Alzheimer’s disease gene: Good for calcification

22. November 2011

Why has the risk gene for Alzheimer's and cardiovascular diseases APOE4 not been selected against during evolution? It's simple: At an early age it supports, for instance, bone health.

The apolipoprotein E (ApoE) has a central role in the body in regulating the homeostasis of cholesterol and triglycerides. The APOE encoding gene is a polymorphic gene; there are three alleles: APOE2, APOE3 and APOE4. The APOE4 variant is the oldest evolved form, and has been identified in several studies as a risk factor in the development of Alzheimer’s disease and cardiovascular disease in older people (late onset). In northern Europe, over 20% of the population are carriers of the APOE4 allele, in southern Europe they number fewer than 10%.

Why in God’s name – or better, in Darwin’s name – has APOE4, despite the negative health effects on the carrier, not been selected against in the course of evolution? This question was put to one excellence cluster research team in inflammation research at Christian-Albrechts-University Kiel, and led to an interesting result: carriers of APOE4 enjoy advantages at a young age over APOE2 and APOE3 carriers.

Inadequate supply of vitamin D

A certain role in protection against Alzheimer’s disease, coronary heart disease and bone disease has been attributed to Vitamin D. It is synthesised in the human body under the influence of solar radiation or obtained through the diet, for example, from fish and dairy products. According to the current National Food Consumption Study 2 of the German Federal Ministry of Food, Agriculture and Consumer Protection, in Germany 40 to 50% of people are undersupplied with vitamin D. In sunny southern European countries, vitamin D supply is largely sufficient.

Patricia Huebbe from the Institute of Human Nutrition and Food Studies and her colleague Gerald Rimbach deal with the interaction of diet and genetics. “We have taken this as an opportunity and asked ourselves whether there is a correlation between the high APOE4 and low vitamin D status in northern Europe and the advent of increased cardiovascular disease and Alzheimer’s, compared with more southerly regions.” Almut Nebel from the Institute of Molecular Biology and director of the Research Group for Healthy Ageing adds: “Especially as the APOE4 gene variant – as far as we know at the moment – does not have a negative impact during the reproductive phase, but only at a later age during which man is no longer biologically reproductive. “

Results of mouse experiments confirmed

The researchers studied transgenic mice carrying the different human APOE variants in their genome. The mice with the APOE4 allele had the highest vitamin D levels, compared to the APOE2 or APOE3 transgenic ones. In order to verify these observations in humans, the researchers examined group plasma and serum samples of a random sample of the population for APOE status and vitamin D levels. The results of mouse experiments were in fact able to be confirmed. Gerald Rimbach summarises the results: “The higher vitamin D status of APOE4 carriers is probably due to better absorption of the vitamin from the diet.

Also, calcium absorption and calcium concentration in the bone is higher in APOE4 mice than in those with APOE3 and APOE2. We have now been able to demonstrate for the first time the influence of APOE4 on vitamin D status. In the reproductive phase of life, APOE4 carriers have an advantage compared to others in that their vitamin D status is higher. This may explain why this gene variant is still to be found, it gives, up to a certain age at least, this advantage.” At the same time the negative effect of the APOE4 allele has perhaps only ended up manifesting itself since people have come to age more healthily and live longer.

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