This session was disappointing, offering nothing really new. What new data were presented appear to be very controversial.

Farrer et al. (Abstract 280) tried to confirm the linkage described by Duke University, North Carolina. They described a linkage with chromosome 12 for familial late-onset Alzheimer's disease (LOAD) (mean age at onset: 70.5 + 10.7 years). This association appears to be independent of ApoE4 status and not related to LRP1 and α2 macroglobulin loci.

Rebeck et al. (Abstract 281) analyzed the LRP exon 3 polymorphism (766) and the α2-macrogobulin V1000I polymorphism in sporadic AD. Regarding the LRP, they found a previously published polymorphism linked to AD. Concerning the α2-macroglobulin, GG frequency is overrepresented in AD. The combined data show a strong association (odd ratio 4.1 (pLilius et al. (Abstract 282; Lannfelt gave the talk) described 11 polymorphisms, all in strong linkage disequilibrium, on the tau gene, including five missense mutations on exons 4A and 6 (not expressed in brain). The 11 polymorphisms segregated together in a Mendelian way as two alleles. Cases with at least one ApoE4 allele and the AA tau genotype showed an increase risk for AD.

Premkumar et al. (Abstract 283): Bleomycin hydrolase (BH) is a Cys protease from the papain family. BH is a good β-secretase candidate. By immunoflurescence, it colocalizes with APP in transfected CHO cells. The BH gene has 12 exons and is localized on chromosome 17q11.1-11.2. There is a potentially functional polymorphism V442I. In their population, the authors did not confirm the increased frequency of the V/V genotype in AD patients previously described by Montoya et al. However, in Ashkenazi Jews and African-American populations, cases with I/I/ genotypes have a higher risk for AD.

Dermaut et al. (abstract 284) demonstrated that the PS1 mutation Glu318Gly is a neutral mutation (polymorphism) and is not related to dementia.

Sandbrink et al. (Abstract 285), confirmed an association of butyrylcholinesterase K variant (BCHE-K with LOAD, as previously described by Lehmann et al. The authors showed that there is no major synergy of BCHE-K and ApoE4.

Casadei et al. (abstract 286), studied three polymorphisms related to IL1 metabolism:

IL-1α -889 promoter polymorphism; IL-1β -511 promoter polymorphism; IL1ra intron 2 polymorphism.

IL1α polymorphism is associated with EOAD; IL1β is less clearly ass0ciated with EOAD, and finally, the question: Is IL1ra intron 2 polymorphism a disease susceptibility trait?

Finally, a poster session by Lambert et al. (Abstract 127), reported on polymorphisms in ApoE promoter that are good candidates to modulate ApoE expression.—Luc Buee


  1. As a quick comment regarding Luc Buee's summary of Dr. Lindsay Farrer's talk on the genetics of AD and chromosome 12 in the Genetics I session of the Sixth Int. Conference on AD in Amsterdam, Dr. Buee reports that Dr. Farrer's genetic linkage findings on chromosome 12 appear to be independent of the A2M and LRP genes. Indeed, Dr. Farrer stated this, but it should be pointed out that his data (which was also those reported by Dr. Peter Hyslop in a plenary talk) show that their two highest linkage peaks occur precisely at two chromosomal sites and DNA markers that are closest to LRP on chromosome 12q and to A2M on chromosome 12p. Thus, their genetic linkage results clearly support the candidacy of both A2M and LRP as putative AD genes. Neither Dr. Farrer, nor Dr. Hyslop actually presented any data that ruled out A2M or LRP as AD genes, other than making statements that they did nto think these were the genes. But, clearly the genetic linkage data they presented were quite compelling in implicating exactly the sites where these two genes reside.

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