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

By Patrick Holford

How does cognitive decline happen?

One theory was that it was to do with the accumulation of amyloid protein, producing amyloid plaque that interferes with brain cell communication. But, despite over 30 clinical trials, lowering amyloid protein has had close to zero clinical effect. But, even if this was part of the problem, one would have to ask why?

There are plenty of left-field theories. One, for example, is that it’s an auto-immune disease whereby the brain starts to destroy itself. There are plenty of diet and lifestyle diseases that tip over into auto-immune diseases. For example, type-2 diabetes can convert to type-1 diabetes and osteoarthritis can convert to rheumatoid arthritis. But even so, one would have to ask why? What would be driving this?

Risk Factors for Alzheimer’s – what do they have in common?

There are over 20 known risk factors that predict future risk for cognitive decline, dementia and/or Alzheimer’s. These include:

Anon-adherence to Mediterranean diet principles
Cardiovascular disease, and high blood pressure
Depression/social isolation/loneliness
Diabetes
Genes (such as senilin) and predisposing genes (eg ApoE4)
Head trauma
High blood homocysteine (a measure of B vitamins)
Insulin resistance
Lack of antioxidants/polyphenols in plant foods
Lack of cognitive stimulation
Lack of exercise and muscle mass – frailty
Lack of folate, B12 and B6
Lack of sleep
Low education level
Low phospholipid and choline intake (in eggs and fish)
Low seafood consumption and a lack of omega-3
Low sunlight exposure
Low vitamin C, D and E intake
Low zinc levels
Medication – antiacids, metformin, diuretics
Metabolic syndrome
Poor gut health and dental health
Poor hearing
Smoking
Stress
Strokes and TIAs (transient ischemic attacks )
Too much sugar, refined, processed, carb-rich foods

So far researchers have looked at individual known risk factors for Alzheimer’s, then tried to change them with some success. The nutritionists have tried to change diet, or give supplements. The pharmacologists have tried to give drugs to lower, for example, high blood pressure or insulin levels. The psychologists have tried to increase cognitive stimulation and address depression and isolation, and insomnia. The sports physiologists have tried to increase exercise. But what do all these factors have in common? Is there a way of looking that ties all these risk factors together into an understanding as to what is actually driving dementia?

The old, but still dominant mindset in science is ‘reductionism’. The idea is to look at one thing, or one risk factor, then change it in a randomised placebo-controlled trial. The idea is that if everyone does this then you could pool all the interventions together to produce a cure. This reminds me of a comment made in the G8 summit on dementia in 2010, in London, when we succeeded in getting a discussion on dementia prevention added to the agenda. The pharma representative said words to the effect of ‘we will solve dementia with multiple drugs, just like we solved AIDS’. The reality is studies giving drugs[1] to lower blood sugar for diabetics, lower blood pressure with anti-hypertensive drugs, lower cholesterol with statins, even lower amyloid protein, have failed. The official cost of all this research is $42.5 billion to date.[2] This is five times more than the cost of the James Webb telescope. This approach clearly isn’t working. The only ‘drugs’ that have worked are homocysteine lowering B vitamins and omega-3 fish oils – and the recent discovery is that they work together, in cooperation.

There’s a new emerging way of doing science which is called ‘systems-based’ science. The physicist, Fritjof Capra, has explained this way of doing science in his book ‘The Web of Life’. He says “Systems thinking emerged from a series of interdisciplinary dialogues among biologists, psychologists, and ecologists, in the 1920s and ’30s. In all these fields, scientists realized that a living system—organism, ecosystem, or social system—is an integrated whole whose properties cannot be reduced to those of smaller parts. The “systemic” properties are properties of the whole, which none of its parts have. So, systems thinking involves a shift of perspective from the parts to the whole. The early systems thinkers coined the phrase, “The whole is more than the sum of its parts.”[3]

Us humans are a complex adaptive system. What’s also been learnt about complex adaptive systems is that they have a certain amount of ‘resilience’ which you can think of as the credit in your health deposit account. When that runs out, disease occurs. Many leaders in the field of nutritional and naturopathic medicine consider that many of the same underlying processes are going wrong in our bodies, which then cause the emergence of a ‘disease’ depending on the organ it strikes – so heart disease, diabetes, arthritis and dementia have similar contributing factors.

At Food for the Brain, we can organise all these risks above into eight domains shown below. It is certainly true that these eight domains of ‘risk’ cover much of what we know about the risks for heart disease, diabetes and arthritis, for example. This partly, but not fully. answers the question about what is actually driving dementia.

Another understanding within systems-based thinking is well illustrated by asking the question ‘what is the difference between an inanimate object, like a bicycle, and an animate organism, such as us?’ A bicycle has ‘parts’ and the parts related to each other, as in functioning together. So do we. But also, there is ‘life’ running through us. You can imagine your brain’s neural network lighting up, with ‘energy’ or signals shooting this way and that. If you have healthy parts, all functioning, but no signals, you’re kind of ‘switched off’.

We call the parts – structure; the relationship of the parts – function; and the life running through the neural network – utilisation. These are shown visually below in a way to illustrate that they are integral, with each dependent on the other.

Now, let’s reorganise all those risk factors accordingly into whether they are primarily required for the structure or function of the neural network, or send messages across it.

If you’ve watched the short animated film ‘how to keep building brain cells at any age‘ you’ll know that the membrane of every brain cell is made by binding omega-3 DHA, rich in seafood, to phospholipids and especially Phosphatidylcholine, rich in eggs and fish, to produce what called ‘phosphorylated DHA’. You need this to have a functioning brain. It actually makes up more than 90 per cent of the structure of your brain.

You’ll also know that the ‘binding’ of these two parts depends on B vitamins, which drive a process called methylation. So, without enough B vitamins your brain and nervous system fall apart. The best measure of methylation, and whether you are getting enough B vitamins, is your blood homocysteine level.  If your homocysteine level is high, you’ve got a problem. Above 11mcmol/l and you’ve got a shrinking brain. More than half of all people over 70 have a homocysteine level above this. It should, therefore, be no surprise to find that, if you have a raised homocysteine level, and are given B vitamins, if you also have a low omega-3 DHA intake or blood level, the B vitamins won’t work. Conversely, if you supplement omega-3 fish oils, but have a raised homocysteine level or lack of B vitamins, the omega-3 won’t work. The full story of the dynamic duo of Omega-3 and  B vitamins is explained here.

It is likely that choline deficiency, which is especially common in those who rarely eat fish or eggs, may also create a similar structural problem in the brain. In animals supplementing choline prevents Alzheimer’s related brain changes.[4]

Protecting the Function of Your Brain

There are many aspects of ‘function’ of the brain. Using a simple car analogy, one thinks of the need for fuel and the need for oil to lubricate the parts. The two main fuels of brain cells are either glucose, derived from carbs, or ketone derived from fat.

If you’ve watched the animated film ‘how to fuel your brain for better memory’, you’ll know about the need for slow-releasing carbs and ketones from a type of fat called a medium chain triglyceride (MCT) and specifically C8 oil.

Too much sugar, and especially fructose and high fructose corn syrup (now used by the food industry to sweeten foods), and too much refined carbohydrates interferes with fuel supply to brain cells by making you ‘insulin resistant’. Insulin receptors, embedded in neuronal membranes, transport glucose into brain cells. If these receptors, which are like doors, are largely shut down, the brain starves of clean fuel. Read professor Robert Lustig’s article “Is sugar killing your brain?’ for the full story.

The alternative brain fuel – ketones, which neurons actually prefer, can be made in the liver from a type of fat called C-8 (caprylic acid triglyceride) which makes up 7 per cent of coconut oil. In a study giving people with memory problems two tablespoons of C8 oil, their brains produced 230 per cent more energy from ketones and their memory improved. The article ‘Is fat the best brain fuel?’ gives you the full story.

The lubricating ‘oil’ in a car analogy would be both dealing with the ‘exhaust fumes’ of the brain’s energy production, namely oxidants. These are mopped up by antioxidants and polyphenols rich in plant foods. That where food such as blueberries and cacao, or vitamin C and E, come in. It’s also why smoking is such a big risk factor.

Another part of ‘function’ is circulation – anything that improves circulation helps the function. Many of the things we’ve mentioned –  lowering homocysteine with B vitamins, omega-3, antioxidants, polyphenols – also help circulation.

Another part of ‘function’ is inflammation. Behind all those ‘metabolic’ diseases -diabetes, heart disease, arthritis to name a few – lies inflammation which doesn’t just affect the specific organ, be it heart of joint, but also the brain.

Use it or Loss it – Why Your Brain Needs Stimulation

One of our experts, Tommy Wood, assistant research professor at the University of Washington in Seattle, focussing on neuroscience, has developed an excellent model for understanding the ‘use it or lose it’ principle. He’s big into exercise.

‘Exercise is important because it makes the brain do things that keep it healthy, such as growth and repair and maintaining temperature and weight,’ he says. ‘When they aren’t stimulated, the health of brain tissues deteriorates with a knock-on effect on memory and thinking.’

And it’s not just physical exercise that does this, we also benefit from the mental exercise involved in likes of solving puzzles or learning a new language. ‘For many people the worst thing they can do for their brain is to retire’, says Wood. ‘They lose much of the stimulation that kept it healthy.’

