Most Dementia is Driven by Diet, Not Genes: The ApoE4 Exaggeration
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. 
There are, however, 76 other genes  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.  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.  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.  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.  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. 
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.  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,  or by supplementing omega-3 to those with lower homocysteine levels  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].)
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