Modulation by DLST of the genetic risk of Alzheimer's disease in a very elderly population

The mitochondrial alpha-ketoglutarate dehydrogenase complex (KGDHC) is defi cient in Alzheimer's disease (AD). The DLST gene encodes the core, dihydrol ipoyl succinyltransferase (DLST) component of KGDHC, and recent reports ind icate an association between polymorphisms of DLST and AD in both white and Japanese patients. We therefore examined the relationship between AD and t he DLST and apolipoprotein E (APOE) genes in elderly (89 +/- 7 years) AD pa tients, in whom the epsilon 4 allele of APOE (APOE4) is a weak risk factor for AD. Polymorphisms of DLST (A19,117G and T19,183C), shown to be of inter est in previous studies, were analyzed by restriction fragment length polym orphism analysis after polymerase chain reaction amplification. In a series of 429 white subjects from two Jewish nursing homes, an association of APO E4 with AD was found only in patients homozygous far the G,C allele of DLST . Similar relationships occurred in the "very elderly" (greater than or equ al to 85 years, n = 302) subgroup of this series, and also in an autopsy se ries (n 225) that included white subjects from the Jewish nursing homes as well as other white subjects. These findings suggest a relationship between APOE4 and a DI;ST locus in the pathogenesis of AD in very elderly subjects .