188
Alzheimer’s Disease
confrmations established the
APOE4
al-
lele as the most important genetic marker
oF risk For the disease identifed so Far, ac-
counting For approximately 50% oF the ge-
netic component oF AD. The Frequency oF
APOE4
allele among AD and control cases
can vary in diFFerent populations, however,
the association with AD is consistent.
Individuals inheriting two copies oF
the
APOE4
allele
have
an
increased
risk and
earlier age oF onset oF AD
than individuals with one
APOE4
allele.
Likewise, individuals with one
APOE4
allele have a greater risk and earlier onset
oF disease than those with no
APOE4
alleles. These data demonstrate that the
eFFect oF
APOE4
on risk and age oF onset
is dose-related. In contrast to the eFFect
oF
APOE4
allele, the
APOE2
allele has
a protective eFFect on AD, as evidenced
by a decreased Frequency oF this allele
in AD cases. The eFFect oF the most
commonly inherited allele,
APOE3
,onrisk
and age oF onset Falls between
APOE4
and
APOE2
. There also appears to be
an interaction oF
APOE
genotypes with
the age oF onset in ±AD. When survival
analysis was used in a large Colombian
kindred carrying a presenilin mutation, the
presence oF an
APOE4
allele was observed
to decrease age oF onset, while presence
oF an
APOE2
allele increased age oF onset.
Although it is still not clear how an
APOE4
allele modifes risk For AD, several studies
suggest that APOE may act via an A
β
-
dependent mechanism.
2.2.2
The Search for New Alzheimer’s
Disease Susceptibility Genes
There are two genetic approaches to fnd-
ing susceptibility loci: Full genome scans
and candidate gene studies. In candidate
gene studies, genes are selected on the
basis oF the known biology oF the dis-
ease or their location within chromosomal
regions implicated in risk For late-onset
AD, and are assessed individually in or-
der to determine whether variants in each
candidate are associated with disease. An
alternative approach, a genome scan, does
not select genes
apr
ior
i
, but instead tests
For linkage or association between the dis-
ease and polymorphic markers that are
spaced evenly through the genome. Asso-
ciation methods use unrelated case-control
samples or siblings who are discordant
For disease, and test For diFFerences in
allele Frequencies between aFFected and
unaFFected individuals. In contrast, linkage
studies use extended Families or aFFected
sibling pairs and look For regions oF the
genome in which there is an increased
allele sharing between aFFected relatives.
To date, only fve late-onset AD genome-
wide screens have been reported. The most
consistent fndings among these studies
are evidences For AD susceptibility loci
on chromosomes 19 (
APOE
), 9, 10, and
12. Since ±AD is closely associated with
elevated A
β
42 levels, some investigators
have hypothesized that loci, which mod-
iFy plasma A
β
42, might also modiFy risk
For AD. Using this approach, evidence
For linkage was observed in the same re-
gion oF chromosome 10 as was observed
in the AD-linkage studies. Over the past
Few years, a large number oF biologically
interestingcandidategenesaswellascan-
didate genes that map within chromosome
regions implicated in risk For late-onset
AD have been evaluated in case-control
populations. The genes that have received
most attention are those encoding
APOE
on chromosome 19,
α
2-macroglobulin and
the LDL-receptor related protein on chro-
mosome 12 and insulin degrading enzyme
and urokinase on chromosome 10. All oF
these genes have been closely linked to A
β
metabolism. However, with the exception
oF the
APOE
gene, whose association with
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