays sharp and I don’t feel hungry,” he says.

3. Go ketogenic for a while.

To tip into ketosis you need to keep carbohydrates very low but our founder Patrick Holford suggests going ketogenic for about a week, or once a month, as a “service” for your brain rather than as a permanent diet.

4. Add C8 oil

This is the shortcut that doesn’t need a strict diet, and it’s covered below.

5. Keep moving.

Cunnane lists moderate, regular exercise alongside ketones as one of his strategies to fuel and protect the brain.[10] Exercise uses up stored glucose, so it nudges the body towards burning fat.

6. Coffee helps too

Coffee gives you energy the way a bank loan gives you wealth, but it does speed up the switch to running on ketones.[5]

If you want to check it’s working, you can measure blood, breath or urine ketones with a home meter. As a rough guide, a blood BHB reading of 0.5 mmol/L or above is usually described as nutritional ketosis. It’s also worth knowing your HbA1c, a blood test that shows your average blood sugar over the past few months. The FFB Alzheimer’s prevention advice is to aim for below 5.4% (36 mmol/mol), and ideally around 5%.

Can MCT oil increase ketones?

Yes. Certain medium-chain fats, particularly C8, can raise blood ketones without the same degree of carbohydrate restriction as a strict ketogenic diet. But the amount, formulation and individual response matter. Medium-chain triglycerides (MCTs) have chains of 6 to 12 carbons (C6, C8, C10 and C12). Unlike most fats, they go straight to the liver, where they are turned into ketones quickly. Of these, C8 (caprylic acid triglyceride, also called tricaprylin) makes ketones the fastest. In a study by Cunnane’s group, C8 raised blood ketones more than C10, other MCTs or coconut oil. C10 came next, but it’s not nearly as effective.[4]

Coconut oil vs C8 oil

This is where a lot of people get caught out. Coconut oil is around 60% MCTs, but only about 12% of those MCTs are C8, so only about 7% of coconut oil is C8. Most of the rest is C12 (lauric acid), which behaves more like an ordinary long-chain fat.

That’s why bulletproof coffee, with a blob of coconut oil or MCT oil in your morning brew, is one way to raise ketones but is much less effective than pure C8 oil. Patrick Holford’s Hybrid Latté is a step up. It’s a coffee made with carb-free almond milk, almond butter, C8 oil, a teaspoon of unsweetened cacao and half a teaspoon of cinnamon.

How to take C8 oil. In Cunnane’s studies, people took about two tablespoons (30g) a day.[8,12] The energy effect lasts a few hours, so it’s best spread across the day. Food for the Brain suggests starting with a teaspoon two or three times a day and building up gradually to two teaspoons three times a day. It has a pleasant, creamy taste. Some people get digestive upset. You can minimise this by building up slowly, taking it with a meal, or blending it into a smoothie or coffee so it’s emulsified.

You can find sources of C8 oil that meet Food for the Brain’s criteria here.

Do foods contain ketones?

Not in any meaningful amount. Ketone bodies are made inside your body, so you don’t get them from food the way you get vitamins. This is a common point of confusion.

Two things cause the mix-up:

“Keto foods” help you make ketones; they don’t contain them. These are mainly fats and oils, especially C8 oil and, to a lesser extent, coconut oil, eaten with very little carbohydrate.

“Raspberry ketone” is not a ketone body. It’s an aroma compound that belongs to the same broad chemical family. It isn’t BHB or acetoacetate, and it doesn’t fuel your brain in the same way.

So if you want more ketones from what you eat, three things matter: what you leave out (sugar and refined carbs), when you eat (longer gaps), and one specific addition (C8 oil).

Are ketones or a ketogenic diet safe?

For most people, raising ketones with a longer overnight fast or some C8 oil is well tolerated. 

A few things are worth knowing:

Early “keto flu”. When people first cut or reduce carbohydrates hard, some feel tired, headachy or foggy for a few days while their body adapts. It usually passes, and many people then report clearer thinking and steadier energy.

Digestive upset from MCT oil. This is the most common side effect, and it’s why building up slowly matters. Start with ½ tsp and slowly build up over time.

Check with your GP first before fasting or starting a ketogenic diet if you take medication for diabetes or blood pressure, are pregnant or breastfeeding, have a history of disordered eating, or have liver, kidney or pancreatic problems.

The bottom line

Your brain has more than one source of fuel. Ketones are an important part of that picture, and research in people with cognitive impairment is encouraging. But we still need to know who benefits, which approach works best and whether any benefits last.

You don’t need to chase a ketone reading to start looking after your brain. Our free Cognitive Function Test and accompanying questionnaire can help you explore your cognitive performance and the diet and lifestyle factors that may deserve attention.

To see what’s happening in your body, the DRIfT® home blood test measures five key biomarkers, including HbA1c for blood sugar balance.

This article is for information only and is not medical advice. It does not replace consultation with a qualified healthcare professional. Please speak to your GP before making significant changes to your diet, fasting or starting supplements, especially if you have a medical condition or take medication.

Autism is one disease where there is a very high ‘inherited’ component.

In studies with genetically identical twins, if one twin has it, the odds of another having a diagnosis is about 60%. But it’s not in the ‘in the genes’ since we share the same ‘environment’ as our siblings.

Perhaps the more interesting question is why the number of children diagnosed with Attention-deficit /hyperactivity disorder (ADHD), autism and other neurodevelopmental disorders classifying them as ‘neurodivergent’, has rocketed in both the UK and US.

One in six children is ‘neurodivergent’ as autism numbers quadruple.

UK figures (see here) which show that just under 1.5 million pupils in England have special educational needs which is one in six children. Autism is the biggest part of this, has been steadily rising in both the Uk and US.

“Now, one in six children in the US are classified as neurodivergent and one in 36 as autistic – a fourfold increase in 20 years.” says pediatric Professor Alessio Fasano from Massachusetts General Hospital for Children, Harvard Medical School.  

—

All down to our increased awareness & better diagnosis?

According to Dr Rona Tutt OBE, past president of the UK’s National Association of Head Teachers “There has been a dramatic increase in the number of people being diagnosed with ASD. Although some of this is due to a broader definition of autism as well as better diagnosis, it raises the question of whether it may also be the result of environmental changes, which have also been dramatic.” 

Some UK schools are reporting as many as one in four children having problems.

Have our genes changed in the past few decades?

Since the genes cannot have changed this rapidly, the increase points to the influence of environmental factors of which there are many candidates.

The main suspects are:

Gut problems
Wheat, milk and sugar
Vaccines
Environmental anti-nutrients and toxins
Social media overuse and social issues
Maternal nutrition and brain formation essential fats 

—

The gut’s role

World-renowned pediatric gastroenterologist, and research scientist Professor Alessio Fasano, MD, directs the Center for Celiac Research and Treatment at Massachusetts General for Children thinks something is going wrong in the gut, with many ASD children reporting gut problems including diarrhoea, constipation, belching and excessive flatulence and ‘dysbiosis’ – abnormal patterns of gut bacteria. In some children, wheat and milk may contribute to these symptoms. His research finds that neurodivergent children show high levels of ‘zonulin’, a family of proteins that regulate the barrier between intestinal cells in the digestive tract that can lead to “leaky gut.” ASD children are often found to have opioid-like wheat and milk proteins in their urine, making these foods especially ‘addictive’.

—

Prenatal nutrition?

Professor Michael Crawford, who heads the Institute of Brain Chemistry and Human Nutrition at the Chelsea & Westminster Hospital says “We can predict which babies are going to have developmental problems from the fats in the mother’s blood. When omega-3 levels are low, the mother produces a non-functional ‘brain fat substitute’ to build their baby’s brain during pregnancy, high levels of which predict problems. The brain is 50% fat, and omega-3 DHA should make up most of the structural fat in brain cells.” Less than 5 per cent of children in the UK achieve the basic dietary recommendations for omega-3 and fish.

—

Methylation & B vitamins

Vitamins may help. ‘A high level of homocysteine, a marker for B vitamin deficiency, predicts ASD and studies have shown that giving homocysteine-lowering vitamin B6, B12 and folate help reduce symptoms.” says Patrick Holford from the Food for the Brain Foundation, which is hosting the masterclass. “Vitamin A improves eye coordination and vision, helping those with autism who don’t look you in the eye and have visual problems.”

A 12-month randomised controlled trial giving omega-3, vitamins, digestive enzymes and a healthy gluten-free, casein-free diet showed major improvement in both autistic symptoms and raising IQ.

