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.