Comments

1. • Rudy Tanzi
     Massachusetts General Hospital
   • Posted: 15 Mar 2002

   The new genome screen on Alzheimer's and Parkinson's diseases reported by Pericak-Vance et al. is a very interesting and provocative paper using age-at-onset (AAO) as a quantitative trait to search for novel AD and PD genes. The most interesting finding is that both AD and PD map to the same region of the long arm of chromosome 10. This is roughly the same region that we found earlier to be linked to AD in a paper published in Science (Bertram et al., 2000). In the same issue, Myers et al. and Ertekin-Taner et al. found evidence for linkage of AD to a more proximal region of the long arm of chromosome 10. This more proximal peak was also supported by mildly suggestive evidence for linkage published by the Duke group in two meeting reports, however, the new peak now reported by Pericak-Vance et al. in their AAO analysis corroborates the one we previously described in the more distal region of chromosome 10 (Bertam et al., 2000).

   Taken together, the authors raise the interesting possibility that there may be two AD loci on chromosome 10: a more distal 10q locus that influences age-at-onset, and a second more proximal 10q locus that influences risk. Obviously, one must be careful in discriminating between loci that confer increased risk for AD as opposed to affecting age-at-onset, since one locus could appear to affect both risk and age-at-onset (e.g., ApoE).

   It is also interesting that some risk-based AD linkage hits on other chromosomes reported by this and other groups (e.g., on chromosomes 12 and 9) do not come up positive in the new AAO-based study. This underscores the importance of continuing to carry out both types of analyses (as long as funding holds up!) Given that a number of different groups are concurrently attempting to identify novel AD genes, the real AD loci, whether for risk, AAO, or both, should eventually surface, and perhaps even be agreed upon...

   Finally, it should be said that the most intriguing aspect of the new Pericak-Vance et al. paper is that the hit on distal region of 10 not only appears to influence AAO for AD, but also for PD. This suggests that perhaps a single gene might be influencing the extent and rate of the neurodegenerative process in both diseases. However, we will not know until the gene(s) are actually identified.—Rudy Tanzi and Lars Bertram, Harvard Medical School.

   References:

   Bertram L, Blacker D, Mullin K, Keeney D, Jones J, Basu S, Yhu S, McInnis MG, Go RC, Vekrellis K, Selkoe DJ, Saunders AJ, Tanzi RE. Evidence for genetic linkage of Alzheimer's disease to chromosome 10q. Science. 2000 Dec 22;290(5500):2302-3. PubMed.

   Myers A, Holmans P, Marshall H, Kwon J, Meyer D, Ramic D, Shears S, Booth J, DeVrieze FW, Crook R, Hamshere M, Abraham R, Tunstall N, Rice F, Carty S, Lillystone S, Kehoe P, Rudrasingham V, Jones L, Lovestone S, Perez-Tur J, Williams J, Owen MJ, Hardy J, Goate AM. Susceptibility locus for Alzheimer's disease on chromosome 10. Science. 2000 Dec 22;290(5500):2304-5. PubMed.

   Ertekin-Taner N, Graff-Radford N, Younkin LH, Eckman C, Adamson J, Schaid DJ, Blangero J, Hutton M, Younkin SG. Heritability of plasma amyloid beta in typical late-onset Alzheimer's disease pedigrees. Genet Epidemiol. 2001 Jul;21(1):19-30. PubMed.

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