Nutrition and functional medicine therapist Anne Pemberton, who specialises in helping those with ASD, is spoke at the Autism Masterclass reports considerable success, not just by improving nutrition but by addressing the psychological and social circumstances of neurodivergent children. “It is critical to work with both mother and child, and not only address critical nutritional issues, stress triggers including early life traumas, and suppressed emotions as a result of their condition and conditioning, and to help them develop a sense of self and mindset. I have seen hundreds of children and adults who usually have major improvements. Peter, age 8, is a case in point. He was diagnosed with ASD and classified as needing special education. 15 months later he’s no longer even classified as ASD.”

So, as you can see, there are many layers to Autism and Neurodivergence.

For more information you can:

Get instant access to our Autism Masterclass to learn from the expert
Find out more about our Smart Kids & Teens Programme here to learn about the program, conference and more!

Failure of yet another anti-amyloid drug is hailed as ‘the beginning of the end for Alzheimer’s’, according to the Times headline today. It certainly was the end for two, possibly three volunteers given the experimental drug, according to the BBC [1] .

Like other anti-amyloid drugs, the level of significant adverse effects was unacceptably high. According to the Eli Lilly’s press release [2] (no trial has been published) one quarter (24%) of those on the drug developed brain swelling and 24% brain bleeding. It is these adverse effects that can cause death. I’m not quite sure how the BBC conclude only ‘1.6% developed dangerous brain swelling’. Perhaps they meant the level of swelling that could be fatal? But brain swelling and bleeding is not a good idea in elderly people with pre-dementia. Apart from anything else this means they’d need frequent and expensive brain scans to check whether or not this was occurring with each monthly treatment.

The press release inflated the apparent benefit in the usual way saying ‘29% less reduction, compared to placebo’ on the main measure of Clinical Dementia Rating , thus showing the relative, not absolute effect on cognitive assessment. What it actually means is that those on the placebo degenerated from a clinical perspective and those on the drug degenerated a bit less so.

The measure in question, Clinical Dementia Rating (Sum of Boxes), is a questionnaire, administered by a health professional who asks the patient’s partner or carer to rate their memory and 6 aspects of their general functional ability as being normal, questionable, mild, moderate or severe. Depending on the carer’s assessment each question adds either zero (if normal), 0.5, 1, 2 or 3 to the ‘Sum of Boxes’ score, which can therefore range from zero (nothing wrong) to 18 (severe impairment in everything). This is balanced by an interview with the participant who answers questions related to each of the domains/aspects of functional ability, and the doctor or rater scores the CDR taking both the subjective and objective evidence into account. The previous anti-amyloid drug trial, which reported less than half a point (0.45) difference, has been criticised for potential ‘unblinding’. This means that the carer or partner, when asked about how they thought the ‘patient’ was doing, might be biased to provide a more optimistic assessment because they knew they were on the drug from the adverse effects and thus hoped there was some improvement.

So, what happened in this trial? Those on the placebo got 2.4 points worse over 18 months and those on the drug treatment got 1.7 points worse. That’s relatively 29% less worse, but the absolute improvement is the difference, namely 0.49 points, similar to the previous ant-amyloid treatment reporting 0.45 points. So, no meaningful difference between the previous failed drug, nor the one before it which reported 0.39 points on an 18-point scale. According to a British Medical Journal editorial “minimum changes of 0.98 in mild cognitive impairment and 1.63 in mild Alzheimer’s disease are meaningful.” [3] This means that these results were clinically meaningless. All data from the drug company’s own press release.

How this hails the ‘beginning of the end’ of Alzheimer’s beggar’s belief. When compared with the effect of B vitamins or omega-3 fish oil in similar randomised controlled placebo trials [4], these results pale into insignificance, and especially the combination of the two[5]. In those with high homocysteine, given B vitamins, and with sufficient omega-3, there was 73% less brain shrinkage [6] and a third ended the trial with an overall Clinical Dementia Rating of zero [7] – i.e. no longer diagnostically labeled as having dementia. In other words, not less worse, but actually better. Why does this not get reported?

Foodforthebrain.org offers a free, validated online Cognitive Function test that includes an assessment of a person’s Dementia Risk Index with guidance on how to reduce that risk.

>> Take the Test here <<

Reference & Links

¹ https://www.bbc.co.uk/news/health-65471914

²  https://investor.lilly.com/news-releases/news-release-details/lillys-donanemab-significantly-slowed-cognitive-and-functional

³  Walsh S, Merrick R, Richard E, Nurock S, Brayne C. Lecanemab for Alzheimer’s disease. BMJ. 2022 Dec 19;379:o3010. doi: 10.1136/bmj.o3010. PMID: 36535691.

⁴  Jernerén F, Cederholm T, Refsum H, Smith AD, Turner C, Palmblad J, Eriksdotter M, Hjorth E, Faxen-Irving G, Wahlund LO, Schultzberg M, Basun H, Freund-Levi Y. Homocysteine Status Modifies the Treatment Effect of Omega-3 Fatty Acids on Cognition in a Randomized Clinical Trial in Mild to Moderate Alzheimer’s Disease: The OmegAD Study. J Alzheimers Dis. 2019;69(1):189-197. doi: 10.3233/JAD-181148. PMID: 30958356; see also Jernerén F, Elshorbagy AK, Oulhaj A, Smith SM, Refsum H, Smith AD (2015). Brain atrophy in cognitively impaired elderly: the importance of long-chain ω-3 fatty acids and B vitamin status in a randomized controlled trial. Am J Clin Nutr. 2015 Jul;102(1):215-21

⁵  Oulhaj, A et al, ‘homocysteine as a predictor of cognitive decline in Alzheimer’s Disease’, Int J Geriatric psychiatry, 25(1): 82-90 (2010)

⁶  Douaud G, Refsum H, de Jager CA, Jacoby R, Nichols TE, Smith SM, Smith AD. Preventing Alzheimer’s disease-related gray matter atrophy by B-vitamin treatment. Proc Natl Acad Sci U S A 2013; 110: 9523-8.

⁷ Oulhaj A, Jernerén F, Refsum H, Smith AD, de Jager CA. Omega-3 Fatty Acid Status Enhances the Prevention of Cognitive Decline by B Vitamins in Mild Cognitive Impairment. J Alzheimers Dis. 2016;50(2):547-57. doi: 10.3233/JAD-150777. PMID: 26757190; PMCID: PMC4927899.

In the UK progress in putting these breakthroughs into action is slow. The two leading charities, the Alzheimer’s Society and Alzheimer’s Research UK (ARUK) fail to mention the importance of homocysteine lowering B vitamins and omega-3 at all and have confirmed that they are not funding any research on their use in prevention or planning to do so. ARUK’s chief medical officer Professor Jon Schott and the Alzheimer’s Society’s associate director of research, Richard Oakley, declined to comment.

ARUK’s Brain Health Check-In, a short 13 question check list, with only one very basic question on diet, says nothing at all about B vitamins or whether or not a person supplements omega-3 fish oils despite ARUK having part-funded the Oxford University research. According to Professor Smith, who was the first Chair of their Scientific Advisory Board “ARUK part-funded our trial on B vitamins, and are aware of the results. I don’t understand why they make no mention of such an effective preventive intervention, that is taking a 10p a day B vitamin supplement if your homocysteine is high. Now we know that those who also supplement with omega-3 fish oil, or eat fish regularly, reduce their risk. These are the easiest two prevention actions anyone can take, with a significant impact on reducing the risk for dementia. Everyone needs to know this.”

“We’ve been applying to UK and EU agencies for the past 8 years to fund the obvious next trial – testing the effects of B vitamins and omega-3 combined to see if they slow, or prevent, conversion from cognitive impairment to dementia, but to no avail.” Says Professor Smith.

Neither the Alzheimer’s Society, nor ARUK are funding any vitamin or omega-3 research and spend virtually none of their annual research pot, which exceeded £37 million last year, on diet or lifestyle prevention which offer the most potential, despite these representing up to half of the risk for Alzheimer’s. Neither would confirm the percentage of their research funds that were being spent on prevention research.

UK Government have pledged to deliver ‘Dementia Moonshot’, doubling dementia research funding to £160 million to ‘fast-track the development of new treatments’, meanwhile ignoring the biggest breakthroughs in diet and lifestyle prevention. Most support is feeding failed drug research. With an estimated $50 billion [12] spent so far on amyloid drugs and research, all of which have failed to produce any clinical benefit, isn’t it time governments and Alzheimer’s charities took prevention seriously?

