APOLIPOPROTEIN-E, EPSILON-4 ALLELE AS A MAJOR RISK FACTOR FOR SPORADIC EARLY AND LATE-ONSET FORMS OF ALZHEIMERS-DISEASE - ANALYSIS OF THE 19Q13.2 CHROMOSOMAL REGION

An association between the 19q13.2 chromosomal region and Alzheimer's disease (AD) has been reported in AD families and for sporadic AD. Rec ent observations provide evidence that the epsilon 4 allele of the apo lipoprotein E gene (APOE), located in this region, is a risk factor fo r late-onset AD. Within this region, other genes possibly involved in the pathophysiology of AD and in strong linkage disequilibrium with th e APOE locus may be responsible for this association. To test this hyp othesis, we analysed the allelic distribution of four polymorphic gene tic markers flanking the APOE gene (D19S178 (CA)n repeat, D19S47 (CA)n repeat, APOCI Hpal restriction fragment length polymorphism, APOCII ( CA)n repeat). We performed these analyses in a sample of late-onset sp oradic cases (n = 36) versus controls (n = 38), and in a sample of ear ly-onset sporadic cases (n = 34) versus controls (n = 36). Early-onset cases were analysed for two cut-offs with late-onset: less than 60 an d less than 65. We observed a significant increased frequency of the A POE epsilon 4 allele in late-onset and early-onset AD with ages at ons et less than 60 and less than 65. The adjusted odds ratio (OR) of the bearers of at least one APOE epsilon 4 allele was 4.10 ([1.84;9.16]) w hen estimated in both populations with a logistic regression model. Su rprisingly, the odds ratio of the bearers of at least one APOE epsilon 2 allele was also significant and equal to 0.11 ([0.02;0.50]) suggest ing a possible protective effect. An association with the disease was also observed for the long alleles of APOCII (CA)n repeat in the late- onset AD (OR = 3.56, [1.19;10.70]), and for the short alleles of D19S1 78 (CA)n repeat in the early-onset AD (OR = 4.44, [1.27;15.49]). In co nclusion, APOE is a major risk factor for early- and late-onset sporad ic AD. The combination of the APOE polymorphism with flanking markers located within the APOE locus significantly improved the association w ith the disease in both populations.