COMPLETE GENOMIC SCREEN IN LATE-ONSET FAMILIAL ALZHEIMERS-DISEASE

Alzheimer's disease (AD) is a complex genetic disorder. Linkage analys is has helped unravel a portion of the genetic component of AD by iden tifying four loci that play a role in the genetics of AD (amyloid prec ursor protein, presenilin 1, presenilin 2, and apolipoprotein E). Thes e loci account for approximately 50% of the genetic etiology of AD. A total genomic screen is an efficient way to identify additional geneti c effects in AD. A series of multiplex late-onset (>60 years) AD famil ies were ascertained (NINDS-ADRDA diagnostic criteria) and sampled. A subset (n = 16) of the largest families (52 affecteds with DNA, 83 una ffecteds with DNA) were used to rapidly screen the genome (ii = 280 ma rkers) for additional major genetic effects. Critical values for regio nal follow-up were p less than or equal to 0.05 for SimIBD or sibpair analysis and/or a LOD score greater than or equal to 1.00. Fifteen reg ions warranted initial follow-up based on these criteria. An additiona l screening set was used (n = 38 families, 89 affecteds with DNA, 216 unaffecteds with DNA) for the follow-up analysis. These analyses revea led four regions of continued interest on chromosomes 4, 6, 12, and 20 . Chromosome 12 presented the strongest results. Peak two point 'affec teds only'' LOD scores were 1.3, 1.6, 2.7, and 2.2 and (affected relat ive pair SimIBD) p values were 0.04, 0.03, 0.14, and 0.04 for D12S373, D12S1057, D12S10341 and D12S390, respectively. These markers span app roximately 30 cm near the centromeric region of chromosome 12. Sibpair analysis resulted in two point Maximum Lod Score (MLS) results of 0.4 , 1.2, 3.2, and 1.0 for the above markers. Multipoint MLS analysis sup ported these findings. Saturation mapping of all available markers in the chromosome 12 region as well as further investigation of the regio ns on 4, 6, and 20 is ongoing with candidate gene analysis to follow. (C) 1998 Elsevier Science Inc.