184
Alzheimer’s Disease
neurotransmission pathways in the brain,
producing dementia.
2
The Genetics of Alzheimer’s Disease
There are two forms of AD: familial
Alzheimer’s disease (FAD), in which the
d
i
s
e
a
s
ei
st
r
an
sm
i
t
t
e
da
sanau
t
o
s
om
a
l
dominant trait; and sporadic AD, which
shows
modest
familial
clustering
and
probably results from the synergistic ac-
tion of genetic and environmental factors.
Sporadic AD can have an early (
<
60 yrs)
or late (
>
60 yrs) age of onset. FAD does
not appear to be clinically or neuropatho-
logically different from the more common
sporadic form of AD, except that it gener-
ally has an earlier age of onset.
2.1
The Genetics of Familial Alzheimer’s
Disease
The existence of families in which AD
segregates as a fully penetrant, autosomal,
dominant trait presents the most striking
evidence for the involvement of genetic
factors in the etiology of AD. Mutations in
three distinct genes,
β
-amyloid precursor
protein (APP),
PS1
(presenilin 1) and
PS2
(presenilin 2) have been identi±ed
to cause FAD.
2.1.1
β
-amyloid Precursor Protein
Mutations
The main component of the AD-associated
senile plaques, A
β
, is derived by the
proteolytic processing of APP. The gene
coding for APP is located on the long
arm of chromosome 21. It contains 18
exons, three of which can be alternatively
spliced to produce a variety of mRNA
species.
The ±rst mutation shown to cause FAD
was a valine to isoleucine substitution at
residue 717 of APP (Fig. 2). To date, 22
APP mutations have been reported, of
which 17 are linked to early-onset AD
(www.alzforum.org). Most mutations lie
within the transmembrane (TM) domain
of APP in the region that is involved
in the generation of the C-terminal end
of A
β
. All TM domain FAD-APP muta-
tions result in an increased production
of the longer, more amyloidogenic form
of A
β
(A
β
42/43). The most severe muta-
tion (T714I) causes a 11-fold increase in
the A
β
42/A
β
40 ratio; it causes both a de-
crease in A
β
40 and an increase in A
β
42
production. Patients carrying the T714I
FAD-APP mutation die in their 40s. FAD
mutations in APP can differentially affect
A
β
-peptide formation by either increas-
ing A
β
42 or decreasing A
β
40, or both.
The Swedish mutation (K670N, M671L)
lies in the region outside of the TM do-
main in which cleavage by
β
-secretase
generates the N-terminal end of the A
β
,
resulting in an increase in both A
β
40
and A
β
42 levels. Five mutations are lo-
cated within the A
β
sequence but outside
the TM domain: Flemish (A692G), Dutch
(E693Q), Arctic (E693G), Italian (E693K),
and Iowa (D694N). Patients carrying these
mutations deposit A
β
in senile plaques
and/or in cerebral vascular walls (cerebral
amyloid angiopathy – CAA) and present
clinically with either AD or hemorrhagic
strokes, or both. For example, Flemish
A692G patients present with both AD and
strokes, while most Dutch E693Q patients
suffer from strokes followed by a progres-
sive multi-infarct dementia (HCHWA-D,
hereditary cerebral hemorrhage with amy-
loidosis Dutch type). Pathologically, Flem-
ish A692G patients demonstrate a classical
AD pathology although with a strong CAA
component, while Dutch APP patients
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