Sleep as a brain protector also fits in here. It’s vital for recovering from both physical and intellectual exercise and to store and organise what you have learnt in the day.

‘But sleep and exercise aren’t enough on their own,’ Wood continues. ‘All that repair and maintenance needs a good supply of nutrients.’

Stress also fits in here because stress, as well as environmental and dietary ‘pollution’ be it from drinking and smoking, dirty air, moulds, even allergens like gluten with can induce ‘brain fog’ often experienced by those with coeliac disease, promote inflammation and inhibit repair and regeneration.

A Unified Model for the Drivers of Cognitive Decline

This systems-based approach to what’s potentially driving cognitive decline makes it obvious that there will never be a single drug or single factor that stops a person developing dementia. Instead, if a person has enough ‘interference’ with the structure, function or utilisation of their brain then there will, inevitably be cognitive decline with age.

At Food for the Brain, when you complete your Cognitive Function Test, you know objectively how you are doing and how much room for improvement there is. Then you are invited to complete the Dementia Risk Index questionnaire, which not only gives you a score out of 100% (you are aiming for a score closer to 0%) but also shows you in which domain you have the most room for improvement.

You are then invited to join COGNITION, which is an interactive brain upgrade programme that targets your weakest areas and shows you the simplest changes that will make the biggest difference to reduce your risk.

The goal is to turn all your reds, oranges and yellows into green, then reassess your cognitive function. By joining you are becoming part of a group of hundreds of thousands of citizen health scientists helping to discover what really works to dementia-proof your diet and lifestyle.

Take the FREE Cognitive Function Test today.

References

[1] Peters R, Breitner J, James S, Jicha GA, Meyer PF, Richards M, Smith AD, Yassine HN, Abner E, Hainsworth AH, Kehoe PG, Beckett N, Weber C, Anderson C, Anstey KJ, Dodge HH. Dementia risk reduction: why haven’t the pharmacological risk reduction trials worked? An in-depth exploration of seven established risk factors. Alzheimers Dement (N Y). 2021 Dec 8;7(1):e12202. doi: 10.1002/trc2.12202. PMID: 34934803; PMCID: PMC8655351.

[2] 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.

[3] Fritjof Capra (2009) The New Facts of Life: Connecting the Dots on Food, Health, and the Environment, Public Library Quarterly, 28:3, 242-248, DOI: 10.1080/01616840903110107

[4] Velazquez R, Ferreira E, Knowles S, Fux C, Rodin A, Winslow W, Oddo S. Lifelong choline supplementation ameliorates Alzheimer’s disease pathology and associated cognitive deficits by attenuating microglia activation. Aging Cell. 2019 Dec;18(6):e13037. doi: 10.1111/acel.13037. Epub 2019 Sep 27. PMID: 31560162; PMCID: PMC6826123.

Responding to the ‘feverish media coverage heralding a new era of disease modifying treatments’, described by the BBC as a ‘momentous breakthrough’ a scathing editorial in the British Medical Journal says: “Hyperbolic rhetoric gives patients and their families false hope, which clinicians must address, and pre-empts regulatory decision making.”

“Such treatment has been long hoped for,” they say. “However, the null effects on cognition of other anti-amyloid agents, the tiny effect on cognition reported for [the new drug] lecanemab and concerns about safety mean that perspective is needed.”

“The prevailing narrative is that this trial “succeeded” where others have “failed.” In reality, lecanemab, like other anti-amyloid agents, successfully cleared amyloid from the brain. This clearance had no discernible effect on cognition in some trials, a very small and non- significant effect in other trials, and a very small significant effect in the latest trial. The overall trial evidence tells us that successful amyloid clearance in adults with early Alzheimer’s disease has either no effect or a tiny effect on cognitive decline.” 

“Previous attempts to quantify the minimum clinically important difference in the trial’s primary outcome measure—the Clinical Dementia Rating (CDR) sum of boxes score (range 0-18 —suggested that minimum changes of 0.98 in mild cognitive impairment and 1.63 in mild Alzheimer’s disease are meaningful. After 18 months of treatment with lecanemab, differences of 0.35 and 0.62 for those with mild cognitive impairment and mild Alzheimer’s disease, respectively, fell well short, representing only around a third of what a minimum clinically important difference might look like.”

Both B vitamins and omega-3 have achieved a clinically significant reduction in the CDR by these criteria, as well as improving other measures of cognition, and in reducing the rate of brain shrinkage. The rate of brain shrinkage reduction of this kind of drug is 2% compared to up to 73% less shrinkage with B vitamins in those with sufficient omega-3. Yet both UK, US and EU government and medical agencies have repeatedly declined funding a definitive trial of both B vitamins and omega-3.

The BMJ editorial expresses serious concerns about safety of this class of drug, which is really an antibody injection. “As with other anti-amyloid agents, lecanemab comes with substantial safety concerns. During the trial, 12.6% of participants treated with lecanemab developed brain oedema (swelling), 22% of whom were symptomatic.  A further 17.3% experienced brain haemorrhage; and 6.9% experienced adverse events severe enough to discontinue the trial.” That means that 30% of drug trial participants had a serious adverse effect.

While the number of deaths in the main trial were comparable between the drug and placebo group “more information is needed about two deaths reported during the trial’s open label extension. Both participants had brain haemorrhage, possibly associated with taking lecanemab alongside anticoagulants or thrombolysis.”

They say that “Lecanemab if licensed is likely to cost tens of thousands of pounds a year for each patient. In addition, health systems would need to provide PET scans or lumbar puncture to determine eligibility, fortnightly infusions of the drug indefinitely, and repeated MRI [scans] to monitor for adverse events, all of which is far beyond the capacity of most countries, even those with well-resourced healthcare systems.” B vitamins and omega-3 have no side-effects, other than knock-on health improvements, and cost pennies, not thousands of pounds.

Pressure for approval and clinical use, the BMJ says, is likely to be fierce. “Viewed objectively, however, lecanemab is not the hoped for “game changer.” Rather, it is further evidence that anti-amyloid therapies do not produce clinically meaningful benefits for people with Alzheimer’s disease. Weighed against the scale and severity of adverse events and substantial practical barriers to widespread use, lecanemab is unlikely to represent a favourable risk-benefit balance for patients or value for money for health systems.”

The fully referenced BMJ editorial can be viewed here.

If you are concerned about age-related cognitive decline, dementia or Alzheimer’s please take our free, validated Cognitive Function Test here and sign up to join our COGNITION programme, to help dementia-proof your diet and lifestyle. Also, please support our work in helping teach people who to prevent dementia by becoming a FRIEND of Food for the Brain here.

A hugely significant study in the British Medical Journal into age-related cognitive decline and dementia has stated that changing your diet and lifestyle from bad to good cuts your future risk of developing dementia by a massive nine times [1]

The study shows, significantly, that whether or not you inherit the ApoE4 ‘Alzheimer’s gene’ that one in five people carry, it makes no difference to the positive reduction in risk achievable by simple diet and lifestyle changes [2].

Eating a healthy diet was also 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.

This study, published on 25th January 2023, followed over 30,000 people over a decade and found that 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 unfavourable 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.

Increasing evidence that Alzheimer’s and Dementia are preventable

“These results provide an optimistic outlook, as they suggest that although genetic risk is not modifiable, a combination of more healthy lifestyle factors are associated with a slower rate of memory decline, regardless of the genetic risk,” wrote the study authors.

This study has been warmly welcomed by charity Food for the Brain, as it backs up their own research and the work they have been actively carrying out for 10  years, to help people reduce their risk of age-related cognitive decline.

Food for the Brain offers a free online assessment of a participant’s diet and lifestyle, called the Dementia Risk Index, which works out a person’s overall risk. The assessment also includes a cognitive function test to assess your memory. This charitable ‘citizen science’ action group have also just launched COGNITION, an interactive, personalised ‘brain upgrade’ programme that then shows you, week-by-week, how to make positive changes to bring your risk closer to zero.

Indeed, the on-line test assesses all the same risk factors the British Medical Journal study has shown impact a person’s future risk – diet, active physical, intellectual, social lifestyle, smoking and drinking habits.  

According to Professor David Smith from the University of Oxford, one of the charity’s scientific advisors, “Genes can only exert effects via non-genetic mechanisms and these mechanisms are often susceptible to modification by, for example, improving one’s diet. This study shows that diet and lifestyle are much more important than inheriting a gene variant such as ApoE4. Less than 1% of Alzheimer’s is directly caused by genes. With no clinically effective drugs, and minimal role of genes, this study confirms that the focus must be on making diet and lifestyle changes that reduce risk of developing dementia, as foodforthebrain.org are doing. It also shows that switching from an average to a healthy lifestyle, with positive diet changes being key, can dramatically reduce a person’s future risk of developing cognitive decline and dementia.” 

Another member of the science team, Dr Celeste de Jager Loots, Research Associate at Imperial College’s  AGE Unit where she researches risk factors and prevention of Alzheimer’s and dementia, explains that “While having inherited certain genes can be used to predict risk of dementia, that risk is changed by making positive diet and lifestyle changes. The emphasis needs to be on changing diet and lifestyle, especially since one cannot change one’s genes. The earlier one starts with a healthy lifestyle the better the chance of preventing effects of genetic risk.”

