Correspondence

Genetics of Neurodegenerative Disorders

N Engl J Med 2003; 349:193-194July 10, 2003

Article

To the Editor:

We disagree with Nussbaum and Ellis's statement that gene variations other than the APOE ε4 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@unipa.it

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

6 References

1. 1

   Nussbaum RL, Ellis CE. Alzheimer's disease and Parkinson's disease. N Engl J Med 2003;348:1356-1364
   Full Text | Web of Science | Medline

2. 2

   Tabor HK, Risch NJ, Myers RM. Candidate-gene approaches for studying complex genetic traits: practical considerations. Nat Rev Genet 2002;3:391-397
   CrossRef | Web of Science | Medline

3. 3

   Akiyama H, Barger S, Barnum S, et al. Inflammation and Alzheimer's disease. Neurobiol Aging 2000;21:383-421
   CrossRef | Web of Science | Medline

4. 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 | Web of Science | Medline

5. 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 | Web of Science | Medline

6. 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
   CrossRef | Web of Science | Medline

Author/Editor Response

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 α₂-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 ε4, 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@nhgri.nih.gov

5 References

1. 1

   Hirschhorn JN, Lohmueller K, Byrne E, Hirschhorn K. A comprehensive review of genetic association studies. Genet Med 2002;4:45-61
   CrossRef | Web of Science | Medline

2. 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 | Web of Science | Medline

3. 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
   CrossRef | Web of Science | Medline

4. 4

   Rudrasingham V, Wavrant-De Vrieze F, Lambert JC, et al. Alpha-2 macroglobulin gene and Alzheimer disease. Nat Genet 1999;22:17-19
   CrossRef | Web of Science | Medline

5. 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 | Web of Science | Medline

Citing Articles (1)

Citing Articles

1. 1

   Michele Mishto, Elena Bellavista, Aurelia Santoro, Alexandra Stolzing, Claudia Ligorio, Benedetta Nacmias, Liana Spazzafumo, Martina Chiappelli, Federico Licastro, Sandro Sorbi, Annalisa Pession, Thomas Ohm, Tilman Grune, Claudio Franceschi. (2006) Immunoproteasome and LMP2 polymorphism in aged and Alzheimer's disease brains. Neurobiology of Aging 27:1, 54-66
   CrossRef