In contrast, the Food for the Brain Foundation are doing just that. “At Foodforthebrain.org we are testing almost 4,000 people every month on our free online Cognitive Function Test, and assessing all risk factors on a 140 question questionnaire, including the need for B vitamins and omega-3. We hope, soon, to introduce a pinprick blood test for both omega-3 and homocysteine. We don’t know why the most evidence-based, easy to action and inexpensive prevention steps are being ignored” says Holford. “Why world class scientists such as Professor David Smith’s team at Oxford University have been unable to get funding for the most essential research is shameful. Right now we know enough to cut the average person’s risk of developing Alzheimer’s by up to two thirds and the number of people developing dementia by a third if only there was the political will to do so.”

One of the reasons for complacency in the UK is the Lancet’s commissioned report on Alzheimer’s prevention chaired by Gillian Livingston, Professor of Psychiatry for Older  People, at the University College London (UCL). The report, first published in 2017, didn’t include B vitamins. Despite being sent all the evidence by Smith. The 2020 revised report still excluded this vital research, as did a follow up report specifically on supplements in 2022. “There are no trials that show that lowering homocysteine has any benefit” she told us yet she had been sent the unequivocal evidence that the B vitamins reduced brain shrinkage by up to 73%, compared to the 2% reduction of anti-amyloid drugs and the combination of omega-3 and B vitamins has lowered the Clinical Dementia Rating (CDR) in placebo controlled trials by three times that reported by the recent anti-amyloid drug, Lecanemab. (see charts below).

When asked about the recent finding of a synergistic effect of B vitamins and omega-3 she said “It sounds a good hypothesis. I hope they can get the funding for it, but raised homocysteine is not common in the wider population and drug companies can’t be expected to fund nutrition trials, so money would have to come from some government agency.”

There is one prevention study, called AppleTree, underway at University College London. It focuses on reducing risk for Alzheimer’s by eating a Mediterranean style diet and lifestyle advice, including encouraging smokers to quit, which is a known risk factor for cognitive decline. One recent study shows that being a smoker increases risk for dementia by 1.5 times and quitting for at least 3 years reduces much of that risk. [13] One in twelve people over 65 smoke.

In contrast, almost half of all people over 65 have raised homocysteine [14] which increases risk for cognitive impairment by up to ten times, according to Chinese research published last year[15]. Lowering homocysteine with B vitamins, and sufficient omega-3, would virtually eliminate that risk. This suggests that targeting B vitamins and omega-3 would be about twenty times more impactful in preventing dementia than quitting smoking. Yet the need for supplemental intake of these nutrients is not part of the Apple Tree protocol.

If you’d like to test your cognitive function and find out how to reduce your risk, register here and join our citizen science campaign.

References

[1] Jernerén F, Elshorbagy AK, Oulhaj A, Smith SM, Refsum H, Smith AD (2015). Brain atrophy in cognitively impaired elderly: the importance of long-chain ω-3 fatty acids and B vitamin status in a randomized controlled trial. Am J Clin Nutr. 2015 Jul;102(1):215-21

[2] Oulhaj, A et al, ‘homocysteine as a predictor of cognitive decline in Alzheimer’s Disease’, Int J Geriatric psychiatry, 25(1): 82-90 (2010)

[3] van Soest, A.P.M., van de Rest, O., Witkamp, R.F. et al. DHA status influences effects of B-vitamin supplementation on cognitive ageing: a post-hoc analysis of the B-proof trial. Eur J Nutr (2022). https://doi.org/10.1007/s00394-022-02924-w

[4] Jernerén F, Cederholm T, Refsum H, Smith AD, Turner C, Palmblad J, Eriksdotter M, Hjorth E, Faxen-Irving G, Wahlund LO, Schultzberg M, Basun H, Freund-Levi Y. Homocysteine Status Modifies the Treatment Effect of Omega-3 Fatty Acids on Cognition in a Randomized Clinical Trial in Mild to Moderate Alzheimer’s Disease: The OmegAD Study. J Alzheimers Dis. 2019;69(1):189-197. doi: 10.3233/JAD-181148. PMID: 30958356.

[5] Walsh S, Merrick R, Richard E, Nurock S, Brayne C. Lecanemab for Alzheimer’s disease. BMJ. 2022 Dec 19;379:o3010. doi: 10.1136/bmj.o3010. PMID: 36535691.

[6] Li M, Li W, Gao Y, Chen Y, Bai D, Weng J, Du Y, Ma F, Wang X, Liu H, Huang G. Effect of folic acid combined with docosahexaenoic acid intervention on mild cognitive impairment in elderly: a randomized double-blind, placebo-controlled trial. Eur J Nutr. 2021 Jun;60(4):1795-1808. doi: 10.1007/s00394-020-02373-3. Epub 2020 Aug 28. PMID: 32856190.

[7] Yu JT, Xu W, Tan CC, Andrieu S, Suckling J, Evangelou E, Pan A, Zhang C, Jia J, Feng L, Kua EH, Wang YJ, Wang HF, Tan MS, Li JQ, Hou XH, Wan Y, Tan L, Mok V, Tan L, Dong Q, Touchon J, Gauthier S, Aisen PS, Vellas B. Evidence-based prevention of Alzheimer’s disease: systematic review and meta-analysis of 243 observational prospective studies and 153 randomised controlled trials. J Neurol Neurosurg Psychiatry. 2020 Nov;91(11):1201-1209. doi: 10.1136/jnnp-2019-321913. Epub 2020 Jul 20. PMID: 32690803; PMCID: PMC7569385.

[8] Huang Y, Deng Y, Zhang P, Lin J, Guo D, Yang L, Liu D, Xu B, Huang C, Zhang H. Associations of fish oil supplementation with incident dementia: Evidence from the UK Biobank cohort study. Front Neurosci. 2022 Sep 7;16:910977. doi: 10.3389/fnins.2022.910977. PMID: 36161159; PMCID: PMC9489907.

[9] Jeong SM, Park J, Han K, Yoo J, Yoo JE, Lee CM, Jung W, Lee J, Kim SY, Shin DW. Association of Changes in Smoking Intensity With Risk of Dementia in Korea. JAMA Netw Open. 2023 Jan 3;6(1):e2251506. doi: 10.1001/jamanetworkopen.2022.51506. PMID: 36656579; PMCID: PMC9857334.

[10] Beydoun MA, Beydoun HA, Gamaldo AA, Teel A, Zonderman AB, Wang Y. Epidemiologic studies of modifiable factors associated with cognition and dementia: systematic review and meta-analysis. BMC Public Health. 2014 Jun 24;14:643. doi: 10.1186/1471-2458-14-643. PMID: 24962204; PMCID: PMC4099157.

[11] Witte AV, Kerti L, Hermannstädter HM, Fiebach JB, Schreiber SJ, Schuchardt JP, Hahn A, Flöel A. Long-chain omega-3 fatty acids improve brain function and structure in older adults. Cereb Cortex. 2014 Nov;24(11):3059-68. doi: 10.1093/cercor/bht163. Epub 2013 Jun 24. PMID: 23796946.

[12] Cummings JL, Goldman DP, Simmons-Stern NR, Ponton E. The costs of developing treatments for Alzheimer’s disease: A retrospective exploration. Alzheimers Dement. 2022 Mar;18(3):469-477. doi: 10.1002/alz.12450. Epub 2021 Sep 28. PMID: 34581499; PMCID: PMC8940715.

[13] Lu Y, Sugawara Y, Zhang S, Tomata Y, Tsuji I. Smoking cessation and incident dementia in elderly Japanese: the Ohsaki Cohort 2006 Study. Eur J Epidemiol. 2020 Sep;35(9):851-860. doi: 10.1007/s10654-020-00612-9. Epub 2020 Feb 15. PMID: 32060675; PMCID: PMC7525275.

[14] Pfeiffer CM, Osterloh JD, Kennedy-Stephenson J, Picciano MF, Yetley EA, Rader JI, Johnson CL. Trends in circulating concentrations of total homocysteine among US adolescents and adults: findings from the 1991-1994 and 1999-2004 National Health and Nutrition Examination Surveys. Clin Chem. 2008 May;54(5):801-13. doi: 10.1373/clinchem.2007.100214. Epub 2008 Mar 28. PMID: 18375482.

[15] Teng Z, Feng J, Liu R, Ji Y, Xu J, Jiang X, Chen H, Dong Y, Meng N, Xiao Y, Xie X and Lv P (2022) Cerebral small vessel disease mediates the association between homocysteine and cognitive function. Front. Aging Neurosci. 14:868777. doi: 10.3389/fnagi.2022.868777

By Jerome Burne &  Patrick Holford

New research shows that the combination of B vitamins and omega-3 are a dynamic duo against dementia, stopping the brain shrinkage that is the hallmark of Alzheimer’s. 