Risk for dementia can be detected from the age of 35 and subtle changes, picked up by Food for the Brain’s cognitive function test, can be seen up to 40 years before a diagnosis. The charity wants anyone over 35 to take the test and start making positive diet and lifestyle changes. “The average person can cut their future risk by three quarters just by making simple diet and lifestyle changes.” says Patrick Holford, who is directing the Alzheimer’s prevention project. “This prevention approach, if we reach enough people, could cut cases of dementia in the UK by a third. That’s why we are urging everyone over 35 to tell everyone they know to take the free and scientifically – validated and free Cognitive Function Test. Alzheimer’s dementia, which accounts for the vast majority of dementia, is irreversible. But it is preventable, as this study shows.”

Two thousand people every month are joining this campaign, assessing and reducing their risk. Over 380,000 people have now taken the test.

References

Jia, J. et al. (2023) “Association between healthy lifestyle and memory decline in older adults: 10 year, population based, prospective Cohort Study,” BMJ [Preprint]. Available at: https://doi.org/10.1136/bmj-2022-072691. [1]

The evidence that only 1% of Alzheimer’s is caused by genes is here: Bekris, L.M. et al. (2010) “Review article: Genetics of Alzheimer Disease,” Journal of Geriatric Psychiatry and Neurology, 23(4), pp. 213–227. Available at: https://doi.org/10.1177/0891988710383571. [2]

Useful links

The free Cognitive Function test and Dementia Risk Index assessment is accessed here: https://foodforthebrain.org.

For more information on the citizen science campaign see ‘Alzheimer’s is Preventable – A Manifesto for Change’.

Patrick Holford, founder of Food for the Brain and voluntary director of the Alzheimer’s Prevention Project and Jessica Ferrari-Wells, Chair of the Board of trustees are available for interview, as are members of the the Scientific Advisory Board are available for interview and comment. 

Neurons, that is brain and nerve cells, are primarily made out of what’s called ‘phosphorylated DHA’. That means the omega-3 fat DHA that is bound to a kind of fat called a phospholipid, as shown in the figure below. 

Seafood contains phosphorylated DHA but DHA supplements, whether derived from fish oil or algae, is not phosphorylated. Hence, it needs to be attached to phospholipids to work. This attachment is done by a B vitamin dependent process called methylation. 

There are several different kinds of phospholipids with strange names all starting with ‘phosphatidyl’ such as phosphatidyl choline, phosphatidyl serine, phosphatidyl inositol and phosphatidyl ethanolamine.  To a large extent these can be made from phosphatidyl choline. As a group of nutrients they are classified as ‘semi-essential’ because we can make some, but not enough for optimal health and especially optimal brain health. 

As a consequence there are moves afoot to classify choline (which can be easily attached to the ‘phosphatidyl’ part) as an essential nutrient with a recommended intake. This has come about due to the growing evidence that insufficient choline in pregnancy leads to cognitive impairment and developmental delay. This is particularly important for vegans because, like the omega-3 fatty acid DHA, there’s not much choline in plant-based foods, but there is some in foods such as quinoa, soya, beans, nuts and broccoli.

Currently an adequate intake of choline is defined as between 400mg and 520mg a day, the latter for pregnant and breast-feeding women. This is based on how much choline you need for healthy fat metabolism, liver function and reducing homocysteine levels. You also need choline to process cholesterol in the liver and brain. As you’ll see in the figure above, cholesterol is a vital brain component. But these levels don’t take into account what’s being learnt about choline’s role in brain development.. A good estimate of optimum daily choline intake would be at least 500mg and maybe double this in pregnancy. 

Most important is choline’s role in building, and maintaining, a healthy brain. A pregnant woman’s intake defines the cognitive abilities of their child. Twenty years ago we knew that pregnant rats fed choline half way through their pregnancy have more connections between brain cells, plus improved learning ability and better memory recall. Now we know it’s true for babies with several recent trials showing similar results indicating that more choline in pregnancy enhances cognitive development.

An example of this is a study which gave women in their third trimester of pregnancy either 480mg of choline or almost double this – 930mg. They then tested the babies’ information processing speed at 4,7,10 and 13 months. Not only were the babies of the mothers given the higher dose faster but also the longer the mother had been given even the lower dose the faster were the child’s reactions. The authors concluded that “even modest increases in maternal choline intake during pregnancy may produce cognitive benefits for offspring ”. Seven years later, there will still memory advantages in the children whose mother had extra choline during pregnancy.

Babies are born with blood choline levels three times higher than their mother, illustrating how vital this nutrient is for building neuronal connections, which newborn babies do at a rate of up to a million new connections a second! An optimal intake for brain function is likely to be a lot higher than the 400 to 500mg recommended for adults, and higher still in pregnancy.

Since brain cells are made of a membrane containing choline (and other phospholipids) attached to the omega-3 fat DHA, without choline the omega-3 doesn’t work. The attaching of the two depends on methylation, a process that is dependent on B vitamins, especially B12, folate and B6. Choline helps methylation and healthy methylation, indicated by a low blood level of homocysteine, helps synthesize choline. You need all three – DHA, choline and B vitamins especially B12. So, if you are lacking in DHA, or in vitamin B12, then you’ll be doubly dependent on getting enough choline.

Choline rich foods – are vegans at risk of deficiency? 

While the richest dietary sources are fish, eggs and organ meats there is significant amounts of choline in plant-based foods, notably soya as in tofu and soya milk, quinoa, nuts and seeds including flax seeds, almonds and peanuts, and cruciferous vegetables including broccoli, cauliflower and Brussels sprouts.

While, on the face of it, it does appear than vegans, especially those planning pregnancy, need to become choline focused in relation to choosing the right daily foods, and possibly supplementing, there is not yet conclusive evidence showing that vegan mothers are at risk, although it is likely that they are. One of the learnings that has come out of studies on omega-3 DHA is than vegan mothers may convert more vegan omega-3 ALA into DHA as an evolutionary imperative – not that a top up with supplementation isn’t still the recommendation. Could it be that vegan mothers make more choline if needed since it is so important for brain development? There are very few studies of vegans to know the answer to this question.

One recent study looked at choline levels in breast-milk of vegans, versus vegetarians and non-vegetarians. There was no significant difference with the author of the study concluding “This suggests that maternal plant-based diet by itself is not a risk factor for low breast-milk choline.” 

The vegan community is certainly divided on this issue. Of course, the safe or cautious position, while the science unravels, is to supplement choline during pregnancy.

What intake of choline can you achieve from a vegan diet alone? Here’s a list of the best plant-based food for choline, compared to egg and fish as a yardstick, listed in order of how much you could get in a reasonable serving*:

FOOD CHOLINE PER SERVING PER 100g

An egg (all in the yolk) 50g 113mg  226mg

Fish eg salmon (100g/3oz) 90mg 90mg

Soya milk (cup – 250g) 57mg 23mg

Shiitake mushrooms (1 cup/145g) 54mg 37mg

Soya flour 12.5g (a cake slice) 24mg 192mg

Peas (1 cup -160g) 47mg 30mg

Quinoa, raw (1/3 cup 60g) 42mg 70mg 

Beans, raw (1/3 cup – 60g) 40mg 67mg

black, white, pinto, kidney

Broccoli, cauliflower 

or sprouts (1 cup/91g) 36mg 40mg  

Tofu (half a cup-125g) 35mg  28mg

Hummus (1/2 cup) 34mg 28mg

Chickpeas (1/4 can) 33mg 33mg

Baked beans (1/4 can) 31mg 31mg

Flaxseeds (small handful) 22mg 78mg

Pistachio (small handful) 20mg 71mg

Pine nuts (small handful) 18mg 65mg

Cashews (small handful) 17mg 61mg

Wholegrain bread (2 slices – 50g) 17mg 34mg

Avocado (1/2) 14mg 28mg

Almonds 50g (small handful) 12mg 42mg

Peanuts (small handful) 12mg 42mg

Wheatgerm (tablespoon 7g) 12mg 178mg

Almonds or peanut butter (tbsp) 10mg 61mg

Source: USDA choline content database and https://nutritiondata.self.com

*Many foods have not been analysed for choline, and measurements do vary, so this is a guide rather than a definitive list.

What does this mean for your daily diet? Here’s a typical vegan daily menu aimed to maximise choline intake and how much it would give you (I’m not including all foods and recipes, just those ingredient that deliver significant amount of choline):

BREAKFAST

A cup of soya milk 57mg

Small handful of nuts or seeds 20mg

(Flax, chia, almonds etc)

LUNCH

A cup of cooked quinoa (1/3 cup raw) 43mg

A serving (100g) of either broccoli, 36mg

cauliflower or Brussels sprouts

Avocado (1/2) 14mg

SNACKS

A tablespoon of almond or peanut butter 10mg

Hummus (1/2 cup) 34mg

Two slices of wholegrain bread 17mg

DINNER

A serving of tofu (125g) or beans 35-40mg

Half a cup of shiitake mushrooms 27mg

A serving (100g) of either broccoli, 36mg

cauliflower or Brussels sprouts

TOTAL 332mg

In reality you are unlikely to achieve this every day, and it would be quite limiting on your food choices, so a realistic target would be to achieve 300mg of choline from food. If you are aiming to achieve 500mg, which is the low end of optimal – more than this may be optimal in pregnancy – that leaves a shortfall of around 200mg of choline, suggesting the need for supplementation.

