Brain Research Bulletin 61 (2003) 1–24
Causative and susceptibility genes for Alzheimer’s disease: a review
A. Rocchia, S. Pellegrinib, G. Sicilianoa,∗, L. Murria
aDepartment of Neurosciences, Neurological Clinics, University of Pisa Medical School, Via Roma 67, 56126 Pisa, Italy
bDepartment of Experimental Pathology and Medical Biotechnology, University of Pisa Medical School, 56127 Pisa, Italy
Received 27 June 2002; received in revised form 7 January 2003; accepted 14 January 2003
Alzheimer’s disease (AD) is the most common type of dementia in the elderly population. Three genes have been identified as responsible
2 (PSEN2) gene. Mutations in these genes, however, account for less than 5% of the total number of AD cases. The remaining 95% of AD
patients are mostly sporadic late-onset cases, with a complex aetiology due to interactions between environmental conditions and genetic
features of the individual. In this paper, we review the most important genes supposed to be involved in the pathogenesis of AD, known as
susceptibility genes, in an attempt to provide a comprehensive picture of what is known about the genetic mechanisms underlying the onset
and progression of AD. Hypotheses about the role of each gene in the pathogenic pathway are discussed, taking into account the functions
and molecular features, if known, of the coded protein. A major susceptibility gene, the apolipoprotein E (APOE) gene, found to be associated
with sporadic late-onset AD cases and the only one, whose role in AD has been confirmed in numerous studies, will be included in a specific
chapter. As the results reported by association studies are conflicting, we conclude that a better understanding of the complex aetiology that
underlies AD may be achieved likely through a multidisciplinary approach that combines clinical and neurophysiological characterization of
AD subtypes and in vivo functional brain imaging studies with molecular investigations of genetic components.
© 2003 Elsevier Science Inc. All rights reserved.
Keywords: Amyloid precursor protein; Presenilin; Apolipoprotein E; Genetic risk factors; Association studies; Polymorphism; Dementia
Alzheimer’s disease (AD), originally described by Alois
Alzheimer in 1907, is the most common cause of dementia
in the elderly, clinically characterized by progressive loss of
cognitive abilities. AD usually begins with episodic mem-
ory impairment and encompasses language, visuospatial
and behavioural dysfunction. Based upon neurological ex-
amination, neuropsychological tests and brain imaging, the
accuracy level of in vivo AD diagnosis can be “probable”,
only the post-mortem detection of the two neuropathologi-
cal hallmarks of AD, the senile plaques and the neurofibril-
lary tangles, allowing a definite diagnosis and excluding the
other types of dementia [16,40,171]. AD is usually classi-
fied according to its age of onset. When the disease occurs
before 65 years of age is called early-onset (“presenile”)
AD form, while late-onset (“senile”) AD occurs in subjects
over 65 years of age. Many research findings regarding
∗Corresponding author. Tel.: +39-050-993046; fax: +39-050-554808.
E-mail address: firstname.lastname@example.org (G. Siciliano).
AD suggest that the former type is familial, inherited as an
autosomal dominant trait, whereas the latter is more fre-
quently sporadic, only a minority of these cases showing a
clear family history with autosomal dominant inheritance.
To date, three genes have been identified whose muta-
tions cause the early-onset familial AD (FAD) and show
nearly 100% penetrance with autosomal dominant inheri-
tance. These genes are the amyloid precursor protein (APP),
the presenilin 1 (PSEN1) and the presenilin 2 (PSEN2)
[132,226]. However, cases in which the disease is inherited
as a mendelian trait are only 5% of all cases . There-
fore, most forms of AD have a complex aetiology due to
environmental and genetic factors which taken alone are
not sufficient to develop the disease. The apolipoprotein E
(APOE) gene is recognized as a major risk factor for com-
plex forms of AD, mainly in sporadic late-onset cases. By
genetic linkage analysis using a collection of late-onset AD
families, APOE was identified as a disease locus because of
its localization in the peak linkage region on chromosome
19 . However, only less than 50% of non-familial AD
cases are carriers of the ApoE ε4 allele, the genetic variant
0361-9230/03/$ – see front matter © 2003 Elsevier Science Inc. All rights reserved.
A. Rocchi et al./Brain Research Bulletin 61 (2003) 1–24
Genes involved in early-onset familial Alzheimer disease (bold) and susceptibility genes for AD
Gene nameChromosomal locationOnset Familial and/or sporadicInvolvement in AD
S and F
S and F (?)
S and F
S and F
that predisposes to AD . Therefore, other susceptibility
genes, in which different polymorphisms influence AD risk,
must be involved in the pathogenesis of the disease .
cated in AD (Table 1), only a few are thought to be causative
for the disease. In the majority of sporadic AD cases ge-
netic factors act as predisposing agents, without the force
to induce the disease but able to increase the risk of disease
above that of the general population. They probably inter-
act with environmental factors or with other pathologic or
physiologic conditions to exert their pathogenic effect. They
may also interact between themselves to further enhance
the probability of inducing the disease (synergistic effect).
On the basis of their function, a number of putative genes
are considered possible candidates for association studies.
The typical approach to evaluate genetic contribution to the
risk for AD is analyzing the frequency distribution in cases
and controls of the allelic variants at polymorphic sites of
the candidate genes. Most of these genes are proteolytic
enzymes, plasma proteins, growth factors or membrane re-
ceptors, which may exist as different genetic variants. Some
polymorphic variants have particular properties that could
explain their role as genetic risk factors; for example, when
they are parts of biochemical pathways, which, if altered,
may contribute to the pathogenesis of AD. A lot of these
genes are involved in APP processing and/or in the degrada-
tion and clearance of ?-amyloid peptide (A?) [85,118,146,
As an alternative to the use of the case-control associa-
tion studies, a positional candidate gene approach can be a
useful tool to identify disease loci by whole-genome scans
for linkage when a familial aggregation of cases is evident.
Recent genome scans have implicated several chromosomes
ing of which are chromosome 9, 10, and 12 [69,123,186].
Many positional candidate genes in the peak linkage regions
have been examined for association with AD, but positive
findings have not been consistently confirmed.
We begin this review about genetic of AD from the three
certain genes whose pathogenic mutations, that cause the
rare early-onset familial form of the disease, have been
identified. The main emphasis of the review is on the other
potential genetic risk factors, in which one or more common
polymorphisms allowed an association analysis or whose
chromosomal location suggested a positional candidate
gene approach. APOE, the gene which has been the focus
of most of the studies, is treated in a section apart, because
it is the only confirmed susceptibility factor in early and
late-onset sporadic AD and it plays a principal role in the
mechanism of disease as the large amount of physiological,
biochemical and molecular data indicate.
2. Causative genes of inherited forms of AD
2.1. Amyloid precursor protein gene
Studies on amyloid precursor protein (APP) as genetic
determinant of AD have begun in the middle 1980s with
the observation that individuals with Down’s syndrome in-
variably develop the clinical and neuropathological features
of AD if they live over 30 years [149,150]. These data
pointed to the involvement of chromosome 21 in AD and
supported the theory that overexpression of a gene mapping
on chromosome 21, present in an extra copy in Down’s
syndrome, could produce the AD phenotype . Indeed,
A. Rocchi et al./Brain Research Bulletin 61 (2003) 1–24
the first genetic linkage was discovered between a locus
on chromosome 21q and autosomal dominant early-onset
familial AD . In the same period, other groups local-
ized the gene coding for APP on chromosome 21, which
became the first gene to be candidate as the responsible
of hereditary AD [81,243]. Finally, sequencing of the APP
gene and screening for mutations were carried out and a
number of mutations was detected only in affected subjects,
confirming APP as a disease gene locus [80,94,173].
The APP gene contains 18 exons and gives rise to at least
eight APP protein isoforms by alternative splicing of exons
7, 8, and 15 . The APP isoforms mainly expressed in
than the non-neuronal forms. The longest isoform is a single
transmembrane spanning polypeptide of 770 amino acids,
with a long extracellular N-terminal segment and a short
C-terminal tail . Alternative splicing of exon 7 results
in one polypeptide of 695 amino acids mainly expressed in
the brain, whereas alternative splicing of exon 8 results in
one polypeptide of 751 amino acids expressed in the brain,
but more common in non-neuronal tissues .
The APP undergoes at least two proteolytic cleavages in
all cells. One pathway involves the membrane-associated
?-secretase, which cleaves APP within the A? domain
and secretes the extracellular N-terminal of APP (soluble
APP). This way is not amyloidogenic as APP cleavage pre-
cludes the formation of ?-amyloid peptide . The other
cleavage pathway, occurring in the endosomal–lysosomal
compartment, involves ?-secretase, which cuts between
residues 671 and 672 of the APP, and yields the N-terminus
of A? peptide. In addition, APP can be processed by
a third proteolytic cleavage, the ?-secretase process that
leads to proteolysis in the vicinity of residue 712 giving
the C-terminus of A? peptide. The combination of ?- and
?-secretase activities cause the release of the A? peptide.