The discovery, hailed as the “a major step towards Alzheimer’s prevention” was first made at the University of Oxford, but has now been confirmed by research groups in Holland, Sweden and China.

Headed by Professor David Smith, former Chair of Pharmacology and Deputy Head of the Division of Medical Sciences at Oxford University and director of the Oxford Project to Investigate Memory and Ageing (OPTIMA), the research has found that giving older people with the first signs of cognitive impairment supplemental B vitamins (B6, B12 and folic acid) at higher levels than can be achieved through diet to those with sufficient omega-3 fats produced 73% less brain shrinkage in a year, compared to placebo. This reduction brought brain shrinkage down to the level found in those elderly with no cognitive decline. The trial was part-funded by Alzheimer’s Research UK (ARUK). “The effect is greater than that of any drug treatment to date – with no adverse effects.” says Professor Smith. In contrast the recent trials of anti-amyloid drugs have reduced brain shrinkage by 2%.

“Brain shrinkage is the hallmark of Alzheimer’s so this was a vital discovery for its prevention” says Patrick Holford, director of the Alzheimer’s Prevention Project at foodforthebrain.org, the UK’s leading dementia prevention charity “However we needed confirmation from other research groups. Now we have it.”.

Three other research groups have confirmed the combined effect of omega-3 and B vitamins is greater than either nutrient on its own.

“You literally cannot build brain cells without both omega-3 fats and sufficient B vitamins” says Holford. “If you give a builder a hammer or a bag of nails you don’t get a house. But if you give them both they can build a house. The B vitamins drive a process called methylation which assembles the critical brain-building fats that make up the membrane of neurons, through which all brain communication happens. Both are vital for building brain cells. Neither can work without the other.”

Watch this one minute film, on how to build new brain cells at any age.

Realising that the combination of B vitamins and omega-3 fats is key, researchers in Holland, who had previously run a major trial called B-proof that had tested the effects of B vitamins on memory but had only found very modest benefits decided to take reanalyse the results of their B vitamin trial according to the participants blood levels of omega-3 at the start of the trial. Sure enough, they found no benefit at all from the B vitamins in those with low omega-3 status, but a massive improvement in cognition in those in the top third of omega-3 levels.[i]

Could this need for both explain why some trials testing omega-3 were also not successful?

The Oxford University researchers, led by Dr Frederik Jerneren, were given access to the blood samples from another trial in Sweden called OmegAD. This trial  had given older people a hefty dose of 2.3grams (two large capsules) of omega-3 fish oils. The trial had apparently failed, showing no significant cognitive benefit. Could faulty methylation, a result of lack of B vitamins, be the reason for the omega-3 fish oils not working?

The Oxford researchers therefore measured homocysteine, a consequence of a lack of B vitamins, in the samples from the OmegAD trial. Dr Jerneren split the participants into thirds – from the lowest to highest level of homocysteine. Those given omega-3 who had  the lowest homocysteine, in other words sufficient in B vitamins, had a highly significant improvement in their clinical dementia rating while those with high homocysteine (poor B vitamin status) had no benefit at all.[ii] The group with sufficient vitamin B showed a reduction in their clinical dementia score that was more than three times that reported from the recent Lecanemab drug trial.[iii]

Meanwhile another trial, this time in China, gave those with pre-dementia either the B vitamin folic acid, or omega-3, or both, compared to placebo. Although B vitamin treatment and omega-3 treatment did slightly improve cognitive cores, the improvement was much greater in those given both thee nutrients.[iv]

With 170 million people over 65, Chinese authorities are taking prevention of dementia extremely seriously to avoid a cerebral tsunami. So, one of their top researchers, Professor Jin-Tai Yu at Shanghai’s Institute of Neurology at Fudan University did one of the most thorough reviews of all risk factors for Alzheimer’s to date.[v]

“Lowering blood homocysteine levels, an established indicator of Alzheimer’s risk, with B vitamins is a most promising treatment.” he concluded. He was also given access to the UK’s Bio Bank data of almost half a million people “Our current research, using data from the UK Bio Bank, shows that having higher blood levels of polyunsaturated fats, including omega-3, and supplementing fish oils, is associated with less risk of dementia. [vi] Moreover, recent studies suggest these two factors – homocysteine lowering B vitamins, and omega-3 – may, in combination, be potentially more beneficial. They are easy to implement. This is worthy of further research”

The UK’s Bio Bank data showed that something as simple as taking fish oils had reduced dementia risk by 9%. This is equivalent to the risk reduction found from quitting smoking.[vii]

US researchers at the National Institutes of Health research have confirmed this, attributing almost a quarter (22%) of Alzheimer’s cases to lack of B vitamins and raised homocysteine levels and the same (22%) to a lack of omega-3 and seafood intake.[viii] This means that about one in three cases of Alzheimer’s could be avoided simply by taking a daily high dose B vitamin supplement and an omega-3 fish oil capsule. This could save 95,000 people a year in the UK from developing dementia. Currently, 790 people – seven double decker buses worth – are diagnosed every single day. However, the benefit is not just in preventing people from dementia in the future. A study of healthy 65-year-olds given omega-3 fish oils showed both improvement in memory and healthier brain tissue within six months.[ix]

The Alzheimer’s prevention charity, foodforthebrain.org, targets eight prevention steps in their on-line Cognitive Function test and Dementia Risk Index questionnaire, including B vitamins and omega-3. “These are the two easiest to change and most evidence based prevention steps anyone can take.” Say Patrick Holford who directs their ‘Alzheimer’s is Preventable’campaign.

Scientists are also investigating other micronutrients and minerals that may affect brain ageing, including the potential role of lithium in brain health.

[i] van Soest, A.P.M., van de Rest, O., Witkamp, R.F. et al. DHA status influences effects of B-vitamin supplementation on cognitive ageing: a post-hoc analysis of the B-proof trial. Eur J Nutr (2022). https://doi.org/10.1007/s00394-022-02924-w

[ii] Jernerén F, Cederholm T, Refsum H, Smith AD, Turner C, Palmblad J, Eriksdotter M, Hjorth E, Faxen-Irving G, Wahlund LO, Schultzberg M, Basun H, Freund-Levi Y. Homocysteine Status Modifies the Treatment Effect of Omega-3 Fatty Acids on Cognition in a Randomized Clinical Trial in Mild to Moderate Alzheimer’s Disease: The OmegAD Study. J Alzheimers Dis. 2019;69(1):189-197. doi: 10.3233/JAD-181148. PMID: 30958356.

[iii] Walsh S, Merrick R, Richard E, Nurock S, Brayne C. Lecanemab for Alzheimer’s disease. BMJ. 2022 Dec 19;379:o3010. doi: 10.1136/bmj.o3010. PMID: 36535691.

[iv] Li M, Li W, Gao Y, Chen Y, Bai D, Weng J, Du Y, Ma F, Wang X, Liu H, Huang G. Effect of folic acid combined with docosahexaenoic acid intervention on mild cognitive impairment in elderly: a randomized double-blind, placebo-controlled trial. Eur J Nutr. 2021 Jun;60(4):1795-1808. doi: 10.1007/s00394-020-02373-3. Epub 2020 Aug 28. PMID: 32856190.

[v] Yu JT, Xu W, Tan CC, Andrieu S, Suckling J, Evangelou E, Pan A, Zhang C, Jia J, Feng L, Kua EH, Wang YJ, Wang HF, Tan MS, Li JQ, Hou XH, Wan Y, Tan L, Mok V, Tan L, Dong Q, Touchon J, Gauthier S, Aisen PS, Vellas B. Evidence-based prevention of Alzheimer’s disease: systematic review and meta-analysis of 243 observational prospective studies and 153 randomised controlled trials. J Neurol Neurosurg Psychiatry. 2020 Nov;91(11):1201-1209. doi: 10.1136/jnnp-2019-321913. Epub 2020 Jul 20. PMID: 32690803; PMCID: PMC7569385.

[vi] Huang Y, Deng Y, Zhang P, Lin J, Guo D, Yang L, Liu D, Xu B, Huang C, Zhang H. Associations of fish oil supplementation with incident dementia: Evidence from the UK Biobank cohort study. Front Neurosci. 2022 Sep 7;16:910977. doi: 10.3389/fnins.2022.910977. PMID: 36161159; PMCID: PMC9489907.

[vii] Jeong SM, Park J, Han K, Yoo J, Yoo JE, Lee CM, Jung W, Lee J, Kim SY, Shin DW. Association of Changes in Smoking Intensity With Risk of Dementia in Korea. JAMA Netw Open. 2023 Jan 3;6(1):e2251506. doi: 10.1001/jamanetworkopen.2022.51506. PMID: 36656579; PMCID: PMC9857334.