The most direct source of choline is from soya-derived lecithin granules and capsules. A flat tablespoon of lecithin granules (7.5g), which has a neutral and pleasant taste and can be sprinkled on cereals, in shakes and soups or eaten as is, provides 1,500 mg of phosphatidylcholine and around 200mg (13 per cent) of choline. Some ‘high phosphatidyl choline’ lecithin, sometimes called ‘high PC lecithin’ is 18 per cent choline, thus you need less – approximately a flat dessertspoon.

One tablespoon of lecithin granules equals three 1,200mg lecithin capsules (if ‘high PC’ two capsules would suffice). We suggest that this is a sensible addition to a completely vegan diet. (If you aspire to be plant-based most, but not all of the time the addition of two eggs, or an egg and a fish serving, would achieve 500mg a day of choline.)

You can also find ‘brain food’ supplements providing a combination of different kinds of phospholipids, not just choline, but its hard to get enough choline from these if your only other food sources are plant-based foods. 

In summary, we need both omega-6 and omega-3 fats, as well as phospholipids.

Have one or two servings a day of dark green, leafy veg – especially those that grow in colder climates such a kale, broccoli, brussels sprouts, or a serving of seaweed as sources of both choline and omega-3.
Have a serving of quinoa, beans or tofu every day, if not two, for choline.
Have a dessertspoon of high PC lecithin, or two capsules of high PC lecithin granules every day. These guidelines are especially important if you are planning a pregnancy, pregnant or breast-feeding.

If you are not completely vegan the best food source for phospholipids and choline are eggs. Eat six eggs a week. The choline is in the yolk. The advice regarding omega-3 – eat three servings of fish a week, is good for choline too but it is present in all fish, not just oily fish high in omega-3 fats.

Have you taken the Cognitive Function Test to find out your Dementia Risk Index score? It’s completely FREE and you can choose to pay for the COGNITION programme afterwards if you need personalised recommendations to help you put diet and lifestyle tips into action.

The BBC’s recent story headed ‘Dementia: Brain check-up tool aims to cut risk at any age’ is a step in the right direction since early prevention is the key to reducing risk. However, the online brain health check, hosted by the Alzheimer’s Research Trust, is very basic, with only a dozen questions, and ignores the key evidence-based and common nutritional risk factors for Alzheimer’s disease. It covers ‘stay sharp’ which is about mental stimulation, ‘stay connected’ which is about social interaction and ‘love your heart’. 

What the test ignores

It ignores the two strongest nutritional risk factors, namely homocysteine lowering B vitamins and omega-3 intake from seafood. The US National Institute for Health’s research [1] attributes 22% of Alzheimer’s risk to each of these. 

‘Love your heart’ gives advice to keep your cholesterol and blood pressure in check and manage diabetes. This refers an individual to their GP who is likely to prescribe statins to lower cholesterol and hypertensive drugs to lower blood pressure. Neither reduce Alzheimer’s risk. A recent major review [2] of the evidence concludes ‘prospective, randomized, placebo‐controlled clinical trials that have failed to provide evidence for the benefit of statin therapy’ and there is ‘insufficient [evidence] to tell us whether reducing BP for dementia risk reduction is effective.’

The same review recommends omega-3 supplementation is start early and maintained and B vitamin supplementation to lower homocysteine, which is cited as the most evidence-based prevention approach considered. This report says “In view of the high population attributable risk, it is important that raised homocysteine can readily be lowered by the oral administration of three B vitamins (folate, B6, and B12). The doses of these vitamins that are required to lower homocysteine are considerably larger than can readily be obtained from the diet.” This is based on evidence of the VITACOG trial [3] which was part funded by the Alzheimer’s Research Trust.

A GP could lower a person’s risk much more effectively by measuring homocysteine in the blood and recommending B vitamin supplements, as well as upping omega-3 intake by eating fish and/or supplementing. This combination has reduced the rate of brain shrinkage by up to 73% in those with pre-dementia [4] but only few GPs do.

The Think Brain Health check does not assess diet, or make specific recommendations, and there’s no mention of protective  supplements, but refers people to the NHS’s ‘eight tips for healthy eating’. These recommend ensuring starchy carbohydrates make up over a third of what you eat, reducing saturated fat and salt. There is no evidence that these reduce risk for Alzheimer’s. Too many carbs may actually be a promoter of cognitive decline. They also recommend eating less sugar, lots of fruit and veg and having at least 2 portions of fish a week, including at least 1 portion of oily fish. There is evidence that these recommendations may reduce dementia risk.

Food For the Brain’s Cognitive Function Test

In sharp contrast foodforthebrain.org’s validated Cognitive Function Test and Dementia Risk Index questionnaire (139 questions) both objectively measure a person’s cognitive function and calculates their risk, then gives specific and actionable instructions as to how a person can reduce their risk, inviting them back every six months to track their progress.

The Cognitive Function Test is free and for those who wish to improve, we have launched COGNITION, a new way to Upgrade your Brain at a low cost of just £5 per month. You can access both tests once logged into your account.

References

1. 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.

2. Peters R, Breitner J, James S, Jicha GA, Meyer PF, Richards M, Smith AD, Yassine HN, Abner E, Hainsworth AH, Kehoe PG, Beckett N, Weber C, Anderson C, Anstey KJ, Dodge HH. Dementia risk reduction: why haven’t the pharmacological risk reduction trials worked? An in-depth exploration of seven established risk factors. Alzheimers Dement (N Y). 2021 Dec 8;7(1):e12202. doi: 10.1002/trc2.12202. PMID: 34934803; PMCID: PMC8655351.

3. Smith AD, Smith SM, de Jager CA, Whitbread P, Johnston C, Agacinski G, Oulhaj A, Bradley KM, Jacoby R, Refsum H. Homocysteine-lowering by B vitamins slows the rate of accelerated brain atrophy in mild cognitive impairment: a randomized controlled trial. PLoS One. 2010 Sep 8;5(9):e12244. doi: 10.1371/journal.pone.0012244. PMID: 20838622; PMCID: PMC2935890.

4. 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.

A recent study of 1,178 women found that those carrying the APOE4 gene taking Hormone Replacement Therapy (HRT) had a better delayed memory score compared to APOE4 carriers that were not taking HRT, and to non-APOE4 carriers.[1] They also had slightly larger brain volumes in certain areas. This study suggested that HRT may help to prevent Dementia. This study was an observational trial, not a clinical trial, meaning the statement remains a hypotheses and requires further randomised controlled trials to investigate further. We analysed the paper and provided our comments below.

Clinical Trials on HRT

Clinical trials to date have not shown benefit of HRT with improving cognitive function. A systematic review of the clinical trial evidence for the effect of HRT on cognitive outcomes did not find benefit.[2] The Women’s Health Initiative Memory Study (WHIMS) conducted a double-blind, placebo-controlled clinical trial examining 8300 women 65 years of age or older over a 2- year period to observe the effects of HRTs and dementia progression. The trial failed to find a beneficial effect for HRT in reducing dementia risk, instead finding an increase in all types of dementia.[3]

The ApoE4 Gene

Roughly 1 in 5 people carry the ApoE4 gene, which accounts for 4 to 6% of risk for dementia and can be modified, downregulating the gene, with positive diet, nutritional supplement and lifestyle changes.[1]

Find out your risk for Dementia

In our Dementia Risk Index, as part of the Cognitive Function test, and COGNITION programme to reduce dementia, we excluded HRT because the evidence was not conclusive or consistent.

Have you tried our free Cognitive Function Test yet? Find out your Alzheimer’s disease risk using our evidence backed Dementia Risk Index. If your risk is high, our clever new programme COGNITION can help you make the right nutrition and lifestyle changes to help improve your score.

References

[1] Saleh RNM, Hornberger M, Ritchie CW, Minihane AM. Hormone replacement therapy is associated with improved cognition and larger brain volumes in at-risk APOE4 women: results from the European Prevention of Alzheimer’s Disease (EPAD) cohort. Alzheimers Res Ther. 2023 Jan 9;15(1):10. doi: 10.1186/s13195-022-01121-5. PMID: 36624497; PMCID: PMC9830747.

[2] Marjoribanks J, Farquhar C, Roberts H, Lethaby A, Lee J. Long-term hormone therapy for perimenopausal and postmenopausal women. Cochrane Database Syst Rev. 2017;1(1):CD004143.

[3] Shumaker SA, Legault C, Rapp SR, et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in post- menopausal women: the Women’s Health Initiative Memory Study: a randomized controlled trial. JAMA. 2003;289(20):2651-2662.

By Patrick Holford

Does what you eat affect your risk for dementia later in life and, if so, what is the best diet to protect your brain and prevent cognitive decline? Many studies have been published with different results ranging from no effect at all, as reported in a study in Sweden[i], to over a 90% reduced risk of Alzheimer’s, as reported in a study in Finland and Sweden which compared those with the a ‘healthy’ versus unhealthy diet in mid-life for future risk of developing Alzheimer’s disease and dementia 14 years later. Those who ate the healthiest diet had an 86-90% decreased risk of developing dementia and a 90-92% decreased risk of developing Alzheimer’s disease.[ii] We have put together a science backed Alzheimer’s Prevention Diet.

