Definition: APOE4 is an isoform of APOE (a lipoprotein involved in lipid trafficking between neurons and astrocytes).
Apolipoprotein E (ApoE) is the major apolipoprotein of the CNS that has a central role in cholesterol transport. In the brain, ApoE is mostly produced by astrocytes, and some binds to specific neuronal receptors for cholesterol uptake. However, neurons also synthesize ApoE.
Amino acid substitutions at positions 112 and 158 define three isoforms in the human population. Isoform 4 (ApoE4) is significantly associated with sporadic Alzheimer disease, whereas isoform 2 might protect against Alzheimer disease (AD).
In aqueous solutions, such as blood and interstitial fluid, hydrophobic lipids (fats) are packaged as lipoproteins. These particles contain proteins called apolipoproteins, which regulate lipid transport and clearance by acting as a ligand for cell surface lipoprotein receptors. ApoE is the primary apolipoprotein expressed in the brain.
In humans, apoE exists as three naturally occurring isoforms, ε2, ε3, and ε4. ApoE4 is the primary risk factor for both familiar and sporadic forms of AD. Prior to this discovery, apoE was identified as a component of senile plaques and peripheral deposits of fibrillar Aβ.
ApoE also associates with the soluble oligomers of Aβ found in the brain, plasma, and CSF.
In vitro data confirms that apoE interacts with both fibrillar and soluble oligomers of Aβ. However, the effect, if any, of apoE isoform on these interactions has been difficult to determine, as the published results are contradictory.
Pathology
APOE4 isoform in Alzheimer disease
Genetic abnormalities in the processing of amyloid precursor protein (APP) that induce an increase in amyloid-β (Aβ) peptide are causal factors, but the presence of the ε4 allele of apolipoprotein E (apoE) is the primary genetic risk factor for Alzheimer disease.
The link between apoE:Aβ interaction and AD remains unclear, as an apoE isoform-specific function has not been established that would explain the correlation between the ε4 allele and the disease. Our research focuses on understanding the effect of apoE isoforms on the structure and function of oligomeric and fibrillar Aβ aggregation assemblies.
APOE in prostatic carcinoma
longevity
In families with late-onset AD, the risk for AD increased from 20% to 90% and mean age of onset decreased from 84 to 68 years with increasing number of apolipoprotein E epsilon 4 (APOE4) alleles.
Overall homozygozity for APOE4 increases the relative risk by 15- to 18-fold. This makes APOE the most effective risk factor for AD aside from age.
References
Adalbert R, Gilley J, Coleman MP. Abeta, tau and ApoE4 in Alzheimer’s disease: the axonal connection. Trends Mol Med. 2007 Apr;13(4):135-42. PMID: 17344096
Reelin, lipoprotein receptors and synaptic plasticity. Joachim Herz and Ying Chen. Nature Reviews Neuroscience 7, 850-859 (November 2006)
Christensen K, Johnson TE, Vaupel JW. The quest for genetic determinants of human longevity: challenges and insights. Nat Rev Genet. 2006 Jun;7(6):436-48. PMID: 16708071
Poirier J. Apolipoprotein E and cholesterol metabolism in the pathogenesis and treatment of Alzheimer’s disease. Trends Mol Med. 2003 Mar;9(3):94-101. PMID: 12657430
Herz J, Beffert U. Apolipoprotein E receptors: linking brain development and Alzheimer’s disease. Nat Rev Neurosci. 2000 Oct;1(1):51-8. PMID: 11252768