On the discovery of the genetic association of Apolipoprotein E genotypes and common late-onset Alzheimer disease

Abstract

The association of Apolipoprotein E-4 with the age of onset of common late-onset Alzheimer's disease (AD) was originally reported in three 1993 papers from the Duke ADRC (Alzheimer's Disease Research Center) group. The Center was investigating two diverse experimental streams that led to this discovery. The first being a genetic linkage study performed in multiplex familial late-onset AD in which a linkage was discovered at chromosome 19q13. The 1991 multilocus analysis of linkage had been considered very controversial. The second stream came from a series of amyloid-beta binding studies in which a consistent protein "impurity" was present on gel separation analyses. After sequencing this "impurity" band, several tryptic peptide sequences were found to be identical for apoE which, at that time, had no known association with Alzheimer's disease. The flash of recognition was the knowledge that APOE was one of the first genes localized to chromosome 19 in the mid-1980's. Within a three week period in late 1992, a highly significant association was identified in clinical patients from multiplex families, in sporadic clinical patients, and in autopsy diagnosed series. Within the first two months of 1993, it was possible to clearly demonstrate that the APOE isoforms were associated with differing ages of onset, but the course of illness following diagnosis was related more to age than APOE genotype. The earliest submitted paper reported the familial association and amyloid-beta binding. The second reported the association with common sporadic late-onset, [not-known to be familial] AD patients. The third reported that APOE4 carriers had earlier rates of onset of clinical disease than APOE2 or APOE3 carriers. Subsequently, over more than a decade, the biological expression of apoE in human neurons was confirmed as distinct from rodent brain. Proteomic experiments and positron emission tomography data have led to a series of clinical trials with agents selected to increase glucose utilization. These agents also regulate inflammatory responses of neural cells. Rosiglitazone, a PPARgamma agonist which also leads to mitochondrial proliferation shown efficacy as a monotherapy in a Phase IIB clinical trial of 511 patients in an APOE allele-specific analysis.