[viii] Beydoun MA, Beydoun HA, Gamaldo AA, Teel A, Zonderman AB, Wang Y. Epidemiologic studies of modifiable factors associated with cognition and dementia: systematic review and meta-analysis. BMC Public Health. 2014 Jun 24;14:643. doi: 10.1186/1471-2458-14-643. PMID: 24962204; PMCID: PMC4099157.

[ix] Witte AV, Kerti L, Hermannstädter HM, Fiebach JB, Schreiber SJ, Schuchardt JP, Hahn A, Flöel A. Long-chain omega-3 fatty acids improve brain function and structure in older adults. Cereb Cortex. 2014 Nov;24(11):3059-68. doi: 10.1093/cercor/bht163. Epub 2013 Jun 24. PMID: 23796946.

By Research Professor Tommy Wood from the University of Washington

Most of us have two types of elderly relatives.

One of them is old – they have trouble walking, they’re in and out of the doctor’s office, and they always seem to repeat the same stories. The other type seems younger than their years they play tennis twice a week, they’re social, and they’re sharp as a tack. How can we become part of the latter group?

When it comes to aging in general and cognitive function in particular, genes obviously play a role, but did you know that lifestyle choices matter even more?[1] So, what are the top lifestyle choices to keep our brains sharp into old age?

As a neuroscientist, this is a question I often get.

Besides the obvious ones – physical activity, strength, sleep, a healthy diet, not smoking – my top tip is this: If you want to stay mentally sharp into old age, keep your brain active. In short, “use it or lose it”.

But what does “using it” look like? In this post I’ll cover some of the evidence around cognitive decline, as well as some practical take-aways for anybody wanting to improve their brain health as they get older.

—

Use it or lose it

The brain is an amazing organ, and it’s more resilient and adaptable than we’ve been led to believe. I’m sure you’ve heard that adults have a fixed amount of brain cells. Then, as we get older (or every time we take a sip of wine) we “lose” some of those brain cells as part of an unstoppable decline towards dementia or Alzheimer’s disease.

But that’s not necessarily true. I like to think about the brain like I think about muscles. In order to grow our muscles, we need to provide a stimulus – like lifting weights in the gym – followed by a period of rest. The opposite also happens – if we stop going to the gym or if we stop using a limb after breaking a bone – our muscles get smaller. Most have experienced this personally, and there’s every indication that your cognitive “muscle” behaves in the same way.

How do we know this? One type of evidence is that longer education seems to reduce dementia in later life. [2]* You might think of education as early cognitive muscle building that you then benefit from throughout life. We see similar effects from other forms of early cognitive stimulus – like protection from neurodegenerative disease in people who grew up bilingual.[3]

But we’re not cognitively doomed after adolescence. One of my favourite studies looked at adults studying “The Knowledge” – memorising ~25,000 streets in central London to become a taxi driver. These participants were in their 30s or 40s, yet they saw a significant increase in the size of the hippocampus, the brain region associated with memory.[4]

We also see the opposite effect – less cognitive stimulus increases the risk of cognitive decline and dementia. This is most easily studied by looking at retirement. Multiple studies in populations across the US, China, and Europe, show that the risk of cognitive decline accelerates after retirement.[5-8] Those that retire later are protected against cognitive decline, even after considering factors that might force early retirement such as poor health. Overall, a recent meta-analysis looking at health and lifestyle factors associated with cognitive decline found that cognitive activity was the single most protective factor – halving the risk of Alzheimer’s disease.[2] This really emphasises the lesson: use it or lose it. What counts as ‘protective cognitive demand’? Doing something badly.

The evidence around retirement and cognitive decline suggests that work is where adults tend to get most of their cognitive activity. However, it’s important to unpick what constitutes cognitive activity that is protective. We may feel that our work demands a lot from our brain, but being “busy” does not necessarily benefit the brain. In fact, it’s often the opposite. Being “busy” tends to come with stress, and though stress is very personal, chronic stress is associated with an increased risk of Alzheimer’s disease.[9] What keeps us busy and stressed – sitting in meetings, reading emails, inputting data – may be time consuming, but rarely requires much brain power.

So, what constitutes protective cognitive demand? Failure.

Activities that provide the greatest cognitive stimulus involve learning and skill development. That means we’re initially bad at them and occasionally fail before we get better. This is the real sticking point for improving brain health – as adults we hate the feeling of being bad at something. Failing is, however, when the magic happens. A fascinating study looked at the brains of musicians.[10] While both professional and amateur musicians’ brains looked younger compared to non-musicians of the same age, the benefit was greatest in amateur musicians. The researchers suggested that playing music is more of a cognitive stimulus for amateurs – it’s harder, so they get more benefit. The cocktail of hormones released as we try, fail, repeat, and learn, provides the ideal environment for the brain to grow and adapt.

How to “use it”

So, how should we apply this knowledge? Below are some of the best and easiest ways to build in cognitive stimuli you can benefit from for years to come.

1 | Pick an activity that’s truly challenging
Cognitive demand requires failure, so pick something you’ll be bad at initially. What’s cognitively challenging is personal, but learning a new language is better than sudoku, building model airplanes is probably better than reading the news, and playing chess is definitely better than scrolling through Instagram. As you get better, add challenge to keep stimulating your brain.

2 | Start small and do something you enjoy
Skill development should be a lifelong process, which means it should be a routine. Start small – for instance 2 minutes a day of playing an instrument or learning a new language. Make sure your new skill is something you enjoy – that makes it easier to stick to and keep as a part of your life.

3 | Move – with a skill component
Movement has some of the best evidence on improving brain health. One of the first studies to show that the hippocampus can grow in adults of retirement age (or older) used a walking intervention – just 40 minutes of brisk walking 3x per week.[11] Other studies have showed increased brain connectivity and function in adults doing resistance training 1-2 times per week.[12] Best is movement that includes balance or motor skills: the added challenge of coordination seems to be particularly protective against cognitive decline.[13] Think yoga, dance, or even skateboarding

4 | Try a new skill that’s social
Social interaction is its own form of cognitive stimulus: social connection is protective of cognitive function, while social isolation has the opposite effect.[14] So what’s better than simply learning a new skill? Doing so with friends. Start a book club to discuss the books you read. Join a knitting circle, language group, or dance class. Volunteer for a local charity. All of these help you learn new skills, with the added benefit of social interaction.

5 | Repeat, repeat, repeat
There are no hard and fast rules about how much or how often to work on a new skill, but once a week is a good start. If it’s a class or a movement practice, maybe 1-3 times per week. If it’s something you can do on your own, you may prefer more frequent, smaller bouts of focused practice. Try using a Pomodoro timer to dig in for 20-30 minutes – a suitable time for most people to keep their undivided attention.
The key is to push right at the boundaries of what you’re capable of – with occasional failure showing that you’re at the right level of difficulty. Keep at it, and you’ll be more likely to be healthy and sharp for decades to come.

Footnote
*It’s worth noting that those who stay in education for longer also tend to be socioeconomically advantaged, but the benefit of longer education seems to hold even accounting for that.

Thank you for reading!

Food for the Brain is a non-for-profit educational and research charity that offers a free Cognitive Function Test and assesses your Dementia Risk Index to be able to advise you on how to dementia-proof your diet and lifestyle.

By completing the Cognitive Function Test you are joining our grassroots research initiative to find out what really works for preventing cognitive decline. We share our ongoing research results with you to help you make brain-friendly choices.

Please support our research by becoming a Friend of Food for the Brain.

