apolipoprotein E

**Structure/genetics:** ApoE is a 299-amino-acid protein encoded by the APOE gene on chromosome 19. Three common alleles (ε2, ε3, ε4) differ at residues 112 and 158: E2 (Cys112, Cys158), E3 (Cys112, Arg158; most common, "neutral"), E4 (Arg112, Arg158). It is synthesized mainly in the liver, and also in the brain (astrocytes, microglia), macrophages, and other tissues.

**Function:** ApoE is a ligand for the LDL receptor (ApoB-100/E receptor) and LDL receptor-related protein 1 (LRP-1). It mediates hepatic clearance of chylomicron remnants and IDL (VLDL remnants). It is also involved in cholesterol transport and lipid redistribution in the CNS and in tissue repair. ApoE is acquired by nascent chylomicrons and VLDL from HDL in the circulation. ApoC-II (also from HDL) activates lipoprotein lipase.

**Clinical associations:** 1. **Type III hyperlipoproteinemia (familial dysbetalipoproteinemia):** - Usually E2/E2 homozygosity. E2 binds the LDL receptor poorly, so chylomicron and VLDL remnants (IDL) accumulate. - Labs: elevated cholesterol and triglycerides. Broad "β" band on lipoprotein electrophoresis, with β-VLDL. - Findings: palmar xanthomas (palmar crease, highly characteristic), tuberoeruptive xanthomas, and premature atherosclerosis (coronary and peripheral vascular disease). - Penetrance is often enhanced by a second hit (obesity, diabetes, hypothyroidism, estrogen deficiency). - Treatment: lifestyle changes, treatment of secondary causes, fibrates, and statins. 2. **Alzheimer disease:** - The ε4 allele is the strongest genetic risk factor for late-onset (sporadic) AD. Risk increases with allele dosage (heterozygotes about 3×, homozygotes about 8–12×). It is also associated with earlier onset. - ε2 is protective. - Proposed mechanisms: impaired Aβ clearance and increased Aβ aggregation, plus neuroinflammation and lipid dysregulation. - Contrast with early-onset familial AD: APP (chromosome 21), presenilin-1 (chromosome 14), and presenilin-2 (chromosome 1). Down syndrome (trisomy 21) also carries AD risk because of the extra APP gene. - ApoE4 is not used for routine diagnostic testing. 3. **Other:** E4 is associated with worse outcomes after traumatic brain injury, cerebral amyloid angiopathy, and cardiovascular disease risk.

**High-yield lipoprotein table:** - ApoA-I: activates LCAT, major HDL protein. - ApoB-48: chylomicron assembly and secretion, from the intestine. It is the only apolipoprotein that does not bind LDL receptors. - ApoB-100: binds the LDL receptor, on VLDL, IDL, and LDL, from the liver. - ApoC-II: lipoprotein lipase cofactor. - ApoE: mediates remnant uptake (chylomicron remnants, IDL, VLDL remnants). - ApoE and ApoC-II are both transferred from HDL to chylomicrons and VLDL.

**Exam pearl:** A patient with palmar xanthomas, elevated cholesterol and triglycerides, and premature atherosclerosis points to ApoE2 homozygosity and type III hyperlipoproteinemia. A question about the strongest genetic risk factor for sporadic late-onset Alzheimer disease points to ApoE4.