The cleavage site of ?-secretase is of critical importance as
it may generate peptides of different lengths: the 40 amino
acid long A? peptide is the most common form usually
produced in the endosomal–lysosomal system by a cleav-
age at residue 712–713, and it is not amyloidogenic. A?
peptides of 42 or 43 amino acids (A?42–43) in length are
generated from a cleavage site after residue 714, and they
are more fibrillogenic and neurotoxic .
The function of APP is still poorly understood. In vitro
studies suggest that secreted APP can function as an au-
tocrine factor by stimulating cell proliferation and cell ad-
hesion and supporting nerve growth factor-induced neurite
outgrowth of PC12 cells [166,220,265]. Other studies have
implied a role for APP in signal transduction  or, in
association with other proteins, e.g. Fe 65, in regulation of
The APP gene mutations are estimated to account for
up to 5% of FAD, with typical age of onset before 65
years. Direct nucleotide sequencing of exon 17 of APP
gene led to the discovery of several missense mutations
in families with early-onset AD. The first mutation from
affected AD individuals was found in a British family
by Goate et al. . The mutation results in a valine to
isoleucine substitution at codon 717 (“London mutation”)
and it is common in several other early-onset AD families.
Different allelic variants at codon 717 have also been re-
vealed by sequencing: Val to Phe, Val to Leu and Val to
Gly [36,175,176], but the most frequent remains Val to Ile
Mutations at codon 670 and 671 were discovered in two
Swedish early-onset AD families, consisting in a double
base pair substitution which results in lysine and methion-
ine being replaced by aspartic acid and leucine (“Swedish
mutation”) immediately before the N-terminal of the A?
The “Flemish mutation” at codon 692 (Ala to Gly),
described by Hendriks et al. , causes an intermediate
phenotype between congophilic angiopathy and AD. Other
pathogenic missense mutations were described at codon 716
, 715 [9,59], 714 , 694 , 693 [109,258], and
665 . This last mutation was found in a subject with
late-onset AD, and it represents the only APP mutation so
far involved in late-onset AD.
The mechanism by which APP missense mutations are
causative for AD is not yet clear. Some of these mutations
might be responsible for an altered metabolism of APP, as
they lie very close to the sites of secretase cleavage flank-
ing A? sequence [59,184,241]. Cell culture studies have
elucidated the effect of some mutations in APP processing.
The Swedish mutation APP 670/671 produces, in trans-
fected fibroblast cell lines compared to the wild type cells,
elevated levels of the soluble A? peptide, which, in normal
conditions, is rapidly cleared [42,105]. Instead, the APP
717 mutations produce more than two-fold of the longer
and more insoluble form of the A? peptide, which rapidly
aggregates to form amyloid depositions . A?42–43
is indicated as neurotoxic and apparently is essential for
initiating the formation of senile plaques .
Some authors have studied the genetic variation in APP
promoter, an essential regulatory element, to find a possible
association with AD. The screening for variants in these reg-
ulatory sequences identified a microsatellite sequence in the
first intron of APP which showed weak association with AD
 and a C → G substitution at position −209 which was
not associated with AD . In a recent study conducted
in a large tri-ethnic population sample, a common +37 G/C
polymorphism and a rare −9 G/C variant were identified in
the core sequences of the proximal APP promoter, but none
of them was likely to contribute to AD susceptibility .
Since most early-onset AD families do not have muta-
tions in the APP gene, it was expected that other AD loci
might exist. In 1992 a locus on the long arm of chromo-
some 14 was detected by linkage analysis and a few years
later a gene, named PSEN1, was identified and isolated
A. Rocchi et al./Brain Research Bulletin 61 (2003) 1–24
by a positional cloning strategy [231,256]. A second gene
was found based on its homology to PSEN1 and mapped
on 1q31–q42 . Mutations in these two genes (PSEN1
and PSEN2) are thought to cause up to 80% of familial
early-onset AD cases. They code for two highly homolo-
gous (67% identity) multi-spanning transmembrane proteins
called presenilins 1 and 2 (PS1 and PS2). Presenilins show
a high degree of conservation between species. Each gene
consists of a total of 13 exons, 10 of which (exons 3–12)
comprise the coding sequence, while the other exons en-
code the untranslated regions [44,206]. PSEN1 and PSEN2
encode, respectively, a 467 and 448 amino acids protein,
primarily localized in the endoplasmic reticulum, Golgi
apparatus and nuclear envelope . The structure of PSs
include eight transmembrane domains and a hydrophilic
intracellular loop region; each PS forms a multisubunit
complex with other proteins under physiological condi-
tions. PS proteins undergo a physiologic endoproteolytic
cleavage to generate stable N- and C-terminal fragments
. In mammalian brain, PSs exist primarily as their
processed fragments. However, the role of this cleavage
event in PSs function remains unclear. Some hypotheses
about PSs function, based on animal models (null PSEN1
mutant), suggest that PSs are involved in developmental
morphogenesis . They also might subserve prote-
olytic processing of specific proteins: there is a growing
evidence that PS1 has ?-secretase activity or at least is a
cofactor for ?-secretase, the enzyme involved in transmem-
brane metabolism of APP and Notch [8,21,86]. In support
of this hypothesis, it has been recently demonstrated that
?-secretase inhibitors bind selectively and specifically to PS
heterodimers . Other studies indicate an important role
of PSs in the regulation of programmed cell death, as for
PS2, whose C-terminal fragment has been shown to inhibit
To date there are more than 120 different mutations
identified in PSEN1 gene (http://molgen-www.uia.ac.be/
ADMutations), while only eight missense mutations have
been identified in PSEN2: one in exon 4 , four in exon
5 [76,126,135,213], two in exon 7 [76,213] and one in exon
In PSEN1 gene most pathogenic mutations are missense
mutations, two are esanucleotide insertions  and one
is a trinucleotide deletion . These mutations are pre-
dominantly located in the highly conserved transmembrane
domains. None of them is a frameshift mutation nor it
causes a protein truncation, suggesting that structural alter-
ations in the presenilins are not compatible with life. Only
two splicing defects have been so far identified: a splice-site
mutation in intron 8 of PS1, resulting in the in-frame dele-
tion of exon 9 plus an amino acid substitution at codon 290
, and the splice donor site mutation in intron 4 of PS1,
resulting in three different transcripts: one with the insertion
of a threonine between codons 113 and 114, and two with
partial or complete deletion of exon 4 [58,214,254]. The
latter two mutations result in a frame-shift and premature
stop codon, but probably the presence of the first type of
transcript is sufficient for life.
The molecular mechanisms by which mutant PS1 exerts
its pathogenic effect are not fully elucidated. Increased
amounts of A? peptides have been observed in cell lines
transfected with mutant PSEN1 . In vivo experiments
have suggested that mutant PS1 proteins influence the
?-secretase-mediated processing of APP at the ?-amyloid
C-terminus, favouring the deposition of long A? [27,277].
Several other studies showed that mutant PS1 increases the
levels of highly fibrillogenic A?42 in endoplasmic reticu-
lum and Golgi compartments . This activity is due to
an apparent gain of function of FAD-linked PS1 protein,
distinct from the normal physiologic role of PS1, consis-
tent with the autosomal dominant pattern of inheritance of
FAD. In addition, none of the PS-interacting proteins have
been shown to play a direct role in the enhanced production
of A?42 mediated by mutant PS1 . The splice-site
mutation in intron 8 of PSEN1 was associated, in four
families, to a form of AD with peculiar neuropathologic
features such as diffuse senile plaques morphologically
different from those usually observed in AD brain .
These plaques do not show amyloid fibrils deposition in
the core and are not associated with surrounding dystrophic
neurites and inflammatory reactions. Such features sug-
gest that ?-amyloid deposition is not the key event in the
pathogenesis of AD, but that the neurotoxic effect of A?42
occurs before its extracellular aggregation, probably by
affecting calcium homeostasis, or by increasing the pro-
duction of free radicals, or by disturbing some intracellular
signalling pathways . These processes are completely
distinct from senile plaques formation and may contribute
to explain the absence of correlation, observed in many
cases, between AD neuropathology and amyloid plaques
The hypothesis that presenilins constitute a novel type of
protease family, and cleave ?APP within the transmembrane
region, remains an issue of debate. Direct proof that they
exert catalytic activity is still lacking. The recent identifi-
cation of additional modulators of ?-secretases like nicas-
trin  indicates that several components are involved.
