Association of a haplotype for tumor necrosis factor in siblings with late-onset Alzheimer disease: the NIMH Alzheimer Disease Genetics Initiative

Am J Med Genet. 2000 Dec 4;96(6):823-30. doi: 10.1002/1096-8628(20001204)96:6<823::aid-ajmg26>;2-i.


Tumor necrosis factor (TNF), a proinflammatory cytokine, may be involved in the pathogenesis of Alzheimer disease (AD) based on observations that senile plaques have been found to upregulate proinflammatory cytokines. Additionally, nonsteroidal anti-inflammatory drugs have been found to delay and prevent 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 polymorphism, and the microsatellite TNFa, whose 2 allele is associated with a high TNF secretion, were typed in 145 families consisting of 562 affected and unaffected siblings. These polymorphisms formed a haplotype, 2-1-2, respectively, that was significantly associated with AD (P = 0.005) using the sibling disequilibrium test. Singly, the TNFa2 allele was also significantly associated (P = 0.04) with AD in these 145 families. This TNF association with AD lends further support for an inflammatory process in the pathogenesis of AD. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:823-830, 2000.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Age of Onset
  • Alleles
  • Alzheimer Disease / genetics*
  • Chromosome Mapping
  • Chromosomes, Human, Pair 6 / genetics
  • DNA / genetics
  • Family Health
  • Gene Frequency
  • Genotype
  • Haplotypes*
  • Humans
  • Lod Score
  • Microsatellite Repeats
  • National Institute of Mental Health (U.S.)
  • Nuclear Family
  • Polymorphism, Genetic
  • Promoter Regions, Genetic / genetics
  • Software
  • Statistics, Nonparametric
  • Tumor Necrosis Factor-alpha / genetics*
  • United States


  • Tumor Necrosis Factor-alpha
  • DNA