The ApoE 4 exaggeration

Patrick Holford, chair of the Expert Group on Alzheimer’s Prevention at foodforthebrain.org comments on the latest study in Nature journal.

The single greatest predictor is the presence of the ApoE4 variant of the ApoE gene, carried by about one in five people have a gene variation called ApoE4. Having this contributes 4 to 6% of the absolute risk for Alzheimer’s disease.¹

(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 4% chance of developing Alzheimer’s, while someone with the ApoE4 gene might have a 5% chance, so their risk has gone up by, in this example, 20%. In absolute terms, the risk would be only 1% higher.)

This study shows two things: the first is that most with the APoE4 show some of the biomarkers for developing Alzheimer’s later on, namely higher levels of toxic amyloid and -p-tau proteins. This is not surprising. However, and this is key, quoting the paper “In the dementia stage, there were no differences in amyloid or tau despite earlier clinical and biomarker changes.” In other words, even this indicator of risk has vanished. This means that, even if you could lower levels earlier in the disease process this is highly unlikely to have any effect.

This so-called ‘Alzheimer’s gene’ 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, genes are not either present and active or not present and 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.

The ApoE4 gene is downregulated by eating a low-glycemic load (GL) or low sugar diet or more ketogenic diet with specific Mediterranean-style food choices including fatty fish, cruciferous vegetables, olive oil, low alcohol consumption. Four supplemental nutrients have reasonably good evidence of down-regulating ApoE4. These are omega-3 DHA, B vitamins (B2, B6, B12 and folate) and vitamin D. ²

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.³ 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.

What the study showed was 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 are associated with a slower rate of memory decline, regardless of the genetic risk,” wrote the study authors.

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. 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.

All major studies on people at risk of or already with dementia or Alzheimer’s have measured whether the study participants do or don’t have the ApoE4 variant. I’ve looked at these studies and they almost all show no difference in outcome if you do or don’t have the gene.

A good analogy is that having the ApoE4 gene variant is like a weak light which, in the darkness, appears to increase risk a bit, but once you shine the strong light of actually doing something such as changing your diet or supplementing omega-3 fish oils, B vitamins or vitamin D there is no difference in outcome between those who had or didn’t have this gene variant.

Please note: the pharmaceutical industry are desperate to promote a drug that lowers amyloid or p-tau. 14 trials have shows that anti-amyloid drugs do lower amyloid but none have had clinically significant effect. In other words the amyloid theory is bust. Amyloid is not a cause of Alzheimer’s. Raised toxic P-tau is a direct consequence of raised homocysteine, driven by a lack of B vitamins. See the p-tau delusion https://foodforthebrain.org/the-p-tau-delusion/. Lowering homocysteine with B vitamins, which is an established cause, lowers p-tau.

1. Heininger, K. (2000), A unifying hypothesis of Alzheimer’s disease. III. Risk factors. Hum. Psychopharmacol. Clin. Exp., 15: 1-70. https://doi.org/10.1002/(SICI)1099-1077(200001)15:1<1::AID-HUP153>3.0.CO;2-1; see also Ridge PG, Mukherjee S, Crane PK, Kauwe JSK, (2013) Alzheimer’s Disease: Analyzing the Missing Heritability. PLoS ONE 8(11): e79771. doi: 10.1371/journal.pone.0079771

2. Norwitz,N.G.;Saif,N.; Ariza, I.E.; Isaacson, R.S. Precision Nutrition for Alzheimer’s Prevention in ApoE4 Carriers. Nutrients 2021, 13, 1362. https://doi.org/10.3390/ nu13041362

3. Jia J, Zhao T, Liu Z et al., Association between healthy lifestyle and memory decline in older adults: 10 year, population based, prospective cohort study BMJ 2023;380:e072691 http://dx.doi.org/10.1136/ bmj-2022-072691

Thank you for reading,

Patrick Holford,
WCH British Isles Steering Committee