Many of these studies are similar in design, by looking at mid-life diet then tracking a group of people over time to see who does or doesn’t develop dementia or its most common type, Alzheimer’s disease. Many also look at some measure of coherence to a ‘Mediterranean’ diet, which usually means eating more fruit, vegetables, legumes, nuts and seeds, as well as more fish, less meat and sometimes some or more wine. Others compare to the standard recommendations for a ‘healthy’ diet made by the country’s authorities. Some foods or drinks could go either way. For example, some studies suggest coffee drinking might reduce risk, yet coffee increases homocysteine levels, which is a strong predictor of risk. Alcohol consumption, especially red wine, may reduce risk in moderation but possibly increase risk in excess.

Another way to answer the question regarding the best anti-dementia diet is to look at studies that have linked specific foods or drinks to risk of cognitive decline then build up the brain-friendly diet from there. These studies can also help define how much of the food or drink is optimal, or too much for those foods or drinks that increase risk.

Protective Foods

One of the first good studies was carried out in Norway more than a decade ago by Eha Nurk and Helga Refsum and colleagues in Norway.[iii] [iv] They found that:

Tea – the more you drink the better. The tea benefit has been confirmed more recently in a study in Singapore, with green tea being marginally better than black tea.[v] However, this benefit was not found in a UK Biobank study, which reported by tea and coffee drinking to be associated with worsening cognition compared to abstainers.[vi]

Chocolate – peaks at 10g, or about 3 pieces – and let’s say dark, 70%+ thus with less sugar is more likely to be better, as sugar is a strong indicator of cognitive decline. More recent studies giving cocoa, a rich source of flavanols, have shown improved cognition, possibly by improving circulation.[vii]

Wine – consumption reduced risk up to 125g a day, which is a small glass. A study in the British Medical Journal in 2018 showed that while abstinence increased risk by 48% having more than 14 units of alcohol a week, which is equivalent to a medium glass of wine every day, increases risk.[viii]

Grains and potatoes – reached a plateau at 100 to 150g a day, which is one or two servings max. High fibre bread was the most beneficial carb food. White bread increased risk. Fruit and veg – although the more you eat the better, benefits start to plateau at 500g a day, which is about five to six servings a day. Of individual vegetables, carrots, cruciferous vegetables and citrus fruit were the most positive as were mushrooms. A more recent study in the US found that those who ate 1.3 portions of green leafy vegetables a day, compared to less than one a week, had a dramatically slower decline in cognitive function, equivalent to being 11 years younger over a 10-year period. Berries are particularly protective, especially blueberries and strawberries.[ix]

Fish – is the most protective. Nurk’s study found a peak benefit at about 100g a day, which is one to two servings. A study of all studies by National Institutes of Health researcher, Beydoun, reported that eating fish once or more each week reduces risk of Alzheimer’s by a third compared with those who eat fish less than once a week.[x]

Olive oil and nuts – seem to be positive aspects associated with a Mediterranean diet.[xi] One study assigned people to a Mediterranean diet supplemented with either a litre a week of olive oil or 30g of nuts a day which is a small handful, versus a control diet with low fat and reported reduced cognitive decline with the extra olive oil or nuts. [xii]

Protective Diets

Early studies on the Mediterranean style diet reported that high adherence versus low adherence reduced risk of Alzheimer’s by a third.[xiii][xiv] A study which followed 2,000 people over 20 years found that adherence to what they defined as healthy diet which meant ‘modifying the quality of fats, increasing vegetable consumption, and decreasing salt and sugar consumption’ was associated with a halving of dementia risk. With the exception of sugar, no individual food predicted risk significantly.[xv]

But the problem with studies like this is the assumptions. In this case ‘modifying the quality of fats’ means using vegetable oils as opposed to margarine or butter and not eating the visible fat on meat. Vegetable oils is rather vague – it could be olive oil or something like sunflower oil. The assumption is that a low-fat diet might be beneficial, yet a high fat, low carb (HFLC) ketogenic diet appears to be protective.

A study in Holland reported ‘that better diet quality related to larger brain volume, grey matter volume, white matter volume, and hippocampal volume. High intake of vegetables, fruit, whole grains, nuts, dairy, and fish and low intake of sugar-containing beverages were associated with larger brain volumes.’[xvi]

Harmful Foods and Diets

Sugar – be it sucrose (white sugar) or fructose comes out consistently negative. Studies report poorer cognition associated with intake of sugar-sweetened beverages in adults (Ye 2011).

Animal studies show sucrose and fructose both impair cognition and brain health (Lakhan 2013) (Orr 2014) which is all consistent with the with the fact that diabetes is a risk factor for cognitive decline (see ‘Is Sugar Killing Your Brain’) and supported by recent human studies on blood glucose as a major predictor of Alzheimer’s and dementia later in life.[xvii]

Even so-called ‘high’ levels within the  normal reference range for blood glucose are linked to decreased grey matter in the brain.[xviii]

The most recent and substantial study relates to ultra-processed foods following around 70,000 people over a decade. The more ultra-processed foods eaten the higher was the risk for both dementia, Alzheimer’s and vascular dementia.[xix] Replacing just 10 per cent of ultra-processed food by weight in one’s diet with an equivalent proportion of unprocessed or minimally processed foods was estimated to lower risk of dementia by 19%. So, get off the junk. Choose whole foods only.

What is it about what you eat that could be protective?

The best candidates are foods high in:

Antioxidant vitamins (C and E)
Fruit and vegetables
Flavanols
Vitamin D
Fish and omega-3 fats
Folate and other B vitamins including b12, only found in animal foods
Phospholipids, found in eggs and fish

Apart from the studies above it is certainly logical to include choline rich foods sources, as a source for phospholipids. In animal studies, giving choline slows down Alzheimer’s disease development.[xx]

Also, consuming two tablespoons C-8 oil, a form of medium chain triglyceride, has been shown to enhance cognition in those with mild cognitive impairment and elevate neuronal energy derived from ketones both in those with MCI and Alzheimer’s.[xxi] Given the preponderance of neurons to prefer ketones to glucose for fuel, and the evidence for benefit, such dietary practices such as 18:6 (eating all food within a 6 hour window) or starting the day with a Hybrid Latté, almost carb-free, high in cacao, C8 oil and almonds from carb-free almond milk and almond butter or following a low carb, high fat (LCHF) ketogenic diet, which has been shown to have beneficial for those with Alzheimer’s,[xxii] should be considered.

Although in some respects conjectural calling on all this evidence, especially given the other health-promoting benefits of these foods, the key components of a diet designed to protect brain health and reduce risk of cognitive decline are:

Eat essential fats and phospholipids

Eat an egg a day, or six eggs a week – preferably free-range, organic, and high in omega-3s. Boil, scramble or poach them, but avoid frying.
Eat a tablespoon of seeds and nuts every day – the best seeds are chia, flax, hemp, pumpkin, higher in omega-3. They’re delicious sprinkled on cereal, soups, and salads. The best nuts are walnuts, pecans, and macadamia nuts.  Each are high in omega-3 but all nuts, including almonds, hazelnuts and unsalted peanuts are good sources of protein and minerals.
Eat cold-water, oily carnivorous fish – have a serving of herring, mackerel, salmon or sardines two or three times a week (limit tuna, unless identified as low in mercury, to three times a month). Vegans need to supplement algal omega-3 DHA, as well as choline or lecithin capsules or granules, rich in phosphatidyl choline.
Use cold-pressed olive oil for salad dressings and other cold uses, such as drizzling on vegetables instead of butter. Substitute frying with steam frying with olive oil, coconut oil or butter, e.g. for onions and garlic, then adding a watery sauce such as lemon juice, tamari and water, to ‘steam’, for example, vegetables perhaps with tofu, fish or chicken.

Eat slow-release carbohydrates

Eat wholefoods – whole grains, lentils, beans, nuts, seeds, fresh fruit, and vegetables – and avoid all white, refined and over-processed foods, as well as any food with added sugar.
Snack on fresh fruit, preferably apples, pears and/or berries, especially blueberries.
Eat less gluten. Try brown rice, rye, oats, quinoa, lentils, beans, or chickpeas.
Avoid fruit juices. Eat fresh fruit instead. Occasionally have unsweetened Montmorency cherry juice or blueberry juice (made from unsweetened concentrate).

Eat antioxidant and vitamin-rich foods

Eat half your diet raw or lightly steamed.
Eat two or more servings a day of fresh fruit, including one of berries.
Eat four servings a day of dark green, leafy and root vegetables such as tenderstem broccoli, broccoli, kale, spinach, watercress, carrots, sweet potatoes, Brussels sprouts, green beans, or peppers, as well as mushrooms. Choose organic where possible.
Have a serving a day of beans, lentils, nuts, or seeds – all high in folate, as are peanuts.

