Alzheimer's disease (AD) is a complex genetic disorder. Linkage analysis has helped unravel a portion of the genetic component of AD by identifying four loci that play a role in the genetics of AD (amyloid precursor protein, presenilin 1, presenilin 2, and apolipoprotein E). These loci account for approximately 50% of the genetic etiology of AD. A total genomic screen is an efficient way to identify additional genetic effects in AD. A series of multiplex late-onset (>60 years) AD families were ascertained (NINDS-ADRDA diagnostic criteria) and sampled. A subset (n = 16) of the largest families (52 affecteds with DNA, 83 unaffecteds with DNA) were used to rapidly screen the genome (n = 280 markers) for additional major genetic effects. Critical values for regional follow-up were p < or =0.05 for SimIBD or sibpair analysis and/or a LOD score > or = 1.00. Fifteen regions warranted initial follow-up based on these criteria. An additional screening set was used (n = 38 families, 89 affecteds with DNA, 216 unaffecteds with DNA) for the follow-up analysis. These analyses revealed four regions of continued interest on chromosomes 4, 6, 12, and 20. Chromosome 12 presented the strongest results. Peak two point "affecteds only" LOD scores were 1.3, 1.6, 2.7, and 2.2 and (affected relative pair SimIBD) p values were 0.04, 0.03, 0.14, and 0.04 for D12S373, D12S1057, D12S1042, and D12S390, respectively. These markers span approximately 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 supported these findings. Saturation mapping of all available markers in the chromosome 12 region as well as further investigation of the regions on 4, 6, and 20 is ongoing with candidate gene analysis to follow.