Association of a haplotype for tumor necrosis factor in siblings with late-onset Alzheimer disease: The NIMH Alzheimer disease genetics initiative

Tumor necrosis factor (TNF), a proinflammatory cytokine, may be involved in the pathogenesis of Alzheimer disease (AD) based on observations that seni le plaques have been found to upregulate proinflammatory cytokines, Additio nally, nonsteroidal anti-inflammatory drugs have been found to delay and pr event the onset of AD. A collaborative genome-wide scan for AD genes in 266 late-onset families implicated a 20 centimorgan region at chromosome 6p21. 3 that includes the TNF gene, Three TNF polymorphisms, a -308 TNF promoter polymorphism, whose TNF2 allele is associated with autoimmune inflammatory diseases and strong transcriptional activity, the -238 TNF promoter polymor phism, and the microsatellite TNFa, whose 2 allele is associated with a hig h TNF secretion, were typed in 145 families consisting of 562 affected and unaffected siblings, These polymorphisms formed a haplotype, 2-1-2, respect ively, that was significantly associated with AD (P = 0.005) using the sibl ing disequilibrium test, Singly, the TNFa2 allele was also significantly as sociated (P = 0.04) with AD in these 145 families, This TNF association wit h AD lends further support for an inflammatory process in the pathogenesis of AD, (C) 2000 Wiley-Liss, Inc.