GENETIC AND PHYSICAL CHARACTERIZATION OF THE EARLY-ONSET ALZHEIMERS-DISEASE AD3 LOCUS ON CHROMOSOME 14Q24.3

Genetic linkage studies have provided significant evidence that a majo r gene defect, AD3, for familial early-onset Alzheimer's disease (EOAD ) is located at chromosome 14q24.3, between the short tandem repeat (S TR) markers D14S52 and D14S53 defining a genetic size of 22.7 cM for t he AD3 candidate region, We constructed a physical map of the AD3 regi on using yeast artificial chromosomes (YACs) selected from both the CE PH and megaCEPH YAC libraries using the AD3 linked STR markers as well as new sequence-tagged sites (STSs) designed based on YAC terminal se quences, The YAC map is contiguous in the region between D14S258 and D 14S53, a region of 8.2 cM, and has an estimated physical size of 4-8 M b, The YAC contig map was used as a framework to localize three known genes, a pseudogene and two brain expressed sequence tags (ESTs). Link age analysis studies in two Belgian chromosome 14 EOAD families AD/A a nd AD/B, identified obligate recombinants in family AD/A with D14S289 and D14S61 reducing the genetic size of the candidate AD3 region subst antially, The minimal AD3 candidate region measured 6.4 cM on the gene tic map and is contained within six overlapping megaCEPH YACs that cov ered a physical distance estimated between 2 and 6 Mb, These YACs as w ell as other YACs in the YAC contig map are valuable resources in gene cloning efforts or genomic sequencing experiments aiming at isolating the AD3 gene.