Genetic Susceptibility Sets for Alzheimer's Disease Identified from Diverse Candidate Loci

Abstract

Alzheimer's disease (AD) has been demonstrated to be associated with gene variants of APOE, but numerous additional candidate loci exist with varying levels of statistical support. We defined susceptibility sets for AD based on information on 18 genetic loci on chromosome 10q (32 loci) and elsewhere (34 loci) and quantitative traits, including CSF tau and Abeta(42) levels. The 938 AD patients and 397 control subjects were enrolled in Scotland and Sweden. A fuzzy latent classification approach -- grade-of-membership analysis (GoM) -- was taken to identify risk sets. Individuals were automatically related to each set via GoM scores. Set I: unaffected + (downward arrow) CSF tau + (upward arrow) CSF Abeta(42) + multiple protective alleles. High intrinsic risk sets II-VI differed in onset age and relevant alleles: close resemblance (i.e., >75% aggregate membership) multiplied risk of AD >100-fold at ages 65 to 84. It is likely that AD has multiple determinants, including APOE polymorphism and gene variants located on chromosome 10q and elsewhere.