Eat enough protein

Have three servings of protein-rich foods a day, if you are a man, and two if you are a woman.
Choose good vegetable protein sources, including beans, lentils, quinoa, tofu, or tempeh (soya) and ‘seed’ vegetables such as peas, broad beans and corn.
If eating animal protein, choose lean meat or preferably fish, organic whenever possible.

Avoid harmful fats

Minimise your intake of fried or processed food and burnt saturated fat on meat, and cheese.
Minimise your consumption of deep-fried food. Poach, steam or steam-fry food instead.

Avoid sugar, reduce caffeine, and drink alcohol in moderation

Avoid adding sugar to dishes and avoid foods and drinks with added sugar. Keep your sugar intake to a minimum, sweetening cereal or desserts with fruit.
Avoid or considerably reduce your consumption of caffeinated drinks. Don’t have more than one caffeinated drink a day. Tea is preferable to coffee.
Drink alcoholic drinks infrequently, and preferably red wine, to a maximum of one small glass (125g) a day.
Have up to three slices of dark chocolate, minimum 70% cacao, or drink unsweetened cacao with milk or plant milk.

Help support Food for the Brain

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

[i] Glans I, Sonestedt E, Nägga K, Gustavsson AM, González-Padilla E, Borne Y, Stomrud E, Melander O, Nilsson P, Palmqvist S, Hansson O. Association Between Dietary Habits in Midlife With Dementia Incidence Over a 20-Year Period. Neurology. 2022 Oct 12:10.1212/WNL.0000000000201336. doi: 10.1212/WNL.0000000000201336. Epub ahead of print. PMID: 36224029.

[ii] Eskelinen MH, Ngandu T, Tuomilehto J, Soininen H, Kivipelto M. Midlife healthy-diet index and late-life dementia and Alzheimer’s disease. Dement Geriatr Cogn Dis Extra. 2011 Jan;1(1):103-12. doi: 10.1159/000327518. Epub 2011 Apr 27. PMID: 22163237; PMCID: PMC3199886.

[iii] Nurk E, Refsum H, Drevon CA, Tell GS, Nygaard HA, Engedal K, Smith AD. Intake of flavonoid-rich wine, tea, and chocolate by elderly men and women is associated with better cognitive test performance. J Nutr. 2009 Jan;139(1):120-7. doi: 10.3945/jn.108.095182. Epub 2008 Dec 3. PMID: 19056649.

[iv] Nurk E, Refsum H, Drevon CA, Tell GS, Nygaard HA, Engedal K, Smith AD. Cognitive performance among the elderly in relation to the intake of plant foods. The Hordaland Health Study. Br J Nutr. 2010 Oct;104(8):1190-201. doi: 10.1017/S0007114510001807. Epub 2010 Jun 16. PMID: 20550741.

[v] Feng L, Chong MS, Lim WS, Lee TS, Kua EH, Ng TP. Tea for Alzheimer Prevention. J Prev Alzheimers Dis. 2015;2(2):136-141. doi: 10.14283/jpad.2015.57. PMID: 29231231.

[vi] Cornelis MC, Weintraub S, Morris MC. Caffeinated Coffee and Tea Consumption, Genetic Variation and Cognitive Function in the UK Biobank. J Nutr. 2020 Aug 1;150(8):2164-2174. doi: 10.1093/jn/nxaa147. PMID: 32495843; PMCID: PMC7398783.

[vii] Lamport DJ, Pal D, Moutsiana C, Field DT, Williams CM, Spencer JP, Butler LT. The effect of flavanol-rich cocoa on cerebral perfusion in healthy older adults during conscious resting state: a placebo controlled, crossover, acute trial. Psychopharmacology (Berl). 2015 Sep;232(17):3227-34. doi: 10.1007/s00213-015-3972-4. Epub 2015 Jun 7. PMID: 26047963; PMCID: PMC4534492.

[viii] Sabia S, Fayosse A, Dumurgier J, Dugravot A, Akbaraly T, Britton A, Kivimäki M, Singh-Manoux A. Alcohol consumption and risk of dementia: 23 year follow-up of Whitehall II cohort study. BMJ. 2018 Aug 1;362:k2927. doi: 10.1136/bmj.k2927. PMID: 30068508; PMCID: PMC6066998.

[ix]  Devore E et al, ‘Dietary intakes of berries and flavonoids in relation to cognitive decline’, Annals of neurology 2012; 72: 135-43; Agarwal P, Holland TM, Wang Y, Bennett DA, Morris MC. Association of Strawberries and Anthocyanidin Intake with Alzheimer’s Dementia Risk. Nutrients. 2019 Dec 14;11(12):3060. doi: 10.3390/nu11123060. PMID: 31847371; PMCID: PMC6950087

[x] 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.

[xi] Román GC, Jackson RE, Reis J, Román AN, Toledo JB, Toledo E. Extra-virgin olive oil for potential prevention of Alzheimer disease. Rev Neurol (Paris). 2019 Dec;175(10):705-723. doi: 10.1016/j.neurol.2019.07.017. Epub 2019 Sep 11. PMID: 31521394.; Salis C, Papageorgiou L, Papakonstantinou E, Hagidimitriou M, Vlachakis D. Olive Oil Polyphenols in Neurodegenerative Pathologies. Adv Exp Med Biol. 2020;1195:77-91. doi: 10.1007/978-3-030-32633-3_12. PMID: 32468462.

[xii] Valls-Pedret C, Sala-Vila A, Serra-Mir M, Corella D, de la Torre R, Martínez-González MÁ, Martínez-Lapiscina EH, Fitó M, Pérez-Heras A, Salas-Salvadó J, Estruch R, Ros E. Mediterranean Diet and Age-Related Cognitive Decline: A Randomized Clinical Trial. JAMA Intern Med. 2015 Jul;175(7):1094-1103. doi: 10.1001/jamainternmed.2015.1668. Erratum in: JAMA Intern Med. 2018 Dec 1;178(12):1731-1732. PMID: 25961184.

[xiii] Singh B, Parsaik AK, Mielke MM, Erwin PJ, Knopman DS, Petersen RC, Roberts RO. Association of mediterranean diet with mild cognitive impairment and Alzheimer’s disease: a systematic review and meta-analysis. J Alzheimers Dis. 2014;39(2):271-82. doi: 10.3233/JAD-130830. PMID: 24164735; PMCID: PMC3946820.

[xiv] Scarmeas N, Stern Y, Tang MX, Mayeux R, Luchsinger JA. Mediterranean diet and risk for Alzheimer’s disease. Ann Neurol. 2006 Jun;59(6):912-21. doi: 10.1002/ana.20854. PMID: 16622828; PMCID: PMC3024594.

[xv] Sindi S, Kåreholt I, Eskelinen M, Hooshmand B, Lehtisalo J, Soininen H, Ngandu T, Kivipelto M. Healthy Dietary Changes in Midlife Are Associated with Reduced Dementia Risk Later in Life. Nutrients. 2018 Nov 3;10(11):1649. doi: 10.3390/nu10111649. PMID: 30400288; PMCID: PMC6265705.

[xvi] Croll PH, Voortman T, Ikram MA, Franco OH, Schoufour JD, Bos D, Vernooij MW. Better diet quality relates to larger brain tissue volumes: The Rotterdam Study. Neurology. 2018 Jun 12;90(24):e2166-e2173. doi: 10.1212/WNL.0000000000005691. Epub 2018 May 16. PMID: 29769374.

[xvii] Zhang X, Tong T, Chang A, Ang TFA, Tao Q, Auerbach S, Devine S, Qiu WQ, Mez J, Massaro J, Lunetta KL, Au R, Farrer LA. Midlife lipid and glucose levels are associated with Alzheimer’s disease. Alzheimers Dement. 2022 Mar 23. doi: 10.1002/alz.12641. Epub ahead of print. PMID: 35319157.

[xviii] Mortby ME, Janke AL, Anstey KJ, Sachdev PS, Cherbuin N. High “normal” blood glucose is associated with decreased brain volume and cognitive performance in the 60s: the PATH through life study. PLoS One. 2013 Sep 4;8(9):e73697. doi: 10.1371/journal.pone.0073697. PMID: 24023897; PMCID: PMC3762736.

[xix] Li H, Li S, Yang H, Zhang Y, Zhang S, Ma Y, Hou Y, Zhang X, Niu K, Borne Y, Wang Y. Association of Ultraprocessed Food Consumption With Risk of Dementia: A Prospective Cohort. Neurology. 2022 Jul 27:10.1212/WNL.0000000000200871. doi: 10.1212/WNL.0000000000200871. Epub ahead of print. PMID: 35896436.

[xx] Velazquez R, Ferreira E, Knowles S, Fux C, Rodin A, Winslow W, Oddo S. Lifelong choline supplementation ameliorates Alzheimer’s disease pathology and associated cognitive deficits by attenuating microglia activation. Aging Cell. 2019 Dec;18(6):e13037. doi: 10.1111/acel.13037. Epub 2019 Sep 27. PMID: 31560162; PMCID: PMC6826123.

[xxi] Fortier M, Castellano CA, St-Pierre V, Myette-Côté É, Langlois F, Roy M, Morin MC, Bocti C, Fulop T, Godin JP, Delannoy C, Cuenoud B, Cunnane SC. A ketogenic drink improves cognition in mild cognitive impairment: Results of a 6-month RCT. Alzheimers Dement. 2021 Mar;17(3):543-552. doi: 10.1002/alz.12206. Epub 2020 Oct 26. PMID: 33103819; PMCID: PMC8048678.

