Durk Pearson & Sandy Shaw’s®
Life Extension NewsTM
Volume 15 No. 4 • August 2012

APOE epsilon 4, Risk Factor for Alzheimer’s Disease:
Why Is It Still in the Gene Pool?

You have to wonder why the well known risk factor for Alzheimer’s disease, APOEepsilon4, is still around. Since it hasn’t disappeared from the gene pool, one has to assume that it is providing something beneficial, at least under certain conditions. An example of a genetic disease that has disastrous effects when an individual inherits two copies of the defective gene, but where there are benefits (a reduced risk of getting malaria) for those with just one copy of the defective gene is sickle cell anemia. Protection against malaria would have been, at least in the areas with endemic malaria, an important advantage. Otherwise, over time, for genes with adverse effects that do not also provide survival advantages at least under some conditions, one would expect they would end up disappearing from the gene pool.

A new paper1 reports that, interestingly, the APOE epsilon4 gene is associated with higher vitamin D levels in mice genetically engineered to carry the gene and also in humans that have the APOEepsilon4 gene. In fact, the paper reports that “[i]n Europe, the epsilon4 allele distribution is positively correlated with geographical latitude, with a >4-fold higher frequency in the north than in the south (e.g., 22.7% in Finland vs. 5.2% in Sardinia.” This would correlate well with the amount of vitamin D created in the skin as a result of sun UVB exposure, with the exposure reduced as one moved farther north. The authors propose, therefore, that “[t]he current investigations suggest the APOE epsilon4 allele as a novel genetic modulator of vitamin D status.”(1) Moreover, patients with Alzheimer’s disease are reported to have a high prevalence of vitamin D deficiency and vitamin D is reported to improve cognition in some AD patients.1a

In fact, a paper published in 19412 reported that people in the United States who lived at higher latitudes, such as in New Hampshire, Vermont, and Massachusetts had overall greater risks of dying of cancer as compared with men and women of similar ages who lived in southern states, such as Texas, Georgia, and Alabama. Vitamin D deficiency has been associated with many types of cancer.2a

In addition, some data have been published on the risk of disease (other than Alzheimer’s disease) for those carrying the APOEepsilon4 allele as compared to those who don’t, such as increased injury following brain trauma. There is an awful lot of downside with this allele. If one needs additional vitamin D, and many people do, taking supplemental vitamin D3 is easy and inexpensive, while having the “advantage” of higher vitamin D levels as a result of carrying the APOEepsilon4 allele is, at least nowadays, no advantage at all.

In fact, a new report3 has just been published on APOE4, in which the “bad” form of APOE has been found to weaken the blood-brain barrier as a result of dysregulation of an inflammatory protein (cyclophilin A) in mice genetically engineered to express human APOE4, whereas this did not happen to mice carrying APOE2 or APOE3. However, as the authors of the commentary accompanying the new paper3a pointed out, “... as it is the lack of APOE3 rather than the presence of APOE4 that triggers the inflammatory response, the role of this pathway in the many patients with Alzheimer’s disease who carry one copy of APOE4 and one of APOE3 is unclear.”


1. Huebbe et al. APOEepsilon4 is associated with higher vitamin D levels in targeted replacement mice and humans. FASEB J 25:3262-3270 (2011).
1a. Lu’o’ng et al. The beneficial role of vitamin D in Alzheimer’s disease. Am J Alzheimers Dis Other Demen 26(7):511-20 (2011 Nov).
2. Apperly. The relation of solar radiation to cancer mortality in North America. Cancer Res 1:191-5 (1941) (2A) See, for example, Tuohimaa. Vitamin D, aging, and cancer. Nutr Rev 66(Suppl 2):5147-52 (2008).
3. Bell et al. Apolipoprotein E controls cerebrovascular integrity via cyclophilin A. Nature 485:512-6 (24 May 2012).
3a. Carmeliet and de Strooper. A breach in the blood-brain barrier. Nature 485:451-2 (2012)

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