APOE ε4 and bapineuzumab

Abstract

Therapeutic development for Alzheimer disease (AD) is in a transitional period. Neurotransmitter-based approaches to date have been moderately beneficial, but only palliative. Strategies aimed at reducing the burden of amyloid-β peptide (Aβ) offer the prospect of modifying the underlying disease processes and ultimately slowing the course of neurodegenerative decline. However, results with amyloid-targeted agents have been disappointing so far. Among the many unknowns confronting the development of successful therapeutic interventions, the role of genetic background looms large. To date, APOE is the most common among a half dozen genetic loci that implicate aberrant metabolism of Aβ in AD as a primary etiologic agent and therapeutic target. Roughly half to two-thirds of patients with AD carry the e4 allele of APOE that conveys an increased risk for the disease. Early work with the cholinesterase inhibitor tacrine raised the possibility that treatment response may be reduced in APOE e4 carriers,1 heralding the routine use of APOE genotyping in subsequent AD trials. Since the APOE e4 allele is associated with increased amyloid burden,2 it theoretically may have a greater influence on Aβ-directed therapies. With this as background, Schenk and colleagues3 formulated the first Aβ vaccine, AN-1792, using a synthetic Aβ peptide. However, problems achieving a robust active immune response in the elderly, coupled with the allergic complications of AN-1792, …