Apolipoprotein E4: Not Just a Genetic Risk Factor

The strongest genetic risk factor for late-onset Alzheimer's disease is the E4 variant of Apolipoprotein E (APOE), meaning that two of the amino acid building blocks of the protein are different. Although 14 percent of the world's population carries this variant, many will not develop the disease. People with one copy of E4 are three to four times more likely to develop Alzheimer's; people with two copies are 15 times more likely to develop the disease [1].

Why does APOE4 raise the risk of Alzheimer's disease? A variety of explanations have been proposed. It's possible that the E4 variant is less capable than other types of APOE4 to repair neurons and serve other functions important for brain health. Alternatively, the E4 variant may have toxic effects on the brain.

Since APOE4 is a primary risk factor for Alzheimer's disease, drugs that target it may prevent the disease. The Alzheimer's Drug Discovery Foundation (ADDF) funds drug discovery to accelerate the development of novel therapeutics specifically targeting APOE pathological mechanisms. To date, 19 projects have been funded, totaling over $4.27 million. More information about these grants can be found in the ADDF grants portfolio.

The E4 variant may also determine the effectiveness of a given prevention strategy. Two examples you may remember from our coverage:

• Scientists observed that physical activity was associated with less brain atrophy in APOE4 carriers but not non-carriers [2].

• The omega-3 fatty acid DHA appears to offer little protection from dementia for APOE4 carriers though it may protect non-carriers [3].

The E4 variant may also determine if anti-hypertensive ACE inhibitor drugs [4], education [5], and non-steroidal anti-inflammatory drugs such as ibuprofen [6] are effective in protecting the brain from aging and dementia. The evidence for these claims is generally very limited. However, it’s clear that protecting ourselves from Alzheimer's disease may require a better understanding of how our genes interact with our health choices.

1. Farrer, L.A., et al., Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA, 1997. 278(16): p. 1349-56.
2. Erickson, K.I., et al., Exercise training increases size of hippocampus and improves memory. Proc Natl Acad Sci U S A, 2011. 108(7): p. 3017-22.
3. Dacks, P.A., D.W. Shineman, and H.M. Fillit, Current evidence for the clinical use of long-chain polyunsaturated n-3 fatty acids to prevent age-related cognitive decline and Alzheimer's disease. J Nutr Health Aging, 2013. 17(3): p. 240-51.
4. Qiu, W.Q., et al., Angiotensin converting enzyme inhibitors and the reduced risk of Alzheimer's disease in the absence of apolipoprotein E4 allele. J Alzheimers Dis, 2013. 37(2): p. 421-8.
5. Vermeiren, A.P., et al., The association between APOE epsilon4 and Alzheimer-type dementia among memory clinic patients is confined to those with a higher education. The DESCRIPA Study. J Alzheimers Dis, 2013. 35(2): p. 241-6.
6. Cole, G.M. and S.A. Frautschy, Mechanisms of action of non-steroidal anti-inflammatory drugs for the prevention of Alzheimer's disease. CNS Neurol Disord Drug Targets, 2010. 9(2): p. 140-8.

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