Nicastrin acts as a key regulator for presenilin-mediated
?-secretase cleavage of ?-APP by forming a functional
complex with PS1 and PS2 [67,106]. Nicastrin was also re-
ported as modulating ?-amyloid production, by binding to
the carboxy-terminal of derivatives of APP . Missense
mutations in a conserved hydrophilic domain of nicastrin
increase A?42 and A?40 peptides secretion, while deletion
in this domain inhibit A? production. Nicastrin and prese-
nilins probably are functional components of a multimeric
complex necessary for the normal function of signalling
pathways through intramembranous proteolysis of precur-
sor proteins such as Notch and APP . Recent works
on the Notch signaling cascade in C. elegans has pointed
out that two other accessories, termed aph-1 and pen-2,
are necessary for ?-secretase activity. Experiments in C.
A. Rocchi et al./Brain Research Bulletin 61 (2003) 1–24
elegans mutants showed that the aph-1 and pen-2 genes
are not only critical for proper Notch pathway function-
ing, but they interact specifically with the presenilin and
nicastrin genes. Human homologous genes of C. elegans
aph-1 and pen-2 map to loci implicated in AD on chromo-
somes 1 and 19 and are broadly expressed, including in the
Several recent studies focused on the direct interaction
between PS1 and the catenin proteins family . Catenins
have at least two distinct cellular functions: they are involved
in cell–cell adhesion mechanisms and they act as signalling
proteins in some transcriptional activation pathways. Cell
cellular large loop of PS1 forming a complex that increases
?-catenin stability . Wild type PS1, as well as mutant
PS1, associates with ?-catenin, but mutant PS1 expression
decreases the stability and/or enhances the degradation
of ?-catenin, thus interfering with the normal metabolic
pathways in which ?-catenin is involved . Moreover,
?-catenin levels are markedly reduced in brains of AD pa-
tients with PSEN1 mutations . Loss of ?-catenin sig-
nalling increases neuronal vulnerability to apoptosis induced
by ?-amyloid protein . Thus, mutations in PSEN1
may increase neuronal apoptosis by altering the stability of
?-catenin, as confirmed by the work of Weihl et al. .
The most recent discoveries about apoptosis in AD
indicate an important role for the cysteine–aspartyl pro-
teases (caspases), which are able to cleave APP and prese-
nilins. Such proteolytic events may occur in pathological
conditions in association with induced cell death. APP
caspase-mediated cleavage occurs at a site distinct from
those processed by secretases, but it represents a general
effect of apoptosis, because it happens during cell death
induced by several stimuli and is not specific of AD .
This apoptosis-associated cleavage of presenilins has a po-
tential role in the pathogenesis of Alzheimer’s disease, since
in cultured cells expressing the asparagine-141 FAD muta-
tion compared to wild-type PS2-expressing cells, the ratio
between alternative and normal PS2 cleavage fragments
is increased . Recently, it has been shown that the
C-terminal fragment of PS2 is phosphorylated in vivo .
Phosphorylation of PS2 inhibits its cleavage by caspase-3,
inducing an anti-apoptotic effect . Alterations in the
PS2 phosphorylation might promote the pathogenesis of
AD by affecting the susceptibility of neurons to apoptotic
stimuli. Similar antiapoptotic effect has also been shown
for PS1, when it undergoes the normal proteolytic pathway.
The caspase cleavage of presenilin C-terminal fragments
seems to inactivate the anti-apoptotic functions of the prese-
nilins and to abrogate the ?-catenin/PS1 interaction .
Mutations in PSEN1 and PSEN2 genes appear to facilitate
the caspase cleavage of presenilins and this may be the
mechanism by which caspases are implicated in the molec-
ular pathology of AD. Finally, it has been reported that APP
cleavage by caspases may contribute to amyloid toxicity
3. Apolipoprotein E
Apolipoprotein E (ApoE) is a plasma glycoprotein with
a molecular mass of 34,200Da synthesized mainly by the
liver, by both neurons and astrocytes in the brain, and also
by other cell types including macrophages and monocytes
. ApoE is involved in the mobilization and redistribu-
tion of cholesterol during neuronal growth and after injury
. It is also involved in many other functions in human
beings, like nerve regeneration, immunoregulation and ac-
tivation of several lipolytic enzymes [148,262]. ApoE con-
tains 299 amino acids, the amino terminal domain (residues
1–191) is a stable globular structure containing the receptor
binding site, while the carboxy-terminal domain (residues
216–299) is helical, less stable, and contains the lipoprotein
binding functions .
A polymorphism of ApoE in human serum was first de-
scribed by Utermann et al. . Further, Zannis et al. 
identified by isoelectric focusing the three major isoforms
of ApoE (ApoE2, ApoE3, and ApoE4) and concluded that a
single locus with three alleles (ε2, ε3, and ε4) is responsible
for this pattern. The ApoE2, ApoE3, and ApoE4 isoforms
differ in amino acid sequence at two sites, residue 112 and
residue 158 (Fig. 1).
The frequencies of the ε2, ε3, and ε4 alleles were esti-
mated at 0.11, 0.72, and 0.17, respectively . Corbo and
Scacchi  analysed the ApoE allele distribution in a va-
riety of populations and found that the ε3 allele is the most
frequent in all human groups. The ε4 allele frequency is
higher in women than in men . The APOE gene was
firstly localized on chromosome 19 because of linkage with
a locus (C3 complement component) known as being on that
chromosome . Genetic mapping was then refined and
APOE assigned to 19q, while C3 locus was localized on the
short arm of chromosome 19 .
Many studies have demonstrated an association between
ε4 allele and late-onset familial and sporadic forms of
Alzheimer’s disease. One of the first and most important of
these studies is that by Corder et al. , who found that the
effect of ε4 allele is “dose-dependent”: the risk for AD in-
creases from 20 to 90% and the mean age of onset decreases
from 84 to 68 years with increasing number of ε4 alleles.
A similar effect of the ε4 allele in early-onset AD families
was observed to be linked to mutations in the APP gene
age of onset could be detected in families with early-onset
AD caused by PSEN1 mutations . The ε4 allele appears
to be a risk factor not as an invariant cause of AD, indicating
Fig. 1. Polymorphisms in ApoE.
A. Rocchi et al./Brain Research Bulletin 61 (2003) 1–24
that other environmental or genetic factors, operating in
combination with the ε4 allele, are necessary to cause AD.
Neuronal regeneration and plastic dendritic remodeling
are severely affected in a number of subcortical areas of AD
patients carrying the ε4 allele . Moreover, the ε4 allele
is strongly associated with increased neuritic plaques and
cerebral amyloid angiopathy in Alzheimer’s disease .
Studies in centenarians revealed that the ε4 allele, which
also promotes premature atherosclerosis, is less frequent in
these individuals than in controls, while the frequency of the
ε2 allele is significantly increased . The ε2 allele has
been shown to have an impact on longevity and may confer
protection against Alzheimer’s disease .
Distinct binding properties of ApoE isoforms to A? pep-
tide  and tau protein  have suggested ways by
which ApoE might mediate its action. In particular, ApoE4
isoform binds to the A? peptide more rapidly than the
ApoE3 isoform. ApoE4 associated with A? peptide forms
ApoE4 does not bind to tau protein in vitro, unlike ApoE2
and ApoE3 . It is possible that the interaction between
ApoE3 and tau protein serves as protection against tau phos-
phorylation and neurofibrillary tangle formation .
4. Candidate susceptibility genes
?2-Macroglobulin (?2M) is a serum pan-protease in-
hibitor, also expressed in the brain, that has been implicated
in AD on the basis of its ability to mediate the clearance
and degradation of A? . ?2M is a component of senile
α2M gene, mapped on chromosome 12p, became a candi-
date as a disease locus for late-onset AD when genetic link-
age was detected in late-onset families for a susceptibility
gene in a region spanning 30cM at the telomeric end of the
short arm of chromosome 12 . Based on the positional
information about the candidate gene, Blacker et al. 
focused on a 5bp deletion/insertion polymorphism of the
α2M gene, located in the 5?splice site of exon 18. By using
a family-based association test method, they found an asso-
ciation between the deletion allele (α2M-D) and late-onset
AD. The observed relation, however, did not appear to
account for the previously published linkage of AD to chro-
mosome 12, which Blacker et al. were unable to detect in
their samples. Subsequently, Alvarez et al.  reported that
α2M-D allele is associated with an increased age-dependent
risk to develop late-onset AD in a sample of patients and
controls from Northern Spain. The allelic association ap-
peared significant only when comparing cases and controls
over 81 years of age. The relation with age was reinforced
since in normal individuals aged over 81 the frequency of
the D allele was the lowest compared to normal individuals
under 65 years and between 65 and 80 years of age.
