Human apolipoprotein (apo) E, long known for its prominent role in cholesterol transport and plasma lipoprotein metabolism, has recently emerged as a major genetic risk factor for Alzheimer's disease, a neurodegenerative disorder. In a variety of populations worldwide, one of the three common alleles of apoE, apoE4, is overrepresented in Alzheimer's subjects compared with age‐ and sex‐ matched controls. The genetic and epidemiologic evidence suggests that apoE is a major susceptibility gene for Alzheimer's disease; it likely accounts for a major portion of the genetic heterogeneity in the disease. Although its role in the development of Alzheimer's disease is unknown, biochemical and cell biology studies are providing important insights into how apoE may be involved in neurodegenerative disorders. Based on an understanding of the structure and function of apoE in lipid transport and cellular metabolism, it is suggested that apoE is involved in a final common pathway of neuronal repair and remodeling: apoE3 (most common allele) supporting effective repair and remodeling after neuronal injury by noxious agents, and apoE4 being less effective in these processes.—Weisgraber, K. H., Mahley, R. W. Human apolipoprotein E: The Alzheimer's disease connection FASEB J. 10, 1485‐1494 (1996)