[xxii] Phillips MCL, Deprez LM, Mortimer GMN, Murtagh DKJ, McCoy S, Mylchreest R, Gilbertson LJ, Clark KM, Simpson PV, McManus EJ, Oh JE, Yadavaraj S, King VM, Pillai A, Romero-Ferrando B, Brinkhuis M, Copeland BM, Samad S, Liao S, Schepel JAC. Randomized crossover trial of a modified ketogenic diet in Alzheimer’s disease. Alzheimers Res Ther. 2021 Feb 23;13(1):51. doi: 10.1186/s13195-021-00783-x. PMID: 33622392; PMCID: PMC7901512.

By Patrick Holford

Why Dementia rates are higher in the west

In some countries, for example India and China, that proportion appears to be less than half that occurring in Britain. When people in one country suffer much more from a disease than people of a similar age in another country, this is a sure sign that the difference has something to do with diet, lifestyle or other environmental factors – or genetic variance. We can rule out genetic differences as the major factor, particularly because Chinese and Indian people who emigrate to Britain soon acquire a similar risk for developing dementia. In any event only one in a hundred cases of Alzheimer’s is caused by genes.²

How many people get diagnosed with dementia?

A decline in memory and concentration is not the same thing as a diagnosis of dementia or probable Alzheimer’s, although it does mean your chances of developing these conditions are higher. Every year roughly 10 million people are diagnosed with dementia – that is one person every 3 seconds³ . Currently, around 900,000 people in the UK have dementia.⁴ By 2050 this will be over 1.53 million. Globally over 50 million have dementia. By 2050 this is expected to increase to 152 million.⁵

Two in three people diagnosed with dementia will end up diagnosed with probable Alzheimer’s, while 17 per cent will be given a diagnosis of vascular dementia, caused by constricted blood flow to the brain due to blocked arteries, and 10% will be given a ‘mixed’ diagnosis, which is usually part Alzheimer’s, part vascular dementia. But the risk factors, and prevention treatments, for Alzheimer’s and vascular dementia are the same. So, combined, well over 80% of all dementia diagnoses should be preventable.

What is dementia?

There are other forms, such as dementia with Lewy bodies, fronto-temporal dementia and dementia caused by a stroke, a bleed in the brain or a brain tumour. But as Alzheimer’s is the most widespread, let’s look at it in depth.

Dementia – including Alzheimer’s – is an insidious condition. In the early stages, sufferers have increasing symptoms of absentmindedness, low mood and an inability to learn new things. Judgement, and their ability to function intellectually and socially, begin to go awry. The person may repeatedly forget to turn off the iron, or may not recall which medicines they took in the morning. They may start to show mild personality changes, such as a lack of spontaneity or a sense of apathy and a tendency to withdraw from social interactions.

Later on, there will be a loss of logic and memory, disorientation and poor coordination. Speech deteriorates and paranoia may appear. At this point, a diagnosis of probable Alzheimer’s disease may be given. Why ‘probable’? Because Alzheimer’s is properly diagnosed, not simply by symptoms, but by the presence of a specific kind of degeneration in a specific part of the brain – and this is difficult to see without the aid of expensive scans.

How was Alzheimer’s discovered?

The German neuropathologist Alois Alzheimer discovered this characteristic degeneration in the brain back in 1906. Using a technique known as silver stain, he examined the brain cells of a woman who died prematurely at 55 with signs of dementia, and found a tangled mess of proteins and clusters of degenerating nerve endings, called neurofibrillary tangles. This condition is associated with a gradual dying-off of neurons and poor communication between neurons. There is also often a build-up of something called beta-amyloid plaque, a protein-like substance that shouldn’t be there.

Since that time, research into Alzheimer’s has continued apace. Largely thanks to the pioneering work of Professor David Smith and colleagues in the University of Oxford’s pharmacology department, we now know that Alzheimer’s is a specific disease process, not just a random, gradual decline in brain cells, and that it originates in a particular brain region. Their Optima (Oxford Project to Investigate Memory and Ageing) study has been running since 1988 and has proved, among other things, that the damage leading to Alzheimer’s begins in a central part of the brain known as the medial temporal lobe.^6-7

Pinpointing the problem area

The medial temporal lobe is vital for both mood and memory. Even though this lobe accounts for only 2 per cent of the brain’s total area, it is essential for the processing of everything we sense, feel or think.

Precisely because it’s in the middle of the head, it’s a difficult region to scan. This is also where there are more neurofibrillary tangles and beta-amyloid plaques – the hallmarks of Alzheimer’s. These indicate damage and chaos to the normal network of neurons and their connections.

Since information is passed from and to the medial temporal lobe from other parts of the brain, as this area becomes more damaged, fewer signals are sent to other parts of the brain. These then also start to decline, becoming more and more disconnected, with ever-decreasing blood flow. The beginning of damage is estimated to occur as early as 40 years before a person is diagnosed with dementia. That is why it is important to start your prevention plan young.

So far we’ve talked about the spread of damage seen in Alzheimer’s, starting with the medial temporal lobe, and radiating out to other areas of the brain, which are in effect starved of signals, much as a muscle atrophies through lack of use. Other indicators of Alzheimer’s are neurofibrillary tangles (p’tau), the lack of blood flow in the brain, and the presence of beta-amyloid plaques. There is also the presence of high levels of homocysteine in the blood.

Exactly which of these factors ‘causes’ Alzheimer’s, or kickstarts the process of damage, is the subject of much debate and ongoing research.

Clues to curbing the epidemic

At the other end of the spectrum, scientists have been looking for ways to prevent Alzheimer’s disease, and are conducting more and more studies revealing the specific dietary and lifestyle factors that greatly increase or decrease risk. Around half of the risk can be prevented.⁸For example, having a high intake of omega-3 fats and B vitamins appears to reduce risk, while consuming a lot of sugar increases the risk. The National Institutes of Health attributes 22% of Alzheimer’s to high homocysteine and 22% to low omega-3/seafood consumption.⁹ What’s more people with pre-dementia with good omega-3 status, given extra B vitamins have a 73% less brain shrinkage than those on placebo.¹⁰

Somewhere in the middle, scientists are discovering how changes in diet could cause changes in the brain. An example of this is the discovery of an enzyme that both regulates insulin – the key hormone for keeping your blood sugar in balance – and beta-amyloid.  There are, however, many other ways, and growing evidence, that sugar and high carb diet driven by eating junk food damages the brain.

The most exciting discovery is the role of B vitamins and how too little can lead to increases in homocysteine in the blood. Since neither beta-amyloid nor those neurofibrillary tangles can be measured before its too late, the discovery that levels of a simple chemical in your blood could be the best predictor of all is the most welcome news – and it should, in our opinion, have revolutionised the early diagnosis and preventative treatment of those most likely to develop Alzheimer’s. There is good evidence that homocysteine, a measure of faulty methylation, is a primary driver of Alzheimer’s for a number of reasons:

Giving people with raised homocysteine and pre-dementia (mild cognitive impairment or MCI) extra homocysteine lowering B vitamins has been shown to reduce the rate of shrinkage of the medial temporal regions by nine fold.
Amyloid blocking drugs have little to marginal effects on the actual disease. A meta-analysis of these drugs that did effectively lower amyloid found virtual no significant cognitive benefit from doing so.¹¹ Measures of Clinical Dementia Ratings show that both homocysteine-lowering B vitamins and Omega-3 fish oil supplements surpass anti-amyloid drugs. (See our newsletter)
The formation of neurofibrillary tangles, associated with p-tau proteins, could be a consequence of faulty methylation (eg raised homocysteine). When p-tau is high so is homocysteine. There are three known ways whereby raised homocysteine would raise p-tau.
Homocysteine is found in the regions of brain damage and is capable itself of causing brain damage.
A raised homocysteine increases the risk of cerebral vascular dysfunction by a remarkable 17 times.¹¹
Every study that has effectively lowered homocysteine in people at risk, eg with MCI or mild Alzheimer’s, has shown benefit, except in the later stages of the disease which may just be too late.

An International Consensus Statement in 2018 concluded that moderately raised plasma total homocysteine (>11mcmol/L), found in half of those over age 70 ¹², is a main cause of age-related cognitive decline and dementia.¹³ Two major meta-analyses of hundreds of studies conclude that raised homocysteine is one of the best evidenced risk factors for AD and accounts for around a fifth of all risk ¹⁴, ¹⁵.

The key to prevention is to understand the contributing factors and to do something about them as soon as possible. Right now, because the thought of Alzheimer’s is so terrifying, most people avoid even seeing their doctor and are usually diagnosed only in the late stages, usually reported by a relative who has found their partner becoming unmanageable. That’s why it is critical to look for the earliest possible signs of cognitive decline, then there’s time to reverse the trend.

The Cognitive Function Test

The Food for the Brain Foundation offer an excellent free online Cognitive Function test and a simple Dementia Risk Index questionnaire which also works out your risk factors and which simple changes will have the most effect. Do please do this yourself and encourage everyone you know over 50 to do the test as well. Prevention, in this case, is the only likely ‘cure’ for this terrible disease.