The association between AD and α2M has been con-
firmed recently by Rudrasingham et al.  and by Dodel
et al. , in a family- and population-based analysis,
respectively, but they did not find any relationship with
patients’ age. In contrast, Dow et al.  and Rogaeva et al.
 failed to confirm such association by comparing cases
and controls from several world-wide populations, but these
two studies were done without stratifying both patients and
controls by age. In agreement with those negative results,
Alvarez et al.  found a non-significant difference in AD
risk when all patients and controls were compared. More
recently, new population-based studies were published in
which α2M deletion/insertion polymorphism was not asso-
ciated with risk of developing AD [79,87,179,234]. Despite
the numerous negative results, the possibility exists that the
α2M deletion polymorphism could be a risk factor only for
familial forms of AD, especially in deletion homozygotes
who were in small excess among AD patients in the study
of Gibson et al. .
If we accept the idea that carrying one or, more likely,
two copies of the α2M-D allele confers an increased risk
to develop AD, then we need to explain how the deletion
may alter the primary structure and function of the protein.
One hypothesis is that the pentanucleotide deletion, being
in close proximity to the splice acceptor site of exon 18,
causes an exon skipping of the α2M mRNA. With a deletion
?2-macroglobulin may be less effective in ?-amyloid bind-
ing and clearance and in preventing its deposition in senile
plaques. Reverse transcription (RT)–PCR of α2M mRNA
extracted from the brains of patients homozygous for the
deletion showed that the putatively deleted exon 18 domain
products from the deletion and insertion homozygotes re-
vealed no alteration in sequence from that expected, despite
the loss of 5bp adjacent to the exon 18. These molecular
findings suggest that α2M deletion might be nonfunctional.
In the coding region of exon 24 of α2M gene, is known
a second polymorphism which determines an amino acidic
substitution (GTC → ATC, Val1000Ile). Liao et al. 
detected an increased risk for AD in carriers of the ho-
mozygous genotype expressing Val despite Ile (G/G). In
combination with ε4, the odds ratio for the association of
G/G genotype with AD increased from 1.77 to 9.68. The
functional implications of this polymorphism are not under-
stood, but we know that it is located close to the active site
of ?2-macroglobulin; moreover, the presence of the G allele
was associated with an increase of A? peptide deposition
in a subset of those cases studied by Liao et al. . How-
ever, following studies did not confirm the positive associa-
tion of Val1000 polymorphism with AD [179,268] although
this polymorphism appeared to be in linkage disequilibrium
with the deletion polymorphism. All these contrasting re-
sults are not resolutive about the role of α2M as a risk factor
for AD. They rather doubt that the locus on chromosome
12 responsible for AD susceptibility corresponds to α2M
and suggest that it could be related to an adjacent gene.
A. Rocchi et al./Brain Research Bulletin 61 (2003) 1–24
4.2. Low density lipoprotein receptor-related
The LRP gene is another good candidate for a potential
association with AD, because of its localization on chromo-
some 12, 50cM apart from ?2M . Moreover, several
observations suggest a potential role for this gene and its
tor expressed in neurons , mediates neurite outgrowth
in an ApoE isoform-dependent manner , is responsible
for the endocytosis of secreted amyloid precursor protein
 and is detected in senile plaques, dystrophic neurites
and reactive astrocytes in AD brain .
Genetic associations between two different LRP polymor-
phisms and AD have been reported. The first polymorphism
is a (TTTC)nrepeat in the 5?-untranslated region of the gene
. Four different alleles have been described to date, cor-
responding to 83, 87, 91, and 95bp PCR products; the 87
and 91bp alleles are the most frequent. Lendon et al. 
reported a significant increase of the 87bp allele in AD cases
in an American population, whereas, in a French population,
Lambert et al.  described the over-representation of the
91bp allele in AD cases, probably because of the different
genetic background between American and French popu-
lations. However, these associations were not confirmed in
other studies [89,161].
The second polymorphism is a silent point substitution
in exon 3, where base 766 is changed from cytosine (C) to
thymine (T) without modifying the amino acid sequence.
Kang et al.  found that the CC genotype was associ-
ated with the risk to develop AD, a finding that was sub-
sequently confirmed by other studies [96,107]. As this is a
neutral variation, the observed association with AD might
only reflect the linkage disequilibrium (LD) between this
polymorphism and a functional variant of the LRP gene.
A novel approach to test the involvement of the LRP gene
in AD was adopted by Verpillat et al.  using haplotype
analysis. Under the hypothesis that a functional variant of
LRP may be in LD with one or both polymorphisms, they
would also be in LD between them, as they are physically
close to each other (“hitchhiking” effect). The separate study
of each polymorphism showed no significant difference in
genotype and allele frequencies between AD cases and con-
trols in a French population, whereas a strong LD was found
considering the alleles of both polymorphisms together. The
two at-risk alleles in the French population, the 91 bp and
C alleles, were negatively associated in controls and posi-
tively associated in AD cases. The frequency of the 91-C
haplotype was higher in AD cases than in controls, although
statistical significance was borderline. On the other side, the
83bp allele was in complete LD with the T allele and there
was no 83-C haplotype.
Haplotype analysis combines information concerning
two or more known polymorphisms in the same candidate
gene by taking into account their dependence. Therefore,
this approach appears to have a greater power than studying
the polymorphisms separately, in order to confirm the ex-
istence of a putative functional variant of a candidate gene.
By assuming that a functional allele is in LD with the poly-
morphisms studied, LD of opposite signs may be observed
in cases and controls, as for the 91bp and C alleles in the
study of Verpillat et al. , and some haplotypes could
be absent as it was the case of the 83-C haplotype.
4.3. LBP-1c/CP2/LSF transcriptional factor
A third possible candidate gene for the association
with AD on chromosome 12, is the transcriptional factor
LBP-1c/CP2/LSF, which lies just 6cM proximal to LRP
and regulates the expression of numerous genes including
Fe65, α2M and IL-1. Recently, an association between a
G/A polymorphism in the 3?-untranslated region of this gene
and sporadic AD in three different populations: French,
British and North Americans have been reported .
The authors found an association between A allele and a
reduced risk of AD suggesting a protective effect of this
allele against the disease. Taylor et al.  replicated this
finding in a series of necropsy confirmed late-onset AD
(LOAD) cases, supporting the hypothesis about a possible
role of LBP-1c/CP2/LSF as LOAD gene on chromosome
12. However, further studies will be necessary to reveal the
real identity of this gene.
4.4. Angiotensin converting enzyme (ACE)
The ACE gene encodes for an enzyme which catalyses
the conversion of angiotensin I to angiotensin II, by cleaving
the two carboxy-terminal amino acids from angiotensin I.
It is also known as dipeptidil-carboxy peptidase-1 (DCP-1).
ACE is widely expressed in the endothelium of cerebral
blood vessels, in neurons of supraoptic and paraventricular
hypothalamic nuclei and in other neurons of basal forebrain
and midbrain, where it contributes to the modulation of pres-
sor response, neurohumoral function and behaviour .
A polymorphism at intron 16 of the ACE gene, consisting
in an insertion/deletion (I/D) of a 287 base pairs sequence,
recently has been found to be associated with AD suscepti-
bility . Indeed, an increased frequency of the insertion
allele was reported among patients with late-onset AD. The
effect of the I allele appears to be dominant, as both the I/I
and I/D genotypes were over-represented in the patients.
The overall odds ratio for AD in carriers of one or two I
alleles was 2.22. These data were confirmed by several in-
dependent studies [4,38,99,182,283]. Two of these studies
[38,283] were done in a cohort of Chinese AD cases and
controls and showed that the ACE-I allele was enriched in
cases compared to controls (odds ratio = 2.09 and 2.88,
respectively). In the Yang’s study  the phenomenon
was restricted to cases presenting AD after the age of 70
years and was independent of APOE genotype. Also Narain
et al.  found no evidence for an interaction between
the APOE and ACE loci; similarly, no interactions were
A. Rocchi et al./Brain Research Bulletin 61 (2003) 1–24
observed between ACE and gender or age at death of the
AD cases. In addition, a meta-analysis of all published re-
ports (12 case-control series in total) suggested that both the
I/I and I/D ACE genotypes are associated with increased
AD risk . Hu et al.  reported a significant asso-
ciation between AD and ACE insertion polymorphism in
the Japanese population, and in a subsequent in vitro study
they demonstrated that ACE inhibits A? aggregation and
supposed that it affects susceptibility to AD by preventing
the accumulation of amyloid plaques . Alvarez et al. 
observed a slightly increased risk for late-onset AD (odds
ratio = 1.28) similar between carriers and non-carriers of
APOE ε4. However, two recent studies reported a nega-
tive association of ACE insertion polymorphism and AD
[74,131], and therefore the supposed role of ACE as risk
factor for AD needs to be further investigated.
