Alzheimer’s Disease
187
two proteins has also led to the identif-
cation oF a phenotypic diFFerence. Overall,
the mutations in
PS1
result in relatively
early and constant age oF onset while those
in
PS2
lead to a somewhat later and more
variable age oF onset. The identifcation
oF a
PS1
N135I mutation, a position and
substitution that corresponds to the
PS2
Volga German mutation, and the fnding
that the aFFected members oF this pedigree
have a relatively constant age oF onset sug-
gests that the observed variations in age
oF onset are dependent on the molecule
itselF as opposed to the specifc position or
nature oF the amino acid substitution.
2.2
The Genetics of Sporadic Alzheimer’s
Disease
While
the
genetics
oF
±AD
is
Fairly
well understood, our understanding oF
themo
recommonspo
rad
icADrema
ins
much less complete. The majority oF
cases have onset
>
60 years. Some Families
have stronger clustering oF AD cases
than others, suggesting that the genetic
component oF the disease can be quite
variable. The estimated cumulative risk
to frst-degree relatives oF AD-aFFected
probands
approaches
50%
by
age
90
compared to a disease risk oF 10 to 15%
in the general population. To date, only
the Apolipoprotein
E
4(
APOE4
) allele has
been linked to increased risk For sporadic
AD. While it is clear that
APOE
is a major
risk Factor For AD, epidemiological studies
estimate that 42 to 68% oF AD cases
do not have an
APOE4
allele, indicating
that additional genetic and environmental
Factors are involved in this Form oF the
disease. The balance oF these risk Factors
most likely determines both the age oF
onset oF the disease and the number oF
aFFected frst-degree relatives.
2.2.1
Apolipoprotein E
Linkage analysis in late-onset AD pedi-
grees led to the observation that these
Families inherit a genetic risk Factor located
on chromosome 19. The deFect involved in
these particular pedigrees is a susceptibil-
ity deFect as opposed to a causative deFect
such as those present in the gene coding
For APP and the presenilins. The inheri-
tance oF the susceptibility gene deFect alone
is not suFfcient to cause the disease, and
one or more secondary events, either en-
vironmental or genetic, must accompany
the inheritance oF the primary deFect to
cause the disease. Association studies have
shown that the chromosome 19 suscepti-
bility gene (localized to 19q13.2) is within
the
APOE
gene locus.
APOE
protein
is
a
lipid-transport
molecule and the primary apolipoprotein
observed in the CNS. It is encoded by
a polymorphic gene that exists as three
alleles designated
APOE2
,
APOE3
,an
d
APOE4
. These genetic variations result
in amino acid substitutions (arginine or
cysteine) at positions 112 and 158 oF
the protein. Thus, whereas the
APOE2
polypeptide has a cysteine at both oF these
positions,
APOE3
has a cysteine at 112
and an arginine at 158, and
APOE4
has
arginine at both positions. In most Cau-
casian populations, the
APOE3
is the most
common allele (Frequency 0.78);
APOE4
(Frequency 0.14) and
APOE2
(Frequency
0.08) are considered variants.
When the association oF the three com-
mon
APOE
alleles with AD was examined
in late-onset AD pedigrees, it was Found
that the
APOE4
allele Frequency was 52%,
compared to 16% For age-matched con-
trols. In addition, in sporadic AD cases,
the
APOE4
allele Frequency was 40%. The
APOE4
association with AD was rapidly
and widely confrmed in patients with Fa-
milial and sporadic AD. These multiple
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