Dr. Benvenga provides evidence to support binding of thyroid hormone to a region of apo E. This observation is interesting, especially given the clinical association between thyroid hormone status and lipoprotein metabolism. Others have shown that thyroid hormone acts at the molecular level to reduce hepatic production of apo E [1] and to up-regulate hepatic low-density lipoprotein receptors [2], for which apo E is a ligand. More studies are required to determine whether any of these mechanisms can explain the association between hypothyroidism and hyperlipidemia, particularly type III hyperlipoproteinemia.

Apolipoprotein E has recently been shown to bind ß-amyloid peptide, a major constituent of the senile plaques found in the brains of patients with Alzheimer disease [3]. Moreover, the E4 isoform of apo E, which has a frequency of about 15% in whites, interacts with ß-amyloid much more avidly than does the common E3 isoform. The higher binding affinity of E4 for ß-amyloid and the capacity of ß-amyloid and E4 to form a complex latticework of monofibrillar structures in vitro provides a mechanism for the well-established statistical association between the E4 isoform and both familial and sporadic Alzheimer disease [4]. Also, the amount of amyloid in the brains of patients with Alzheimer disease was found to be highest in patients homozygous for E4, who also experience the earliest clinical manifestations of the disease. Finally, apo E was found to have an isoform-specific effect on neuronal growth in dorsal-root ganglia [5], with the E3 isoform stimulating and the E4 isoform impairing neurite outgrowth and neuronal elongation.

Recent biochemical, genetic, morphologic, and pathologic findings lend compelling evidence to support an important role for the E4 isoform of apo E in the pathogenesis of Alzheimer disease. Although these results are consistent and exciting, no prospective evidence suggests that apo E genotyping can be used clinically to identify persons at risk for Alzheimer disease. Also, no evidence suggests that interference with the apo E-amyloid interaction can produce a clinical benefit for persons predisposed to Alzheimer disease. Nevertheless, the established roles of apo E in plasma lipoprotein metabolism (and now within the central nervous system) make it a serious contender for consideration as one of the biomedical molecules of the year.