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Reported by Luc Buee, INSERM.
18 July, 1998 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 Univ. 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 APOE epsilon 4 status and not related to LRP1 and
alpha-2 macroglobulin loci.
Rebeck et al. (abstract 281) analyzed the
LRP exon 3 polymorphism (766) and the alpha 2-macrogobulin V1000I polymorphism
in sporadic AD. Regarding the LRP, they found a previously published polymorphism
linked to AD. Concerning the alpha 2-macroglobulin, GG frequency is overrepresented
in AD. The combined data show a strong association (odd ratio 4.1 (p<0.02))
independently of ApoE genotypes.
Lilius et al. (abstract
282; Lannfelt gave the talk) described 11 polymorphisms, all in strong
linkage disequilibrium, on the tau gene, including 5 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 ApoE
epsilon 4 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 ß secretase candidate. By immunoflurescence, it co-localizes
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 ApoE-epsilon 4.
Casadei, et al. (abstract 286), studied three polymorphisms
related to IL1 metabolism:
IL-1alpha -889 promoter polymorphism
IL-1ß -511 promoter polymorphism
IL1ra intron 2 polymorphism.
IL1alpha polymorphism is associated with EOAD, IL1ß
is less clearly assciated 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.
Comment by R. Tanzi (7 August 1998)
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 6th 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