Is food triggering brain fog, low mood & lethargy? And our collaboration with YorkTest

Have you ever wondered if what you eat has anything to do with your mood, energy levels and ability to concentrate? Do you ever experience ‘brain fog’ and tiredness and wonder why you feel anxious and low when others seem to cope?

 New research is showing that what happens in your gut after eating food has a direct effect on your brain and how you feel. Simple diet changes can have profound effects. Stephanie, a 28-year-old lawyer, is a case in point. “After a week the brain fog and tiredness were significantly better and then after a few weeks, all of my symptoms had gone!” Wanita , age 41, who was signed off work, had complete relief from her anxiety and fatigue and she was then able to return back. Her doctor had recommended anti-depressants. Nicola, age 51, had constantly felt tired and lethargic, with brain fog and the inability to concentrate. “If I didn’t eat regularly, I felt worse, so I was constantly grazing on food. I know now I was eating the wrong foods which didn’t help”. Now she says “I feel so much better in myself and have a lot more energy. The best thing is to not have brain fog.”

What they all had in common were specific food intolerances whereby their gut and immune system reacted, creating a kind of inflammation and reactivity that can both cause gut issues such as IBS, pain and bloating, but also psychological issues such as brain fog, anxiety and depression. The ability of foods to trigger mental health issues has been known for a remarkably long time. Back in 1980 Dr Joseph Egger, writing in the Lancet medical journal (1) reported: “The results showed that allergies alone, not placebos, were able to produce the following symptoms: severe depression, nervousness, feeling of anger without a particular object, loss of motivation and severe mental blankness.” But why certain foods in certain people could produce mood changes and brain fog wasn’t known.

Researchers in the US (2) China (3), Poland (4) and the UK (5) have found out why and it’s all to do with ‘food intolerance’ that is unique to the individual. While classic allergies cause the body to product IgE antibodies that attack the offending allergen, depression, brain fog and even schizophrenia, according to research at Johns Hopkins University School of Medicine in the US, can occur when a person’s immune system produces a different kind of ‘IgG’ antibody that attacks their offending foods. 

What Stephanie, Wanita and Nicola had in common is they are part of research that has involved thousands of people, all having an IgG food intolerance test administered via a home test kit provided by YorkTest, and then avoided their ‘reactive’ foods. 

Scientific Director at YorkTest, Dr Gill Hart, says “YorkTest pioneered food IgG testing developing our first food intolerance test back in 1998 in collaboration with scientists from the University of York. Since then, YorkTest has provided over half a million tests. The tests are accurate, have been shown to be effective and have demonstrated >98% reproducibility. For those with high food IgG reactivity, the pattern of IgG trigger foods is unique to each individual. The tests provide valuable information, and with nutritional advice provided as part of the Food Intolerance Test, people feel fully supported in making the required dietary changes. The good news is that food intolerances aren’t necessarily for life, and those taking the test and changing their diet have reported improvements over a relatively short period of time”. 

Unlike conventional IgE allergies, which can last for life, IgG antibodies “die off” so, theoretically, if you avoid the offending food for at least three months, you may be able to reintroduce the food without reacting. However, it is worth doing this systematically because some people do continue to react.

Nine in ten people having the test, and avoiding their offending foods report improvement in mood, brain fog and lethargy (5). See the table below for reported results from YorkTest’s research.

YorkTest are a supporter of Food for the Brain and offer our Friends £10 off the price of a test in the UK. If you live in the UK go to yorktest.com and enter the discount code FFB10 in the basket.

If you live in the US go to yorktest.com/us and enter FFB10US in the basket for your $10 discount. YorkTest will match your discount with a donation to Food for the Brain to help us help more people regain mental health through optimum nutrition.

CLICK HERE TO GET YOUR YORK TEST IN THE UK & IRL

CLICK HERE TO GET YOUR YORK TEST IN THE USA

REFERENCES

1. Egger J et al, The Lancet 865-869, October 15, 1980

2.. Severance E et al (2015) IgG dynamics of dietary antigens point to cerebrospinal fluid barrier or flow dysfunction in first-episode schizophrenia. Brain Behav Immun. 44:148–58  

3. Tao R et al (2019) Chronic Food Antigen-specific IgG-mediated Hypersensitivity Reaction as A Risk Factor for Adolescent Depressive Disorder. Genomics Proteomics Bioinformatics 17(2):183-189.

4. Karakuła-Juchnowicz H et al (2017) The role of IgG hypersensitivity in the pathogenesis and therapy of depressive disorders. Nutr Neurosci 20:110-8; see also Karakula-Juchnowicz H et al (2018) The Food-Specific Serum IgG Reactivity in Major Depressive Disorder Patients, Irritable Bowel Syndrome Patients and Healthy Controls. Nutrients 10:548; 

5. Hart G (2017) Food-specific IgG guided elimination diet; a role in mental health? BAOJ Nutrition 3:3:033  

6.  Hardman G and Hart G, 2007: Dietary advice based on food-specific IgG results. Nutrition and Food Science 37, 16-23 https://www.emerald.com/insight/content/doi/10.1108/00346650710726913/full/html

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.