Cholesterol Levels in Later Life Depend in Part on Apolipoprotein E Allele Status

Variations in the APOE gene modify the rise and fall of serum cholesterol levels from midlife to late life, and in order to efficiently modify cholesterol through the life span, it is important that the physician takes into account the patient's APOE allele status.

Apolipoprotein E (apoE), which is 299 amino acids long, comprises a class of apolipoprotein found in the chylomicron and intermediate-density lipoprotein (IDL) fraction that is essential for the normal catabolism of triglyceride-rich lipoprotein constituents. In peripheral tissues, apoE is primarily produced by the liver and macrophages and mediates cholesterol metabolism in an isoform-dependent manner.


The APOE gene is polymorphic, with three major alleles: APOE2, APOE3, and APOE4. Although these allelic forms differ from each other by only one or two amino acids at positions 112 and 158, these differences alter apoE structure and function. These have physiological consequences: apoE2, which has an allele frequency of approximately 7%, percent binds poorly to cell surface receptors while apoE3 and apoE4 bind well. ApoE2 is associated with both increased and decreased risk for atherosclerosis. ApoE3 has an allele frequency of approximately 79% and is considered the "neutral" apo E genotype. ApoE4 has an allele frequency of approximately 14% and has been implicated in atherosclerosis, Alzheimer's disease, and several other pathogenic states.

Investigators at the University of Texas Medical Branch (Galveston, USA) and colleagues at the University of Kentucky (Lexington, USA) analyzed data from blood samples of nearly 600 participants in the Framingham Heart Study Original Cohort to determine if variations in apoE influenced trajectories of total cholesterol, HDL cholesterol, and total: HDL cholesterol ratio from midlife through late life.

Results revealed that subjects with apoE2 had lower total cholesterol levels, higher HDL cholesterol levels, and lower total:HDL cholesterol ratios from midlife to late life compared to apoE3 and apoE4 subjects. Statistically significant differences in life span cholesterol trajectories according to gender and use of cholesterol-lowering medications were also detected. Individuals who lived past 90 years of age had higher total cholesterol during late life compared to adults who did not reach this age. This finding may have important implications for continuing the practice of prescribing cholesterol-lowering medications to the elderly.

“The increased risk for cognitive and cardiovascular diseases among older adults who carry an APOE4 allele may be due, in part, to the fact that these individuals are predisposed to having higher total cholesterol and lower HDL cholesterol from midlife through late life, compared to people with the APOE 3 variant,” said first author Dr. Brian Downer, postdoctoral research fellow at the University of Texas Medical Branch. “The decreased risk for these diseases associated with the APOE2 allele may be due to the lower total cholesterol and higher HDL cholesterol across the life span. Further research is needed to determine if reducing total cholesterol and increasing HDL cholesterol decreases the risk for cognitive and vascular diseases among adults who carry APOE4 alleles.”

“The findings from this study have important implications to public health,” said Dr. Downer. “To efficiently modify cholesterol, and as a result, disease risk, it is important to consider how APOE allele status influences cholesterol levels from midlife through late life. The relationship between APOE, cholesterol and longevity is complex and it is important to continue conducting research in this area so that older adults know how to appropriately manage cholesterol levels during old age.”

The study was published in the October 16, 2014, online edition of the International Journal of Environmental Research and Public Health.

Related Links:
University of Texas Medical Branch
University of Kentucky