References

Lourida I, Hannon E, Littlejohns TJ, Langa KM, Hyppönen E, Kuźma E, Llewellyn DJ. Association of Lifestyle and Genetic Risk With Incidence of Dementia. Jama. 2019;322(5):430-7. doi: 10.1001/jama.2019.9879.
Yu JT, Xu W, Tan CC, Andrieu S, Suckling J, Evangelou E, Pan A, Zhang C, Jia J, Feng L, Kua EH, Wang YJ, Wang HF, Tan MS, Li JQ, Hou XH, Wan Y, Tan L, Mok V, Tan L, Dong Q, Touchon J, Gauthier S, Aisen PS, Vellas B. Evidence-based prevention of Alzheimer’s disease: systematic review and meta-analysis of 243 observational prospective studies and 153 randomised controlled trials. J Neurol
Neurosurg Psychiatry. 2020;91(11):1201-9. Epub 2020/07/22. doi: 10.1136/jnnp-2019-321913. PubMed PMID: 32690803; PMCID: PMC7569385.
Sala A, Malpetti M, Farsad M, Lubian F, Magnani G, Frasca Polara G, Epiney JB, Abutalebi J, Assal F, Garibotto V, Perani D. Lifelong bilingualism and mechanisms of neuroprotection in Alzheimer dementia. Hum Brain Mapp. 2022;43(2):581-92. Epub 2021/11/04. doi: 10.1002/hbm.25605. PubMed PMID: 34729858; PMCID: PMC8720191.
Woollett K, Maguire EA. Acquiring “the Knowledge” of London’s layout drives structural brain changes. Current biology : CB. 2011;21(24):2109-14. Epub 2011/12/08. doi: 0.1016/j.cub.2011.11.018. PubMed PMID: 22169537.
Hale JM, Bijlsma MJ, Lorenti A. Does postponing retirement affect cognitive function? A counterfactual experiment to disentangle life course risk factors. SSM – Population Health. 2021;15:100855. doi: https://doi.org/10.1016/j.ssmph.2021.100855.
Dufouil C, Pereira E, Chêne G, Glymour MM, Alpérovitch A, Saubusse E, Risse- Fleury M, Heuls B, Salord JC, Brieu MA, Forette F. Older age at retirement is associated with decreased risk of dementia. Eur J Epidemiol. 2014;29(5):353-61. Epub 2014/05/06. doi: 10.1007/s10654-014-9906-3. PubMed PMID: 24791704.
Nikolov P, Adelman AM. Do Pension Benefits Accelerate Cognitive Decline? Evidence from Rural China. Labor: Public Policy & Regulation eJournal. 2019. Sundström A, Rönnlund M, Josefsson M. A nationwide Swedish study of age at retirement and dementia risk. Int J Geriatr Psychiatry. 2020;35(10):1243-9. Epub 2020/06/20. doi: 10.1002/gps.5363. PubMed PMID: 32557831.
Ye Y, Li J, Yuan Z. Effect of antioxidant vitamin supplementation on cardiovascular outcomes: A meta-analysis of randomized controlled trials. PloS One. 2013;8:e56803. doi:10.1371/journal.pone.0056803.
Rogenmoser L, Kernbach J, Schlaug G, Gaser C. Keeping brains young with making music. Brain Struct Funct. 2018;223(1):297-305. Epub 2017/08/18. doi: 10.1007/s00429-017-1491-2. PubMed PMID: 28815301.
Erickson KI, Voss MW, Prakash RS, Basak C, Szabo A, Chaddock L, Kim JS, Heo S, Alves H, White SM, Wojcicki TR, Mailey E, Vieira VJ, Martin SA, Pence BD, Woods JA, McAuley E, Kramer AF. Exercise training increases size of hippocampus and improves memory. Proceedings of the National Academy of Sciences. 2011;108(7):3017. doi: 10.1073/pnas.1015950108.
Herold F, Törpel A, Schega L, Müller NG. Functional and/or structural brain changes in response to resistance exercises and resistance training lead to cognitive improvements – a systematic review. Eur Rev Aging Phys Act. 2019;16:10. Epub 2019/07/25. doi: 10.1186/s11556-019-0217-2. PubMed PMID: 31333805; PMCID: PMC6617693.
Ludyga S, Gerber M, Pühse U, Looser VN, Kamijo K. Systematic review and meta- analysis investigating moderators of long-term effects of exercise on cognition in healthy individuals. Nature Human Behaviour. 2020;4(6):603-12. doi: 10.1038/s41562-020-0851-8.
Penninkilampi R, Casey AN, Singh MF, Brodaty H. The Association between Social Engagement, Loneliness, and Risk of Dementia: A Systematic Review and Meta-Analysis. J Alzheimers Dis. 2018;66(4):1619-33. Epub 2018/11/20. doi: 10.3233/jad- PubMed PMID: 30452410.

Study Finds Mediterranean and MIND Diets Are Linked to Fewer Alzheimer’s Brain Changes

Research suggests these eating patterns may help support long-term brain health

Following a Mediterranean or MIND diet has consistently been associated with better cognitive health. In recent years, the connection between the mind diet, Alzheimer’s disease and overall brain health has become a focus of research. Research also suggests that people who adhere more closely to these dietary patterns have fewer of the brain changes associated with Alzheimer’s disease.

One study published in Neurology found that people who most closely followed the Mediterranean or MIND diet had fewer amyloid plaques and tau tangles, the two hallmark features of Alzheimer’s disease. They also had lower overall Alzheimer’s pathology at autopsy.

Although this research cannot prove that diet prevents Alzheimer’s disease, it adds to a growing body of evidence linking healthy dietary patterns with better brain health as we age.

One of the study’s most striking findings was that participants with the highest adherence to the MIND diet had levels of amyloid plaques and tau tangles comparable to those seen in people around 12 years younger than those with the lowest adherence. This comparison reflects differences in Alzheimer’s-related brain pathology rather than actual biological age.

The researchers also found that even meeting the recommended intake for a single food group, such as vegetables or fruit, was associated with lower amyloid pathology, equivalent to around four years less brain ageing. The strongest association was seen with green leafy vegetables, with people eating the most greens showing substantially fewer Alzheimer’s-related brain changes than those eating the least.

What are amyloid plaques and tau tangles?

Amyloid plaques are deposits of beta amyloid protein that accumulate between brain cells. Tau tangles are abnormal bundles of tau protein that build up inside neurons.

Both are considered hallmark features of Alzheimer’s disease and are commonly found in the brains of people with dementia.

However, Alzheimer’s disease is complex. Scientists now recognise that inflammation, vascular disease, genetics, insulin resistance and other lifestyle factors all contribute to the disease process. Amyloid and tau are important, but they are only part of the story.

Can diet reduce amyloid plaques?

There is currently no evidence that any diet can remove existing amyloid plaques.

However, research suggests that people who consistently follow dietary patterns such as the Mediterranean and MIND diets tend to have fewer Alzheimer’s-related brain changes and a lower risk of cognitive decline.

Rather than reversing Alzheimer’s disease, these diets appear to support long-term brain health through multiple mechanisms, including reduced inflammation, improved vascular health and better overall nutrition.

Why might diet influence brain health?

Researchers believe several mechanisms may explain these findings.

Healthy dietary patterns are rich in nutrients that may help:

reduce chronic inflammation
improve blood flow to the brain
protect brain cells from oxidative stress
support healthy nerve cell function
maintain cardiovascular health, which is closely linked to brain health

Rather than relying on a single nutrient, these dietary patterns combine many foods that work together over time.

Why were leafy greens highlighted?

Among all the foods analysed, green leafy vegetables showed one of the strongest associations with lower Alzheimer’s pathology.

Leafy greens provide several nutrients that support normal brain function, including:

folate
vitamin K
lutein
magnesium
dietary nitrates

Although researchers cannot say that leafy greens alone reduce Alzheimer’s risk, regularly eating them is consistently associated with better cognitive ageing across multiple studies. The findings from this study suggest that increasing the intake of foods such as leafy greens, berries, whole grains, olive oil and fish as part of an overall healthy dietary pattern may help support long-term brain health.

How strong is the evidence?

This study was observational, meaning it identified associations rather than proving cause and effect.

That means researchers cannot conclude that the Mediterranean or MIND diet directly prevented Alzheimer’s disease.

However, these findings are consistent with many previous studies linking healthy dietary patterns with better cognitive health and a lower risk of dementia.

Taken together, the evidence suggests that diet is likely to be one important part of maintaining brain health, alongside regular physical activity, quality sleep, social engagement and management of cardiovascular risk factors.

What this research means?

This study adds another piece to the growing evidence that long-term dietary habits may influence how the brain ages.

Rather than focusing on individual “superfoods,” the findings support the importance of an overall healthy eating pattern that includes plenty of vegetables, healthy fats, legumes, whole grains and other minimally processed foods.

While more research is needed, studies suggest that the Mediterranean and MIND diets may help reduce Alzheimer’s disease related brain changes and support long term brain health when followed consistently as part of a healthy lifestyle.

Practical takeaways

The greatest benefits are likely to come from following these habits consistently over many years, rather than relying on short-term dietary changes or individual foods or supplements.

Want to learn more? Explore our guide to the Mediterranean and MIND diets to discover how these eating patterns compare and how to incorporate them into your daily routine.

Related reading:

The Alzheimer’s Prevention Diet
Alzheimer’s: Why Prevention is Better than Cure
Groundbreaking New Research: The Key to Reducing Dementia Risk
Mediterranean Diet & Depression

By Patrick Holford

Taking vitamin D supplements may help ward off dementia, according to a new, large-scale study involving over twelve thousand dementia-free 70+ year olds in the US. More than a third (37%) took supplements of vitamin D. After adjusting for baseline age, sex, education, race, cognitive diagnosis, depression, and APOE4 status, exposure to prescribed vitamin D supplements was associated with 40% lower incidence of dementia during a ten-year period.

