Identification of novel genes in late-onset Alzheimer's disease

Four genes affecting Alzheimer's Disease (AD)(AP, PS1, PS2, and APOE) have been identified and a fifth potential gene localized to chromosome 12. Coll ectively these genes explain at most half of the genetic effect in AD. Unde rstanding the genetics of AD is critical to developing new treatments. The quest to find the remaining AD genes led us to undertake a large genomic sc reen using over 466 families (730 affected sibpairs) in late-onset AD. In c onjunction with this increase in power, we initiated several novel approach es to identify potential AD-related genes. This included stratification of the data into an autopsy-confirmed subset of 199 AD families. Each of these targeted analyses resulted in the identification of novel regions containi ng potential AD genetic risk factors. Our most significant finding was on c hromosome 9 in the autopsy-confirmed subset where we obtained an MLS of 4.3 1. These approaches, together with new methodologies such as conditional li nkage analysis, generalized family-based association tests (PDT), and a new generation of genetic markers (SNPs), opens the door for additional AD gen e discovery. Such strategies are necessary if we are to understand the subt le and complex threads that, woven together, create the intricate tapestry of AD. (C) 2000 Elsevier Science B.V. All rights reserved.