The physiological relevance of the ACE I/D polymor-
phism, although still unclear, has been associated with vari-
ations of plasma ACE levels and with the risk of myocardial
infarction . Recent reports sustain the hypothesis of
tight links between vascular and neurodegenerative diseases
and there is a growing evidence that the renin–angiotensin
system plays a part in the pathogenesis of AD . The
involvement of ACE in blood pressure regulation, partly
controlled by angiotensin II through arterial vasoconstric-
tion and increase in aldosterone synthesis could contribute
to this association . Kehoe et al.  suggested that
other functions of ACE, such as its role in the inflammatory
cascade, may be relevant in AD pathogenesis.
4.5. Very low density lipoprotein receptor (VLDL-R)
The VLDL-R gene, located on chromosome 9, expresses
a cell-surface molecule specialized for the internalization
of multiple ligands, including apoE-containing lipoprotein
particles, via clathrin-coated pits . Among the LDL re-
ceptor family, the VLDL receptor, the LDL receptor-related
protein (LRP) and the apoE receptor 2 are preferentially
expressed in the brain . These receptors have been
suspected to be involved in Alzheimer’s disease at various
levels and have been extensively explored in the attempt to
approach the possible mechanisms involved in the APOE
ε4 conferred risk for AD.
VLDL-R is present on resting and activated microglia,
particularly those associated with senile plaques . The
potential of some genetic variants of VLDL-R in influenc-
ing the APOE metabolism in the brain led to investigate
the VLDL-R gene as a potential risk factor for AD. A
polymorphic trinucleotide (CGG) repeat sequence in the
5?-untranslated region, with alleles ranging from four to
nine repeats, was analyzed in many case-control studies.
allele confers an increased risk for AD, which decreases
with age, in subjects with at least one APOE ε4 allele .
The association of the VLDL-R gene polymorphism with
AD, confirmed in the Japanese patients by Yamanaka et al.
, is not commonly observed in patients from other
ethnic backgrounds. This observation was reported by the
same authors, who replicated the association study in a Cau-
casian population without finding any significant difference
between AD cases and controls in allele frequencies of the
CGG repeat polymorphism . Evidence of a negative
association seems to be common in Caucasian Americans,
as also two other independent studies in the same population
failed to detect linkage and/or association between VLDL-R
and AD [132,207]. Stratification by age at onset and APOE
genotype also failed to show significant results. In con-
trast, in a Caucasian population of European origin results
were similar to those from the Japanese study . Among
these patients, the APOE ε4 allele carriers, with at least one
VLDL-R five repeats allele, had a significantly increased
probability to develop AD after 65 years of age .
A case-control study in late-onset AD patients and con-
trol subjects of a relatively homogeneous population from
Northern Ireland, showed that carriers of the nine repeats
homozygous genotype had a higher risk of developing AD
. In contrast to results from the Japanese study, in this
group of patients, the five-repeat allele frequency was found
to be significantly reduced. Negative results of association
have been reported in other recent studies carried out in dif-
ferent populations [37,41,72].
Although the genetic studies conducted in distinct
populations on the CGG repeat polymorphism in the
5?-untranslated region of the VLDL-R gene obtained incon-
sistent results, we could not exclude a possible involvement
of the VLDL receptor in AD. Most recently, 10 novel sin-
gle nucleotide polymorphisms (SNPs) have been identified
in the coding region and 3?-untranslated region of VLDL-R
 providing additional tools to investigate VLDL-R
for genetic association and linkage studies and to explain
the potentially important role of VLDL-R in lipoprotein
metabolism and Alzheimer’s disease.
4.6. Butyrylcholinesterase gene
Genetic studies on butyrylcholinesterase (BChE) in-
volvement in AD are of great relevance because of the
well-known damage of the cholinergic system that is as-
sociated with AD, primarily consisting in neuronal cell
loss in specific areas of cholinergic function . Further-
more, ultrastructural observations showed the colocalization
between cholinesterases and sites of neurofibrillary degen-
eration (tangles) and senile plaques in AD brains [82,83],
whereas biochemical analyses detected reduced acetyl-
cholinesterase and choline-acetyltransferase activities and
increased butyrylcholinesterase activity in the hippocampus
and temporal cortex of Alzheimer patients . Interest-
ingly, after the age of 60, there is a positive correlation
between BChE activity in the brain and increasing age
also in non-demented individuals, in contrast with acetyl-
cholinesterase activity which shows no correlation with
age . These findings, together with other histochemi-
A. Rocchi et al./Brain Research Bulletin 61 (2003) 1–24
cal observations, gave rise to an hypothesis about the role
of BChE in AD: the progressively more extensive BChE
reactivity of plaques may participate in their transforma-
tion from a relatively benign form to pathogenic structures
associated with neuritic degeneration and dementia .
An histochemical study showed that BChE reactivity was
not found in areas with diffuse A? plaques, but was as-
sociated with plaques of compact ?-pleated conformation
, suggesting that the deposition of BChE in senile
plaques follows a close parallelism with the progressive
aggregation of amyloid ?-protein, supporting the possibil-
ity that butyrylcholinesterase may play some roles in the
maturation of these structures. Cholinesterases associated
with the pathological lesions of AD most likely have no-
cholinergic functions in the pathogenesis of AD. The pos-
tulated functions include acting as proteases/peptidases and
participating directly in the amyloidogenic processing of
APP . It has been supposed that BChE may determine
the transformation of A? from a pre-clinical stage of plaque
deposition to an eventually neurotoxic form with the known
pathological effect on brain tissue and mental function .
In order to clarify the functional mechanisms by which
BChE enters in the pathogenesis of AD, genetic studies
were undertaken starting from 1997. Among the numerous
phenotypic variants of BChE, to date only the one known as
the K variant has been analysed in genetic association stud-
ies. The K-variant is characterized by a single nucleotide
substitution (G1615A) resulting in an amino acid change
(Ala to Thr). This mutation reduces the catalytic activity
of the enzyme by one-third . A synergistic effect with
APOE gene has been detected in carriers of the APOE ε4
allele, which causes an increase by 36 times of the AD
risk, when compared with individuals who have neither the
APOE ε4 allele nor the BChE-K allele . The effect of
the K variant on the risk of AD is more evident in the pa-
tients who were older than 75 years at disease onset .
These data suggested that BChE-K, or a nearby gene on
chromosome 3 (BChE is located on 3q26.1), acts in syn-
ergy with APOE ε4 as a susceptibility gene for late-onset
AD. These findings, obtained in Caucasian British white
subjects, have been replicated in investigations in Western
Australian patients , Caucasian Canadians  and
again in Caucasian British subjects . However, most
investigations have failed to confirm the association be-
tween BChE-K and AD [49,129,233]. One of these studies
by Brindle et al.  also ruled out the existence of an an-
other gene nearby on chromosome 3 as a cause of familial
or sporadic AD, after examining the segregation of three
genetic markers on chromosome 3 close to BChE .
Furthermore, to make the role of the K variant of BChE
in AD pathogenesis even more controversial, some studies
have suggested that this variant may have a protective effect
against AD [95,128,129]. Indeed, considered the role that
BChE might have in the maturation of senile plaques and
that the K-variant has a reduced enzymatic activity, the wild
type allele of BChE gene could be expected to be responsible
of increased risk for AD. Mattila et al.  reported find-
ings consistent with this hypothesis in a study conducted
in Finnish subjects; they also confirmed the synergy with
the APOE ε4 allele. Despite the about report by Brindle
et al. , the possibility exists, however, that the BChE
locus is not a susceptibility factor, but it may be in linkage
disequilibrium with other factor/s present in its proximity.
4.7. α1-Antichymotrypsin (ACT) gene
Inflammatory processes are thought to be important
contributors to the pathogenesis of AD and many pro-
teins involved in inflammatory reactions have been found
associated with AD brain lesions . Among them,
?1-antichymotrypsin (ACT), an acute-phase proteinase in-
hibitor of the serpin family (serine protease inhibitors),
has been suggested to be involved in AD by several ob-
servations [1,2,196]. Originally, by the combination of two
approaches, molecular cloning and immunohistochemical
analysis, ?1-antichymotrypsin was identified as one of the
components of senile plaques where it binds to ?-amyloid
with high affinity . An antiserum against isolated AD
amyloid deposits detected immunoreactivity in normal liver
. The anti-amyloid antiserum was then used to screen a
liver cDNA expression library and three related clones were
isolated. DNA sequence analysis showed that these clones
coded for ?1-antichymotrypsin. Antisera against purified
?1-antichymotrypsin were shown to stain Alzheimer amy-
loid deposits . However, one possibility was that ACT
found in plaques could be derived from the high levels of
ACT in the serum of patients. This doubt was resolved by
demonstrating with Northern analysis and in situ hybridiza-
tion with cDNA probes, that ?1-antichymotrypsin mRNA
is also expressed in the brain, and at much higher levels in
AD brains than in control brain . Pathological expres-
sion of ACT occurs particularly in astrocytes from areas
that develop amyloid lesions [2,196].
