APOE

A key gene associated with Alzheimer's disease was identified by scientists working in Neurology at Duke University Medical Center. Dr. Margaret Perick-Vance and Dr. Alan Roses were instrumental in showing that the expression of an APOE4 gene allele significantly increases the risk for AD. Individuals who are homozygous for the APOE4 gene (APOE4/4) (about 7% of the human population) have earlier onset of AD and more severe pathology than individuals who do not express APOE4. The APOE gene codes for apolipoprotein E (apoE), initially described as a lipid transport protein. While apoE is required for growth and repair of neurons, our lab was the first to show that apoE is also a global regulator of inflammation and macrophage function. The presence of the APOE4 gene increases the pro-inflammatory phase of the innate immune response. Essentially all aspects of the acute stages of inflammation are increased, including production of NO, TNFa, IL-6 and other cytokines and proteases, thereby worsening the self-directed damage that can be caused by inflammation during injury or disease.

This finding is consistent with the increased damage observed in individuals expressing an APOE4 gene and explains, at least in part, why APOE4 affects almost all (if not all) human diseases. Our recent article below describes multiple aspects of APOE's action on inflammation and microglial function. This paper shows that despite changes in apoE protein levels in both APOE3 and APOE4 mice, the presence of APOE4 in particular leads to increased inflammation.

Readings:

Interestingly, the presence of the APOE4 gene is not all bad. It is tempting to speculate that an increased pro-inflammatory status could be useful in environments with high numbers of parasites or infectious conditions. In his treatise on the role of meat-eating in human evolution. Dr. Caleb Finch describes how APOE3 has essentially replaced the APOE4 gene (the primitive allele) over time, possibly because apoE3 is better than apoE4 in cholesterol regulation and in supplying cells with lipids. On the other hand, early humans did not live long enough to suffer diseases of aging, but instead lived in highly infectious environments. Under these circumstances, ApoE4 would provide some evolutionary benefit. To read more, see Dr. Finch's articles; Q Rev Biol. 2004 Mar;79(1):3-50 or Curr Alzheimer Res. 2007 Apr;4(2):185-9.

A modern-day example of the utility of the APOE4 gene is found in children exposed to chronic diarrheal diseases. Dr. Richard Guerrant and colleagues have shown that the presence of the APOE4 gene in young children with chronic disease improves long-term outcomes. Oriá RB, Patrick PD, Blackman JA, Lima AA, Guerrant RL Role of apolipoprotein E4 in protecting children against early childhood diarrhea outcomes and implications for later development. Med Hypotheses. 2007;68(5):1099-107.

Our work on arginine transport suggests a reason for why this happens and requires an understanding of arginase-NOS balance.