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Volume 349:193-194 July 10, 2003 Number 2
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Genetics of Neurodegenerative Disorders

 

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To the Editor: We disagree with Nussbaum and Ellis's statement that gene variations other than the APOE {epsilon}4 allele are elusive in the nonfamilial form of Alzheimer's disease (April 3 issue).1 The candidate-gene approach has already identified genes with a potential role in the etiology of the disease.2 In addition, over the past 15 years, a number of inflammatory mediators have been observed in the brain affected by Alzheimer's disease. In this disease, inflammation clearly occurs in pathologically vulnerable regions of the brain and may influence other neuropathologic hallmarks of the disease, although it is unclear whether altered immune responses constitute an event secondary to ongoing neurodegeneration or whether they participate in its ignition.3 However, several polymorphisms in genes encoding immune molecules have been associated with an increased or decreased risk of Alzheimer's disease,4,5 suggesting a genetic link between immunoinflammatory processes and Alzheimer's disease. Genetic variants associated with a decreased risk of Alzheimer's disease also seem to increase the chance of reaching the extreme limit of the human life span.6 Therefore, the role of immunoinflammatory responses in Alzheimer's disease and longevity deserves further study.


Calogero Caruso, M.D.
Università di Palermo
90134 Palermo, Italy
marcoc{at}unipa.it


Claudio Franceschi, M.D.
Federico Licastro, M.D.
Università di Bologna
40126 Bologna, Italy

References

  1. Nussbaum RL, Ellis CE. Alzheimer's disease and Parkinson's disease. N Engl J Med 2003;348:1356-1364. [Free Full Text]
  2. Tabor HK, Risch NJ, Myers RM. Candidate-gene approaches for studying complex genetic traits: practical considerations. Nat Rev Genet 2002;3:391-397. [ISI][Medline]
  3. Akiyama H, Barger S, Barnum S, et al. Inflammation and Alzheimer's disease. Neurobiol Aging 2000;21:383-421. [CrossRef][ISI][Medline]
  4. Licastro F, Chiappelli M. Brain immune responses cognitive decline and dementia: relationship with phenotype expression and genetic background. Mech Ageing Dev 2003;124:539-548. [CrossRef][Medline]
  5. Lio D, Licastro F, Scola L, et al. Interleukin-10 promoter polymorphism in sporadic Alzheimer's disease. Genes Immun 2003;4:234-238. [CrossRef][Medline]
  6. Lio D, Scola L, Crivello A, et al. Inflammation, genetics, and longevity: further studies on the protective effects in men of IL-10 -1082 promoter SNP and its interaction with TNF-alpha -308 promoter SNP. J Med Genet 2003;40:296-299. [Free Full Text]
 
The authors reply: Our review article was meant to provide a brief update for clinicians on the progress made in applying genomic science to the understanding of two neurodegenerative disorders. There are alleles at many loci other than APOE for which an association with Alzheimer's disease has been proposed.1 However, many of these studies have yet to be replicated, and among those that have been replicated, controversy persists.1 For example, an association between Alzheimer's disease and alleles at the {alpha}2-macroglobulin locus has been proposed2,3 but has not been replicated for at least one of the alleles.4,5 For the purposes of our review article, we decided to draw a distinction between these putative associations and the association with APOE {epsilon}4, which has been confirmed in a sufficient number of studies for some to suggest that an APOE genotype test might be useful for clinical applications. We look forward to the association studies that Caruso et al. list and will await their replication by other investigators.


Robert Nussbaum, M.D.
Christopher Ellis, Ph.D.
National Human Genome Research Institute
Bethesda, MD 20892-4472
rlnuss{at}nhgri.nih.gov

References

  1. Hirschhorn JN, Lohmueller K, Byrne E, Hirschhorn K. A comprehensive review of genetic association studies. Genet Med 2002;4:45-61. [ISI][Medline]
  2. Blacker D, Wilcox MA, Laird NM, et al. Alpha-2 macroglobulin is genetically associated with Alzheimer disease. Nat Genet 1998;19:357-360. [CrossRef][ISI][Medline]
  3. Liao A, Nitsch RM, Greenberg SM, et al. Genetic association of an alpha2-macroglobulin (Val1000Ile) polymorphism and Alzheimer's disease. Hum Mol Genet 1998;7:1953-1956. [Free Full Text]
  4. Rudrasingham V, Wavrant-De Vrièze F, Lambert JC, et al. Alpha-2 macroglobulin gene and Alzheimer disease. Nat Genet 1999;22:17-19. [CrossRef][ISI][Medline]
  5. Dow DJ, Lindsey N, Cairns NJ, et al. Alpha-2 macroglobulin polymorphism and Alzheimer disease risk in the UK. Nat Genet 1999;22:16-17. [CrossRef][ISI][Medline]

 

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