A specific association between ACT and ?-amyloid was
also shown immunohistochemically: ACT protein was not
detected in the amyloid deposits which contain as their
major component a protein different from the ?-protein,
such as those of Creutzfeldt–Jakob disease or familial amy-
loidotic neuropathy (non-?-protein amyloidoses), but it was
found in Down’s syndrome, normal aging, and hereditary
cerebral haemorrhage with amyloidosis of Dutch origin
. The paper by Das and Potter  was the first one
to show that ACT synthesis is induced, in cultured human
astrocytes, by IL-1, a lymphokine whose expression is
strongly up-regulated in microglial cells from affected areas
of AD brain. Recently, this inflammatory cascade has been
extended to include the APP, because IL-1 also upregulates
the production of APP in astrocytes, but at the translational
rather than at the transcriptional level . IL-1 and ACT
expression by microglia and astrocytes respectively showed
a regional different distribution, because confluent mixed
glial cultures containing both astrocytes and microglia
A. Rocchi et al./Brain Research Bulletin 61 (2003) 1–24
prepared from human cerebellum or brain stem did not
express ACT unless supplemented with exogenous IL-1,
whereas similar glial cultures from human cortex (which
develops amyloid plaques in AD) spontaneously expressed
IL-1 and ACT as they reached confluence . Further-
more, immunoreactivity for these acute phase proteins could
not be detected in the amorphous plaques in the cerebellar
cortex , suggesting that a local inflammatory reaction,
maybe the IL1-induced expression of ACT, may help to
determine the regional specificity of amyloid deposition by
inducing the production of pathological chaperones .
Furthermore, increased levels of ACT are affected by APOE
genotype: AD patients with APOE ε4 allele show increased
levels of ACT and an increased number of diffuse microglia
positive cells .
ACT in senile plaques has the ability to promote aggrega-
or ApoE to the A?-peptide promotes a 10- to 20-fold
increase in filament formation .
different cell types of brain tissue in various neurological
diseases. The pattern of ACT over-expression in AD brain
correlates with activated astrocytes in the typical areas tar-
geted by the neurodegenerative process, and it is positively
regulated by IL-1 which has a similar regional pattern of
expression. In amyloid deposits ACT is found only in as-
sociation with the ?-protein, suggesting a possible role in
the processing of the ?-APP or in the stabilization of the
?-protein amyloid deposits.
Another aspect that has been taken into account is the
usefulness of ACT as a diagnostic marker of AD. Serum
levels of this and other protease inhibitors (?1-antitrypsin
and inter-?-trypsin inhibitor) were measured in AD patients,
and only levels of ?1-antichymotrypsin were significantly
higher in AD patients compared with the control groups
(healthy subjects, patients with vascular dementia, patients
with mixed type dementia, and three groups of patients
concentration of ?1-antichymotrypsin seemed to increase
slightly in advanced stages of the disease. These findings
suggest that serum concentration of ?1-antichymotrypsin
may prove useful as a diagnostic marker of AD [141,156].
As a consequence of these important biochemical find-
ings, molecular genetic studies were undertaken to ascertain
if ACT could give a genetic contribution to AD, and to
discover genetic variants of the protein with functional rele-
vance for understanding the development of AD pathology.
?1-Antichymotrypsin gene is located on chromosome
14q32.1 . It contains a common bi-allelic polymor-
phism, A/T transversion, resulting in either an alanine (Ala)
or a threonine (Thr) at codon 15 in the signal peptide se-
quence of the ACT protein. The alanine allele has been
associated with an increased risk for AD in only APOE ε4
carriers [108,284]. Kamboh et al.  have also identi-
fied a unique combination of the ACT/AA and APOE 4/4
genotypes as a potential susceptibility marker for AD, as its
frequency was 1/17 in the AD group compared with 1/313
in the control general population.
However, the combination of the APOE ε4 allele and the
ACT/AA genotype may simply result in a lower age of on-
set, as suggested by Talbot et al. . They observed that
neither the A nor the T allele showed an increased incidence
among AD patients compared with controls, even when tak-
ing APOE genotype into account. This is in contrast with
the results of the above cited reports and it seems to suggest
that ACT/AA genotype may have an effect only on the risk
for early-onset AD.
To date only a few works have confirmed the association
of AD with the signal peptide polymorphism in ACT gene,
without a full concordance about the interaction with APOE
ε4 allele. In contrast, numerous studies reported negative
findings of association in almost all kinds of populations.
Among these papers it is worthy mentioning the study by
Licastro et al. , who showed a positive association
for ACT T/T genotype and early-onset sporadic AD, inde-
pendently from ApoE genotype. This finding is similar to
that reported by Talbot et al.  for the A/A genotype
and thus it would be of interest to know the functional
properties of the two genetic variants of ACT protein. An
analogue polymorphism within the IL-1beta gene, which
affects plasma levels of IL-1beta, was then analysed and AD
patients with the ACT T/T or IL-1beta T/T genotype showed
the highest levels of plasma ACT or IL-1beta, respectively.
The concomitant presence of these two genotypes increased
the risk for AD and decreased the age at onset of the disease
Other polymorphisms of the ACT gene are currently un-
der investigation. The coding region of the ACT gene was
screened in Han-Chinese population for polymorphisms that
could be associated with AD: seven polymorphic sites in-
cluding 25A → G, 39G → A, 370C → T, 662T → G,
892C → T, 923T → C, and 1332A → G were detected.
The 25A → G was the only one to have been reported pre-
viously, whereas all the others were novel .
In the same Chinese population, a dinucleotide repeat
was examined for allelic association with AD: A6 allele was
negatively associated with AD. However, after stratification
by ApoE genotype, this effect was revealed in non-ApoE ε4
carriers only . On the other hand, the A10 allele of this
microsatellite marker was reported acting as a risk factor for
late-onset AD, in combination with ApoE ε4 .
Another polymorphism (G → T) was also described in
the promoter region of the ACT gene and the T allele was
shown to be associated with a 22% increase in the mean
plasma ACT concentration . By reporter gene studies,
the T allele was found to be consistently associated with
higher mean basal expression both in a human liver cell-line
(32%) and in a human glial cell-line (30%) . The T al-
lele in the promoter region is also in almost complete linkage
disequilibrium with the T allele in the signal peptide region
of the ACT gene. This is the first description of a polymor-
A. Rocchi et al./Brain Research Bulletin 61 (2003) 1–24
phism in the ACT gene directly associated with altered gene
Wang et al.  described other polymorphic sites in the
ACT gene: 76A → G, 241G → A, 250C → T, 324A → G,
G → A in intron 4 and 3?-UTR C → A. Between these
sites, the codon 241A allele and the codon 250T allele were
associated with protective effects against AD, irrespective of
the APOE ε4 status; the codon 324G allele was associated
with a marginal protective effect, whereas the codon 76G
and the intron 4G alleles were associated with a modest
risk of AD. Excepted for the codon 250 and the codon 324
with the signal peptide polymorphism.
In summary, the ACT gene harbours several potentially
important variable sites, which are associated with either
an increased or decreased risk of AD. These non-random
combinations of risk and protective alleles might explain the
contrasting results reported about the role of ACT gene in
4.8. Insulin degrading enzyme (IDE)
Recent papers provide strong evidence for a novel can-
didate gene for AD, the IDE, located on chromosome
10q23–q25 [22,71]. Vekrellis et al.  demonstrated the
central role of IDE in the degradation and clearance of
?-amyloid secreted by microglial cells and neurons; other
authors identified in a whole genome screen a novel sus-
ceptibility locus on chromosome 10q (81cM on the map)
in linkage with late-onset AD, which induces A? deposi-
tion and increases the risk for AD independently of ApoE
genotype [69,177]. However, the gene for IDE maps 30cM
distal to that peak of linkage .
Nonetheless, Bertram et al.  performed genetic link-
age analyses with six genetic short tandem repeat (STR)
markers close to the presumed location of the IDE gene.
Due to the lack of functional polymorphisms in the IDE
gene locus, they adopted a positional approach to the can-
didate gene. In addition, another marker (D10S1225) was
genotyped. It is located 32–47cM proximal to this region
and lies closest to the linkage peak previously identified by
Myers et al. . Genetic linkage in late-onset AD fami-
lies was detected with four markers near IDE locus (between
115 and 127cM) but not with D10S1225. Finally, physical
mapping data showed that IDE and its closest marker lie on
the same bacterial artificial chromosome (GenBank acces-
sion number AL356128).