For more on Alzheimer’s see our article on Preventing Alzheimer’s Disease

Help support Food for the Brain

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

Rowe J., Kahn R., ‘Human ageing: usual and successful’, Science, 237 (4811): 143-9 (1987).
 Bekris, L et al., ‘Genetics of Alzheimer disease’ Journal of Geriatric Psychiatry and Neurology 2010, 23(4) 213-227).
Smith A.D., ‘Homocysteine, B vitamins and cognitive deficit in the elderly’, American Journal of Clinical Nutrition, 75:785-6 (2002).
https://www.alzheimers.org.uk/about-us/policy-and-influencing/dementia-scale-impact-numbers
World Alzheimer Report. (2018). Available online at: https://www.alzint.org/resource/world-alzheimer-report-2018
Bradley K.M. et al., ‘Cerebral perfusion SPET correlated with Braak pathological stage in Alzheimer’s disease’, Brain, 125:1772-81 (2002); see alsp Jobst K.A. et al., ‘Detection in life of confirmed Alzheimer’s disease using a simple measurement of medial temporal lobe atrophy by computed tomography’, Lancet, 340:1179-83 (1992).
Jobst K.A. et al., ‘Association of atrophy of the medial temporal lobe with reduced blood flow in the posterior parietotemporal cortex in patients with a clinical and pathological diagnosis of Alzheimer’s disease’, J Neurol  Neurosurg Psychiat, 55:190-4 (1992); see also Jobst K.A. et al., ‘Rapidly progressing atrophy of medial temporal lobe in Alzheimer’s disease’, Lancet, 343:829-30 (1994).
Smith,D., Jaffe,K. ‘Dementia (Including Alzheimer’s Disease)can be Prevented: Statement Supported by International Experts’ Journal of Alzheimer’s Disease 38 (2014) 699–703
M. Beydoun et al, ‘Epidemiologic studies of modifiable factors associated with cognition and dementia: systematic review and meta-analysis BMC Public Health 2014, 14:64 [http://www.biomedcentral.com/1471-2458/14/643]
Jernerén F, Elshorbagy AK, Oulhaj A, Smith SM, Refsum H, Smith AD. Brain atrophy in cognitively impaired elderly: the importance of long-chain ω-3 fatty acids and B vitamin status in a randomized controlled trial. American Journal of Clinical Nutrition. 2015;102:215-21.
Teng Z, Feng J, Liu R, Ji Y, Xu J, Jiang X, Chen H, Dong Y, Meng N, Xiao Y, Xie X, Lv P. Cerebral small vessel disease mediates the association between homocysteine and cognitive function. Front Aging Neurosci. 2022 Jul 15;14:868777. doi: 10.3389/fnagi.2022.868777. PMID: 35912072; PMCID: PMC9335204.
Smith AD Effect of reductions in amyloid levels on cognitive change in randomized trials: instrumental variable meta-analysis BMJ 2021;372:n156
Smith AD, Smith SM, de Jager CA, Whitbread P, Johnston C, Agacinski G, et al. Homocysteine-lowering by B vitamins slows the rate of accelerated brain atrophy in mild cognitive impairment. A randomized controlled trial. PLoS ONE. 2010; 5: e12244.
Smith AD, Refsum H, Bottiglieri T, Fenech M, Hooshmand B, McCaddon A, et al. Homocysteine and dementia: An international consensus statement. J Alzheimers Dis. 2018; 62: 561-70
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; 14: 643.
Yu JT, Xu W, Tan CC, Andrieu S, Suckling J, Evangelou E, et al. 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: 1201-9

By Patrick Holford

A global conference of leading world experts in dementia prevention has today identified four easy ways that could reduce risk of dementia by half and eight that could cut your risk by two thirds. 

The research was shared, for the first time, at the Alzheimer’s Prevention Conference, organised by the charitable foundation Food for the Brain. 

The new research showed that there are four easy ways to cut your risk of dementia in half:

1. Supplementing omega-3 fish oils

According to a new study of almost half a million participants of the UK’s Biobank supplementing fish oils cuts dementia risk.^[i] This new research was presented at the conference by China’s leading dementia prevention expert from Shanghai’s Fudan University, Professor Jin-Tai Yu, “Our current research, using data from the UK Bio Bank, shows that having a higher blood levels of omega-3, and supplementing fish oils, is associated with less risk of dementia.”

Other studies reported by Dr Simon Dyall, clinical neuroscientist at the University of Roehampton, showed that a higher intake of fish was associated with cutting risk of Alzheimer’s disease by a third.^[ii] “Half your brain is fat, and a type of omega- 3 called DHA has a very important role in the communication between brain cells.” said Dyall.

2. B Vitamins

According to Professor Yu, another very promising prevention treatment is B vitamins.^[i] “Lowering blood homocysteine levels, an established indicator of Alzheimer’s risk, with B vitamins is a most promising treatment.” Raised homocysteine is found in one in two people over 70.

In a trial at Oxford University by Professor David Smith, who was presenting at the conference, giving high dose B vitamins versus placebos, resulted in 52% less brain shrinkage and little further memory loss.^[ii]

Combining omega-3 and vitamin B. The discovery of the synergistic role of omega-3 led the Oxford Professor to reanalyse blood samples taken at the start of the trial for omega-3. They found that those with low omega-3 DHA blood levels, one of the main nutrients found in fish and fish oil supplements, had no benefit from the B vitamins, while those with high omega-3 DHA had 73% less shrinkage and almost nine times less shrinkage of the Alzheimer’s related areas of the brain.^[iii]

Furthermore, another study in Sweden, that had given omega-3 fish oil supplements, reanalysed their results and found those with good B vitamin status substantially reduced their dementia risk.^[iv]

A third study in the US, called ‘B proof’, that had given B vitamins with marginal improvements, reanalysed their results and found that those with higher omega-3 levels also had a much greater improvement.^[i]

“Research shows that you get impressive results if you give omega-3 and B vitamins together rather than on their own.” Says Professor Smith. 

While US National Institutes of Health researchers attributed 22% to lack of seafood or omega-3 and another 22% to the B vitamin factor they also attributed 32% of risk to inactive lifestyle.^[ii]

3. Exercise

“For many people the worst thing they can do for their brain is to retire”

Keeping your brain active. Another expert at the conference, Tommy Wood, Assistant Professor at the University of Washington, showed that your muscle mass predicts brain volume. “Exercise, especially resistance exercise, is important because it makes the brain do things that keep it healthy, such as growth and repair.” he says. “When they aren’t stimulated, the health of brain tissues deteriorates, with a knock-on effect on memory and thinking.”

And it’s not just physical exercise that does this, we also benefit from the mental exercise involved in activities like solving puzzles or learning a new language. “For many people the worst thing they can do for their brain is to retire”, says Wood. “They lose much of the stimulation that kept it healthy.” 

4. Sugar

“Sugar levels at age 35 predict Alzheimer’s risk later in life”

While it has long been known that diabetics have a much higher risk for dementia, a recent study at Boston University School of Medicine, found that higher blood sugar levels at age 35, but still in the ‘normal’ non-diabetic range, predict Alzheimer’s later in life.^[i] Talking at the conference Professor Robert Lustig, from the University of California, said, ”A high level of sugar and insulin in the blood – linked with a high carbohydrate diet – is definitely a driver for Alzheimer’s.” 

The conference, hosted by the UK charity foodforthebrain.org, identified eight domains of risk, in other words, four more actions you can take to reduce your risk of dementia: eating antioxidants from fruit and veg; having a healthy gut; sleeping well; and controlling stress. 

Targeting all eight risk factors earlier in life may reduce risk by two thirds. 

But how do you know what your risk is and what and how to change to reduce your risk? That’s what the charity, the Food for the Brain Foundation has been working on for a decade. On their website, foodforthebrain.org, you can do a free Cognitive Function Test. Almost 380,000 people have taken the test and, according to research by NHS and University College London researchers, 88% find it useful. You then complete a questionnaire that works out your future dementia risk index. It also tells you exactly what’s driving your risk up and what to do about it. By downloading the COGNITION app you can tack your progress, get advice on how to reduce your risk further, and get support to help you dementia-proof your diet and lifestyle.

Do the test now and reduce your risk!

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 bybecoming a Friend of Food for the Brain.

References:

^[1] Yu JT et al, Circulating polyunsaturated fatty acids, fish oil supplementation, and risk of incident dementia: a prospective cohort study of 440,750 participants, BMC medicine (pending publication)

^[2] Wu S, Ding Y, Wu F, Li R, Hou J, Mao P. Omega-3 fatty acids intake and risks of dementia and Alzheimer’s disease: a meta-analysis. Neurosci Biobehav Rev. 2015 Jan;48:1-9. doi: 10.1016/j.neubiorev.2014.11.008. Epub 2014 Nov 21. PMID: 25446949.

^[3] 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.

^[4] Smith, A.D. et al., ‘Homocysteine-lowering by B vitamins slows the rate of accelerated brain atrophy in mild cognitive impairment: a randomized controlled trial’, Public Library of Science ONE, 5(9) (2010)

^[5] 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

^[6] 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.

^[7] 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

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