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Alzheimer Disease [AD] is a complex yet strongly genetic, heterogeneous 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 I and II and APOE]. We have previously shown that these loci account for about 50% of the genetic etiology of AD with the APOE locus remaining the single most significant biological factor yet identified. A total genomic screen is one of the most efficient ways to identify additional genetic effects in AD. Sixty seven multiplex late-onset [>65 years] AD families were originally ascertained (NINDS-ADRDA diagnostic criteria) and sampled. A subset of the largest families were used to rapidly screen the genome for additional major genetic effects in late-onset familial AD. Screening families had 2 or more sampled affected individuals and no APOE 4/4 homozygotes. The data were analyzed in a multi analytical approach using both LOD score and non-parametric methods of analysis [APM, sibpair]. Critical values for follow-up analysis were a p-value < 0.05 for APM or sibpair and/or a LOD score >1.0. Promising regions were those that met critical values on two out of three tests. Ten regions warranting follow-up were determined on chromosomes 2, 3, 4, 6, 5, 10, 12, and 21. Multipoint exclusion analysis of these regions is in process as well as well as additional genotyping in a second set of 55 AD families. Genes in confirmed regions will be examined as potential AD susceptibility loci. These analyses will be followed by a total genome scan on the complete data set of 234 multiplex late-onset AD families [>500 affecteds with DNA] that we now have available in order to determine the extent of the effect of all major as well as moderate AD susceptibility loci. This effort will identify the remaining genetic effects of AD, opening the door to the identification of gene/gene and gene/environment interactions.