Overall, these findings indicate an AD gene on the long
arm of chromosome 10, but it remains unclear whether the
two linkage peaks represent an association to one or two
underlying loci. Therefore, more detailed studies of linkage
disequilibrium and assessment of candidate genes will be
Boussaha et al.  found no association between two
intronic SNPs of IDE gene and AD in a case-control study
including 388 French individuals. However, they could not
exclude that a part of the IDE locus was not covered by their
markers and then, that the extent of linkage disequilibrium
blocks may be population dependent. Larger samples would
be required to characterize IDE as such a risk factor.
4.9. Transferrin C2 (Tf C2)
Since 1993 studies have been carried out about transferrin
(Tf), suggested to be a risk factor for AD on the basis of
hypotheses about a causal link between oxidative stress and
The involvement of some genetic variants of Tf in the
pathogenesis of AD would support such hypotheses. The
principal function of Tf is to transport iron in the blood. An
additional function is to prevent free radical reactions by
removing iron from the Fenton reaction, thereby inhibiting
the formation of hydroxyl radicals which are in turn respon-
sible for damage to cell membranes by lipid peroxidation
A variant of transferrin known as Tf C2 was found to be
more frequent in patients with late-onset AD [181,260]. No
association has been detected with vascular dementia ,
and the presence of both transferrin C2 and APOE ε4 alleles
decreases the age at onset of AD.
In contrast with these results, Hussain et al.  found
that the Tf C2 allele was associated with individuals not
carrying the APOE ε4 allele and supposed that any effect of
the C2 allele may be due to a closely linked gene and not
to the Tf gene itself.
At this point, it would be useful to determine the influence
of the Tf gene and surrounding markers, in relation with the
APOE genotype, in a larger AD population.
4.10. Cathepsin D (CatD)
CatD is an intracellular protease with the ability to cleave
APP into amyloidogenic components, as shown by in vitro
experiments . This finding led to the hypothesis that
CatD may be one of the two unidentified proteases (?- and
?-secretases) responsible for the generation of A?. The pro-
teolytic activity of CatD is not only restricted to the cleavage
of APP, but it can also degrade the tau protein to generate
fragments with intact microtubule binding domains. This ac-
tivity could have a role in the pathogenesis of paired helical
A polymorphism in the exon 2 of the catD gene (C → T
transition, Ala → Val at position 224) has been described
. This polymorphism leads to an increased pro-CatD
secretion and altered intracellular maturation. Two studies,
performed in independent samples of AD patients compared
with non-demented controls, have shown a significant over
representation of the T allele of the catD gene, indepen-
dently of the APOE genotype [192,194]. These studies also
suggested an additive effect of the APOE and catD geno-
types on AD risk, because the presence of the APOE ε4 and
the catD T alleles was accompanied by a 10-fold increased
A. Rocchi et al./Brain Research Bulletin 61 (2003) 1–24
risk of AD compared with subjects carrying neither of these
Subsequently, many other authors reported opposite re-
sults. They could not find any association between the
T-allele of the catD gene and AD in different groups of
patients [17,23,25,50,154,160,164], and thus they did not
support a role for the catD gene as a genetic risk factor in
the development of AD.
4.11. Bleomycin hydrolase (BH)
Bleomycin hydrolase, a cysteine protease, is considered
to be a candidate for the ?-secretase, like cathepsin D, be-
ing involved in the secretion of A? peptide . BH gene
consists of 12 exons and it is located on 17q11.1–11.2 .
A single nucleotide polymorphism (A1450G) was identified
of the protein (I443V). The G/G genotype of BH gene was
identified as a significant risk factor for the development
of sporadic AD in subjects not carrying the APOE ε4 al-
lele . The over-representation of the G/G genotype in
AD patients has been confirmed by Papassotiropoulos et al.
, but it was more pronounced in APOE ε4 carriers, even
without interactions between the two risk factors. However,
two previous independent studies had failed to confirm the
association between the BH G/G genotype and AD [73,250].
4.12. Transforming growth factor-β1 (TGF-β1)
Transforming growth factor-?1 is a candidate gene for
AD, located on chromosome 19q13.1–13.3. TGF-?1 is a
cytokine reported to be overexpressed in AD brains ,
that consists of three isoforms, derived from proteolytic
processing of the 390 amino acids precursor. In the ner-
vous system, TGF-?1 has been shown to be, like ApoE, an
important factor in cellular responses to brain injury .
Three SNPs were analysed to investigate the possible
association of TGF-?1 with the risk of AD , two of
them are located in the upstream region of the gene at
position −800 (G → A) and −509 (C → T) from the
transcription starting site, and the third is a missense mu-
tation at codon 263 in exon 5 (Thr → Ile). There was no
statistically significant difference in genotype or allele fre-
quencies distribution between AD cases and controls for the
−800 and codon 263 polymorphisms, whereas the geno-
type distribution at the −509 site was different: the −509
T/T genotype was more represented in AD patients than in
controls. Since the TGF-?1 and APOE genes are located
in close proximity on chromosome 19, it could be possible
that the observed association was due to linkage disequilib-
rium with the APOE ε4 allele. However, when the data were
stratified by the APOE ε4 status, the distribution of the three
polymorphisms was comparable between cases and controls
among both APOE ε4 carriers and non-carriers. More-
over, Araria-Goumidi et al. , in a study conducted in a
larger sample of AD patients, did not find any association
between TGF-?1 polymorphisms and risk of AD. These
latter results are in agreement with recent animal data which
show that an overproduction of TGF-?1 result in a vigor-
ous microglial activation and in a reduction of ? peptide
accumulation in human APP transgenic mice, due to an
enhanced A? clearance .
4.13. 5-HT transporter (5-HTT)
Gene variants of the serotonergic neurotransmitter system
are under discussion as important factors in the pathophys-
iology of AD, because of the changes in this system which
have been observed in AD . A possible association be-
tween AD and a deletion/insertion polymorphism within the
promoter region of the serotonin transporter gene has been
investigated by different independent groups with conflict-
ing results [100,120,136,253]. This polymorphism consists
of a short (S) and a long (L) variant of the 5-HTT promoter,
whereby the short variant exhibits a significantly reduced
transcriptional activity [45,90].
As reported by Hu et al. , AD patients, compared
with a group of non-demented controls, showed a higher
frequency of the S allele and SS genotype. Considering a
possible association between the 5-HTT polymorphism and
the APOE polymorphism, no differences in the frequencies
of 5-HTT alleles and genotypes could be detected between
carriers and non-carriers of the APOE ε4 allele. A reduced
activity of the 5-HTT promoter, due to a higher prevalence
of the SS genotype among AD patients, could contribute
to explain some of the symptoms observed in AD patients,
such as depression. It could also be responsible for certain
serotonin receptor changes and the decreased number of
5-HTT sites in the dorsal raphe nucleus, hippocampus and
enthorinal cortex observed in AD patients [53,245].
Kunugi et al. , however, in contrast with the results
by Hu et al. , were not be able to find a different
frequency of 5-HTT promoter polymorphism in a group of
Japanese AD patients and controls, but this could be due
exclusively to the different genetic background of the two
populations. Further studies in other populations will be nec-
essary to assess the role of 5-HTT promoter polymorphism
4.14. Apolipoprotein E promoter polymorphisms
Because ApoE has a critical importance in the mainte-
nance of the central nervous system integrity and because it
is associated with AD as a strong risk factor, any variation
in ApoE structure or function might be a susceptibility fac-
tor to neurodegeneration of AD type. Genetic variants of the
APOE coding sequence are the most studied; however, ex-
pression regulatory regions of the APOE gene recently have
attracted an increasing interest.
The first report about the presence of polymorphisms in
the regulatory region of APOE was made by Mui et al.
, who described a biallelic polymorphism in the intron
A. Rocchi et al./Brain Research Bulletin 61 (2003) 1–24
1 enhancer element of the APOE proximal promoter (+113
G/C). In the same study, this polymorphism was also de-
scribed as being in strong linkage disequilibrium with the
APOE ε4 allele. This observation could explain the reported
weak association between this polymorphism and AD. In
 found a significant association between the +113 C
allele and the risk for AD independently from the APOE ε4
allele status. Subsequently, three other SNPs were detected
in the proximal promoter: −491 A/T, −427 T/C, and −219
have the potential for affecting the binding of transcription
factors to the APOE promoter. If this is true, they would be
functional polymorphisms and they could influence the sus-
ceptibility to AD by regulating the ApoE expression level.
Many studies have been carried out to test if there are dif-
ferences in the transcriptional activity of the APOE gene.
