LINKAGE AND HAPLOTYPE ANALYSIS OF FAMILIAL EARLY-ONSET ALZHEIMER-DISEASE IN JAPANESE POPULATION

Linkage and haplotype analysis of eleven early-onset Alzheimer disease (AD) families was performed in relation to D21S210 and microsatellite DNA polymorphisms localized on chromosome 14q24.3. Linkage analysis of eight informative families out of eleven early-onset AD families disclosed the highest LOD score of 3.45 (theta=0.00) at D14S77, while the locus of beta/A4 amyloid protein precursor gene was formally excluded within 10 cM from D21S210, given the evidence of recombinations in five families. Transmission disequilibrium study between the patients and controls without dementia indicated significant differences at D14S43 (p=0.0001) and D14S71 (p=0.02). Association study between genotypes linked or related to onset of AD and those of control also revealed a significant difference at D14S43 (p<0.05), suggesting the existence of linkage disequilibrium. Moreover, the haplotypes at D14S43 linked with the onset of AD indicated a significant relationship with the mean age at onset. These results support that the major locus of early-onset familial AD is located on 14q24.3, and its close linkage to D14S43 and the existence of allelic heterogeneity were suggested.