Posted 12 August 2005

Cholesterol and AD
By Chris Masterjohn

The product of the ε4 allele of apolipoprotein E (ApoE4) is less efficient at delivering cholesterol to cells. This appears to be contradicted by in vitro evidence that it is slightly more efficient at internalizing cholesterol than the product of the ε3 allele (ApoE3) when incubated in β-VLDL, but it is supported by observations that ApoE4 has a preferential affinity for low-cholesterol lipoproteins.

Dr. Iwo Bohr suggested in his recent hypothesis (1) that ApoE4 is less efficient at delivering cholesterol to cells, citing Lane and Farlow (2), extrapolating from their discussion of the deficiency of free fatty acid delivery resulting from the suppression of lipoprotein lipase, which is a result of the preferential affinity of ApoE4 for high-triglyceride lipoproteins, displacing ApoC-II. Dr. Bohr also notes higher cholesterol levels associated with ApoE4, which could be indicative of deficient delivery to cells. However, this suggestion seemed to be contradicted by in vitro evidence from Zheng-Shong et al., who showed in 1998 that ApoE4 was slightly more efficient than ApoE3, both incubated in β-VLDL, at internalizing cholesterol in neuronal cell culture (3). The observation of Zheng-Shong et al. has diminished relevance to in vivo dynamics because it utilized only β-VLDL rather than a full spectrum of lipoproteins.

The discussion of Lane and Farlow referring to ApoE4's preferential affinity for high-triglyceride lipoproteins relative to ApoE3 and ApoE2 should be supplemented with the corollary of this observation: ApoE4 demonstrates a preferential affinity for low-cholesterol lipoproteins. According to Figure 2.10 in Dr. Mary G. Enig's Know Your Fats (4), there is an inverse relationship between percentage cholesterol and percentage triglyceride in lipoproteins, excluding HDL. Triglycerides range from 89 percent of chylomicrons to 7 percent of IDLs, while cholesterol ranges from 4 percent of chylomicrons to 44 percent of IDLs. Thus, the preferential affinity of ApoE4 for high-triglyceride lipoproteins, namely chylomicrons and VLDL, should translate as a preferential affinity of ApoE4 for low-cholesterol lipoproteins.

It is my hypothesis that ApoE4 results in less efficient delivery of cholesterol to neuronal cells primarily through its preferential affinity for high-triglyceride, low-cholesterol lipoproteins, relative to ApoE3 and ApoE2. This supports Dr. Bohr's suggestion that ApoE4's causal contribution to Alzheimer disease is related to its inability to efficiently deliver cholesterol to cells, which is necessary for proper cholinergic function.

I will be discussing this observation further in an upcoming article on my website Cholesterol-And-Health.com, which will be referred to as Part II of Myth: Cholesterol Causes Alzheimer's Disease.

2. Lane RM, Farlow MR. Lipid homeostasis and apolipoprotein E in the development and progression of Alzheimer's disease. J Lipid Res. 2005 May;46(5):949-68. Epub 2005 Feb 16. Abstract

3. Ji ZS, Pitas RE, Mahley RW. Differential Cellular Accumulation/Retention of Apolipoprotein E Mediated by Cell Surface Heparan Sulfate Proteoglycans. The Journal of Biological Chemistry. 1998 May 29;273(22):13452-13460. Abstract

4. Enig, Mary G., PhD, Know Your Fats: The Complete Primer for Understanding the Nutrition of Fats, Oils, and Cholesterol, Silver Spring: Bethseda Press, 2000, p70F.