The study, carried out by researchers from the University of Calgary’s Hotchkiss Brain Institute in Canada and the University of Exeter in the UK, has been published in the journal Alzheimer’s & Dementia. The team found that taking vitamin D was associated with living dementia-free for longer, and they also found 40 per cent fewer dementia diagnoses in the group who took supplements.

Professor Zahinoor Ismail, of the University of Calgary and University of Exeter, who led the research, said: “We know that vitamin D has some effects in the brain that could have implications for reducing dementia, however so far, research has yielded conflicting results. Our findings give key insights into groups who might be specifically targeted for vitamin D supplementation. Overall, we found evidence to suggest that earlier supplementation might be particularly beneficial, before the onset of cognitive decline.”

One of the problems in relation to vitamin D and cognition is the use of variable amounts of vitamin D, and the lack of reporting regarding blood levels at baseline and conclusion of trials. This study has the same issue. We do not know the dose taken nor the starting and end blood levels of those supplementing or not.

A review by Dr William Grant, Director of Sunlight, Nutrition and Health Research Center, who is the expert on our Scientific advisory Board shows that the higher the blood level of vitamin D (25-hydroxyvitamin D [25(OH)D] is the form measured in the blood serum) the lower is the risk of developing Alzheimer’s as well as dementia in general. The mechanisms identified as potentially explaining its benefit include reduced brain aging, cellular senescence, mitochondrial dysfunction and oxidative stress as well as higher high-density lipoprotein (HDL). Observational study findings indicate that blood levels above 30 ng/mL (75 nmol/L) reduce dementia risk by about 40% and Alzheimer’s risk by about 30% compared to those with blood levels below 12 ng/mL (30 nmol/L) which is broadly consistent with the scale of benefit reported in this trial. You can read Dr William Grant’s full review entitled “The role of vitamin D in reducing risk of Alzheimer’s disease” here.

 “In this study, while Vitamin D was effective in all groups, the team found that the beneficial effects were significantly greater in females, compared to males. Similarly, effects were greater in people with normal cognition, compared to those who reported signs of mild cognitive impairment – changes to cognition which have been linked to a higher risk of dementia.

Dr William Grant says “It is unlikely that vitamin D supplementation is of much use for treating advanced stages of these diseases, although it would be useful in reducing risk of other vitamin D-sensitive adverse health outcomes.” Overall, he says “The evidence regarding vitamin D satisfies the criteria for causality in a biological system for reducing risk of cognitive function, Alzheimer’s and vascular dementia. Thus, vitamin D supplementation can be recommended as an additional way to reduce risk of these diseases. It should also be useful for reducing the rate of progression of these diseases.”

The mechanism(s) for explaining the beneficial effects of vitamin D are not yet clear, however one interesting finding was that the effects of vitamin D were also significantly greater in people who did not carry the APOEe4 gene, known to present a higher risk for Alzheimer’s dementia, compared to non-carriers. The authors suggest that people who carry the APOE4 gene absorb vitamin D better from their intestine, which might reduce the vitamin D supplementation effect due to higher baseline vitamin D levels. However, no blood levels were drawn to test this hypothesis.

Co-author Dr Byron Creese, at the University of Exeter, said: “Preventing dementia or even delaying its onset is vitally important given the growing numbers of people affected.  The link with vitamin D in this study suggests that taking vitamin D supplements may be beneficial in preventing or delaying dementia, but we now need clinical trials to confirm whether this is really the case.  The ongoing VitaMIND study at the University of Exeter is exploring this issue further by randomly assigning participants to either take vitamin D or placebo and examining changes in memory and thinking tests over time.”

At Food for the Brain those taking the Cognitive Function Test also answer questions about their use, and level of vitamin D, if known. We hope, soon, to start offering vitamin D testing to further research the effects of vitamin D in relation to cognitive decline to be able to track progress both cognitive changes against vitamin D blood levels and intake, to help determine an optimal daily intake or blood level. We are also working with the charitable Grassroots Health Nutrient Research Institute who have tested thousands of people’s blood vitamin D level and are now encouraging them to take Food for the Brain’s Cognitive Function Test. You can join their Vitamin D action group here.

Listen to Patrick Holford’s podcast explaining the role of vitamin D in Alzheimer’s disease here.

Originally published on Orthomolecular Medicine News Service [15th February 2023]

In the days of Hippocrates, diseases were blamed on the gods. He didn’t buy that and explored the causes of disease saying ‘let food be thy medicine’. Nowadays a lot of diseases are being blamed on genes – because knowledge about genes and their effects has advanced tremendously over the last several decades. Genes are the code, or instructions, to assemble proteins, for example to make an enzyme, a hormone or a biochemical such as cholesterol or phospholipids.

Take Alzheimer’s, which accounts for two thirds of dementia, as an example. There are only three genes that can cause Alzheimer’s (APP, PSEN1, PSEN2), and these account for considerably less than one in a hundred cases of Alzheimer’s. [1]

There are, however, 76 other genes [2] which appear to confer a very small additional risk. Taken together, estimates suggest that 75-85% of the risk can be explained by combining these into a polygenic risk score. [3] The single greatest predictor is the presence of the ApoE4 variant of the ApoE gene, carried by about one in five people. It is considered to contribute 4 to 6% of the absolute risk for Alzheimer’s disease. [4,5]

This is often exaggerated as a risk factor because, if a person has the ApoE4 gene, and changes nothing, they have about a 20% greater chance of developing Alzheimer’s later in life than someone who doesn’t. This is called ‘relative risk’. It doesn’t mean, however, that someone with the ApoE4 gene has a 20% chance of developing Alzheimer’s. This is because, as an example, a person without the ApoE4 gene at a certain age might have a 5% chance of developing Alzheimer’s, while someone with the ApoE4 gene might have a 6% chance, so their risk has gone up by, in this example, 20%. In absolute terms, the risk would be only 1% higher.

Predicting risk and actually reducing risk with modifications of diet and lifestyle are two different things. The predictive risk for Alzheimer’s of having a low intake of seafood and/or omega-3 fats is 22%, and so is having a low intake of B vitamins resulting in a high blood homocysteine level. Smoking confers a similar risk. [6] Other big risk factors are an inactive lifestyle and low level of education. Add in predictive genes and apparent risk adds to well over 100% partly because there is overlap.

But the only way to find out how much you can actually reduce a person’s risk by is to either conduct ‘observational’ studies looking at, e.g. smokers vs non-smokers, or people with a good versus a bad diet, and see how many develop dementia. Even better is to change something, such as looking at what happens when a person stops smoking, or supplements omega-3 fish oils or homocysteine lowering B vitamins.

Modifying ApoE4 with orthomolecular medicine

All these so-called Alzheimer’s genes, with the exception of the causative ones, can only exert effects via non-genetic mechanisms and these mechanisms are often susceptible to modification with a person’s nutrition having the most direct influence. In other words, gene variants that are present are not either active or inactive. Even if you have a gene variant such as ApoE4 it is more like a dimmer switch and can be ‘over-expressed’ or ‘down-regulated’, turned up or dimmed down. That is why approximately half of women with the BRCA gene develop breast cancer and half don’t. The environment the gene is exposed to makes all the difference.

The expression and harmful effects of the ApoE4 gene appear to be downregulated by eating a low-glycemic load (GL) diet or a more ketogenic diet with specific Mediterranean-style food choices including fatty fish, cruciferous vegetables, olive oil, and low alcohol consumption. Six supplemental nutrients have reasonably good evidence of down-regulating ApoE4. These are omega-3 DHA, B vitamins (B2, B6, B12 and folate) vitamins D3 and K2, quercitin and resveratrol. [7] This approach to modifying the effects of the genes we inherit with personalised nutrition is a fundamental tenet of orthomolecular medicine, sometimes called personalised, precision or optimum nutrition.

But what happens to risk if a person is doing these things already? A good example of this is a recent study in China, involving 29,072 people of which 20% had the ApoE4 gene. [8] Each participant had their diet and lifestyle assessed over the 10 year period of the study to see who would or wouldn’t develop cognitive decline or dementia.

The study showed that whether or not a person had the ApoE4 ‘Alzheimer’s gene’ made no difference to the positive reduction in risk achievable by simple diet and lifestyle changes. “These results provide an optimistic outlook, as they suggest that although genetic risk is not modifiable, a combination of more healthy lifestyle factors is associated with a slower rate of memory decline, regardless of the genetic risk,” wrote the study authors.

Eating a healthy diet was the most important prevention step, followed by an active lifestyle, with one’s intellectual life, then physical activity, then social interactions being the next most important steps. Eating a healthy diet was about twice as important as exercise in predicting cognitive decline. Those with a healthy diet were about seven times less likely to have age-related cognitive decline or dementia than those with an ‘average’ diet and about nine times less likely to develop dementia than those with an unfavorable diet.

The assessment of a healthy diet was based on intake of fish, eggs, fruits, vegetables, legumes, nuts and tea, among other foods known to predict lower risk.

B vitamins modify methylation of genes linked to dementia

Other Alzheimer’s related genes affect a process called methylation. Healthy methylation depends on adequate B vitamin intake, primarily B6, B12 and folate. Inheriting a variant of a key methylation gene, MTHFR 677TT increases risk for Alzheimer’s. [9-11] About one in three people have this gene variant. It impacts risk by raising homocysteine, a toxic amino acid that damages the brain and blood vessels. Having a raised homocysteine level increases risk for cerebrovascular dysfunction 17-fold. [12]

Since methylation is needed to make phospholipids, biochemicals essential for the brain also found in eggs and fish, having a poor diet in this respect creates more methylation demand and, consequently, greater need for B vitamins.

In a placebo controlled study of older people with mild cognitive impairment, about a third of participants had the MTHFR variant that increases Alzheimer’s risk. But supplementing with B vitamins effectively lowered homocysteine in both those with and without this ‘Alzheimer’s’ gene. The B vitamin supplement almost arrested further memory decline and slowed the rate of brain shrinkage by 52%, [13,14] reducing shrinkage of the Alzheimer’s areas of the brain by 9-fold. [15] Whether a person did or didn’t have this ‘Alzheimer’s’ gene made no difference to the beneficial effect of the B vitamins.

Those with adequate omega-3 blood levels had even less brain shrinkage – 73% less than the placebo group. [16-17] Two other studies have found major protection either by giving B vitamins to those with adequate omega-3 intake, [18] or by supplementing omega-3 to those with lower homocysteine levels [19] further confirming that you need both B vitamins and omega-3 fats to keep neurons healthy – an example of synergy – regardless of one’s genes. Whether a person did or didn’t have the MTHFR variant made no significant difference.

Too often genes are blamed as drivers of disease even though (with the exception of rare causative genes) the primary drivers are what you put in your mouth or how you live your life – both factors under our control. For example, DNA genetic testing can cause panic when an individual is informed they have a dozen or more gene variants. Over-emphazing the importance of genes discourages people from preventing their own disease by improving diet and lifestyle.

Find out your dementia risk

You can find out what’s driving your risk and which diet and lifestyle changes will make the biggest difference by doing the Cognitive Function Test at foodforthebrain.org and joining COGNITION, the brain upgrade program. Not only do you help yourself, you also help the hundreds of thousands of people who would benefit from the research we support at Food for the Brain to reduce risk of dementia.

About Patrick Holford

(Patrick Holford , BSc, DipION, FBANT, NTCRP is widely published and a member of the Orthomolecular Medicine Hall of Fame. He is the director of the non-profit, UK-based “Alzheimer’s is Preventable” campaign [ foodforthebrain.org].)

References

1. Bekris LM, Yu CE, Bird TD, Tsuang DW. (2010) Genetics of Alzheimer disease. J Geriatr Psychiatry Neurol. 23:213-227. https://pubmed.ncbi.nlm.nih.gov/21045163

2. Bellenguez C, Küçük F, Jansen IE, et al. (2022) New insights into the genetic etiology of Alzheimer-s disease and related dementias. Nat Genet. 54:412-436. https://pubmed.ncbi.nlm.nih.gov/35379992

3. Escott-Price V, Myers AJ, Huentelman M, Hardy J. (2017) Polygenic risk score analysis of pathologically confirmed Alzheimer disease. Ann Neurol. 82:311-314. https://pubmed.ncbi.nlm.nih.gov/28727176

4. Heininger K (2000), A unifying hypothesis of Alzheimer’s disease. III. Risk factors. Hum Psychopharmacol Clin Exp. 15:1-70. https://pubmed.ncbi.nlm.nih.gov/12404343

5. Ridge PG, Mukherjee S, Crane PK, Kauwe JSK, (2013) Alzheimer’s Disease: Analyzing the Missing Heritability. PLoS One. 8(11): e79771. https://pubmed.ncbi.nlm.nih.gov/24244562

6. Beydoun MA, Beydoun HA, Gamaldo AA, et al. (2014) Epidemiologic studies of modifiable factors associated with cognition and dementia: systematic review and meta-analysis. BMC Public Health. 14:643. https://pubmed.ncbi.nlm.nih.gov/24962204

7. Norwitz NG, Saif N, Ariza I.E, Isaacson RS (2021) Precision Nutrition for Alzheimer’s Prevention in ApoE4 Carriers. Nutrients 13:1362. https://pubmed.ncbi.nlm.nih.gov/33921683

8. Jia J, Zhao T, Liu Z et al. (2023) Association between healthy lifestyle and memory decline in older adults: 10 year, population based, prospective cohort study. BMJ 380:e072691. https://pubmed.ncbi.nlm.nih.gov/36696990

9. Morris AA, Kožich V, Santra S, et al. (2017) Guidelines for the diagnosis and management of cystathionine beta-synthase deficiency. J Inherit Metab Dis. 40:49-74. https://pubmed.ncbi.nlm.nih.gov/27778219

10. Bouguerra K, Tazir M, Melouli H, Khelil M. (2022) The methylenetetrahydrofolate reductase C677T and A1298C genetic polymorphisms and plasma homocysteine in Alzheimer’s disease in an Algerian population. Int J Neurosci. 29:1-6. https://pubmed.ncbi.nlm.nih.gov/36580407

11. Zuin M, Cervellati C, Trentini A, et al. (2021) Methylenetetrahydrofolate reductase C667T polymorphism and susceptibility to late-onset Alzheimer’s disease in the Italian population. Minerva Med. 112:365-371. https://pubmed.ncbi.nlm.nih.gov/32700867

12. Teng Z, Feng J, Liu R, et al. (2022) Cerebral small vessel disease mediates the association between homocysteine and cognitive function. Front. Aging Neurosci. 14:868777. https://pubmed.ncbi.nlm.nih.gov/35912072

13. Smith AD, Smith SM, de Jager CA, et al. (2010) Homocysteine-lowering by B vitamins slows the rate of accelerated brain atrophy in mild cognitive impairment: a randomized controlled trial. PLoS One. 5(9):e12244. https://pubmed.ncbi.nlm.nih.gov/20838622

14. Smith AD, Refsum H. (2016) Homocysteine, B vitamins, and cognitive impairment. Annu Rev Nutr. 36: 211-239. https://pubmed.ncbi.nlm.nih.gov/27431367

15. Douaud G, Refsum H, de Jager CA, et al. (2013) Preventing Alzheimer’s disease-related gray matter atrophy by B-vitamin treatment. Proc Natl Acad Sci USA 110:9523-9528. https://pubmed.ncbi.nlm.nih.gov/23690582

16. Jernerén F, Elshorbagy AK, Oulhaj A, et al. (2015) Brain atrophy in cognitively impaired elderly: the importance of long-chain omega-3 fatty acids and B vitamin status in a randomized controlled trial. Am J Clin Nutr. 102:215-221. https://pubmed.ncbi.nlm.nih.gov/25877495

17. Oulhaj A, Jernerén F, Refsum H, et al. (2016) Omega-3 fatty acid status enhances the prevention of cognitive decline by B vitamins in Mild Cognitive Impairment. J Alzheimer’s Dis. 50:547-557. https://pubmed.ncbi.nlm.nih.gov/26757190

18. van Soest, A.P.M., van de Rest, O., Witkamp, R.F. et al. (2022) DHA status influences effects of B-vitamin supplementation on cognitive ageing: a post-hoc analysis of the B-proof trial. Eur J Nutr. 61:3731-3739. https://pubmed.ncbi.nlm.nih.gov/35704085

19. Jernerén F, Cederholm T, Refsum H, et al. (2019) Homocysteine Status Modifies the Treatment Effect of Omega-3 Fatty Acids on Cognition in a Randomized Clinical Trial in Mild to Moderate Alzheimer’s Disease: The OmegAD Study. J Alzheimers Dis. 69:189-197. https://pubmed.ncbi.nlm.nih.gov/30958356