−491A, −427C and −219G alleles have been described
as promoting a higher transcriptional activity than −491T,
−427T and −219T, respectively [13,127]; +113 G/C has
not been yet analysed from a functional perspective.
Bullido et al.  found an increased risk for AD in
individuals homozygous for the −491A allele of APOE
promoter, indicating that the risk for AD positively corre-
lates with the transcriptional activity of the APOE gene.
Surprisingly, the risk was most prominent in those patients
not carrying the APOE ε4 allele, but this observation led to
exclude that the association was due to a linkage disequi-
librium. Alvarez-Arcaya et al.  were not able to find an
association between −491A allele and the risk for AD, but
they reported that persons homozygous for the T allele had
a significantly reduced risk of AD (P = 0.006).
In the last years, conflicting results have been obtained in
the attempt to confirm the association between the −491A
polymorphism and AD [93,216,250,292]. A small number
of studies are available about the −219 T/G polymorphism
and they are not in agreement with each other [125,210].
Recently, Lambert et al.  reported that the role of the
−491A polymorphism in the AD risk was completely inde-
pendent from the APOE ε4 allele status, whereas the role of
the −219T polymorphism was independent only in the old-
est people, suggesting for the first time an age accentuated
In summary, functional data indicate the relevance of
ApoE expression on the risk for AD, whereas association
data are still not conclusive to determine the role of each
4.15. Nitric oxide synthase (NOS3)
Another one of the several candidate genes proposed as
susceptibility factors for AD is the endothelial nitric oxide
synthase (NOS3), located on chromosome 7q35 . The
NOS3 endothelial product (eNOS) has a high concentration
in hippocampal pyramidal neurons, one of the principal sites
of AD pathology . Moreover, nitric oxide (NO) produc-
tion by microglial cells, astrocytes and brain endothelium is
enhanced in AD patients because of a strikingly increased
expression of eNOS . In addition, ?-amyloid peptide has
been reported to stimulate NO production in astrocytes and
microglial cells . Finally, there is a growing evidence that
NO is involved in neuronal death in AD and that the ox-
idative stress caused by increased NO synthesis in the brain
could be a pathogenetic mechanism for AD .
Dahiyat et al.  hypothesized that polymorphic
variants in the NOS3 gene might facilitate degenerative
changes deriving from an interaction between ?-amyloid
and endothelial cells. A common structural polymorphism,
Glu/Asp, at codon 298 of NOS3 has been analysed and the
homozygous Glu 298 genotype has been found significantly
over-represented in late-onset AD (LOAD) patients com-
pared with control individuals. A similar but non-significant
trend was present in early-onset AD. These data suggest that
NOS3 Glu/Glu 298 homozygous genotype might be a risk
factor for LOAD. It is not easy to explain how a conserva-
tive amino acid change (Glu/Asp) could be able to modify
the structure and the function of the protein. Endothelial
NOS3 exists mainly as a membrane bound enzyme (90%)
and in a minor part as a cytosolic enzyme (10%), and an
hypothesis could be that the variation influences the ability
of the protein to bind itself to the membrane. Another pos-
sibility is that the variation simply could be associated with
another unknown pathological locus.
4.16. Cystatin C (CST3)
Cystatin C is an extracellular inhibitor of cysteine pro-
teases secreted by monocytes/macrophages . Immuno-
histochemical studies have demonstrated the colocalization
of the ?-amyloid protein and cystatin C within arteriolar
walls in the AD brain . Cystatin C peptides acquire
amyloidogenic properties when a mutation at position 68
(L68Q) of the protein is present . The mutant protein
forms dimers of greater stability than wild type protein, re-
sulting in reduced secretion and intracellular accumulation.
This mutation leads to one of the familial cerebral amyloid
angiopathies, Hereditary Cerebral Hemorrhage with amy-
loidosis type 1, characterized by a form of amyloidosis,
restricted to the small vasculature of the brain, in which
cystatin C deposition causes the progressive loss of smooth
muscle cells and microvascular degeneration with cerebral
haemorrhage . The pathogenic mechanism is related
likely to the altered secretion of cystatin C observed in vitro
and to the reduced rate of its synthesis observed in cultured
monocytes derived from patients who carry the mutation.
The biochemical similarities between cerebral amyloidosis
angiopathy and AD, and the colocalization of A? and cys-
tatin C indicate the CST3 gene as an interesting candidate
for further investigation.
The approach used to evaluate the genetic contribution of
CST3 to the risk of AD is a typical case-control study. CST3
known polymorphisms are located in the 5?flanking region
A. Rocchi et al./Brain Research Bulletin 61 (2003) 1–24
(−157 G/C) and in the exon 1 (+73 G/A, Ala → Thr). The
allelic association of these polymorphisms with late-onset
AD has been reported in Americans by Finckh et al.  and
in Caucasians by Crawford et al.  and Beyer et al. .
In this latter study the G/G genotype related to the poly-
morphism in the exon 1 was described as an age-dependent
risk factor for late-onset AD, as the risk increased only in
the group over 80 years of age. In contrast, in the control
group the G/G genotype frequency decreased after 80 years
of age. To date no functional effect of the cystatin C exon 1
polymorphism has been reported. Given its location in the
penultimate amino acid of the signal peptide, it could be
possible that this polymorphism modifies the secretory pro-
cessing pathway for cystatin C.
However, a study conducted in a Japanese population
 failed to detect any association between either poly-
morphisms and AD, indicating that also for this gene further
studies are necessary to understand better its implications in
4.17. Presenilin 1 promoter polymorphisms
The role of genetic variations of PSEN1 in complex forms
of AD is unclear. Despite an initial observation of an associ-
ation between a SNP in the intron 8 of PSEN1 and late-onset
AD , subsequent studies did not confirm the associ-
ation in late or early-onset AD and no functional role has
been ascribed to this polymorphism . To explain these
conflicting results, it has been suggested that the disease
associated allele might be in linkage disequilibrium with a
functional variant elsewhere in the gene .
The −48 C/T polymorphism in the PSEN1 gene pro-
moter is a possible candidate for linkage and it has recently
been associated with an increased risk for early-onset AD
in a population-based sample [247,259]. Because PS1
pathogenic mutations affect APP metabolism increasing
A? deposition in senile plaques, Lambert et al. 
have hypothesized that this promoter polymorphism might
also modulate A? load in AD brains causing a differen-
tial PSEN1 gene expression. In immunohistochemically
stained sections from frozen brain tissues of AD cases they
quantified the proportion of tissue area occupied by A?40,
A?42(43)and total A?. All the three measures of A? load
were significantly increased in −48 CC carriers.
Lambert et al.  also found a significant difference
for the alleles distribution between the AD and control pop-
ulation, confirming previous results [247,259]. The −48 CC
genotype was associated with an increased risk for AD. The
effect of this polymorphism was similar whether familial
or sporadic cases were analysed separately. These effects
appeared to be independent of the APOE ε4 allele and no
interaction with age or sex was detected. Interestingly, the
−48 CC genotype had a stronger effect in early-onset AD
cases compared to late-onset cases, as the dominant AD mu-
tations in the PSEN1 gene do. Thus, the −48 CC polymor-
phism may have a major relevance in earlier onset forms of
AD, as suggested also by the lack of association in another
late-onset cohort of cases reported by Dermaut et al. 
and Araria-Goumidi et al. .
5. Concluding remarks
In the last decade the use of molecular genetics strategies
has allowed investigators to examine a variety of putative
susceptibility genes for AD on the basis of their chromo-
somal localization (positional studies) or their function
(candidate genes studies). The role of none of these ex-
amined genes, however, resulted as strong and widespread
confirmed in determining AD pathogenesis as the role of
the APOE polymorphism. Nevertheless, considering that as
many as 50% of sporadic AD cases do not possess the ε4
allele of APOE gene, that many early-onset AD cases are
not explained by mutations in APP or presenilins genes and
that late-onset AD cases have a complex aetiology surely
due to more than one single gene alteration, the hypothesis
that other genetic loci might be involved in AD remains a
valid issue. The abundance of contrasting results reported
by association studies is probably caused by the fact that
the published studies tend to consider only a small num-
ber of sequence variations in candidate disease genes in a
much too limited number of DNA samples. Only a few of
the detected disease associations could be replicated when
retested with independent clinical materials , so one
of the principal doubts is whether these findings can be
generalized to other populations with different genetic and
environmental risk profiles. In fact, both bias and genuine
population diversity might explain why association studies
often tend to overestimate the disease protection or predis-
position conferred by a genetic polymorphism. One possi-
bility for overcoming these difficulties is offered by the new
developing high-throughput molecular technologies. SNPs
genotyping of patients by using microarray platforms, for
example, permits to examine hundreds of polymorphisms
in many DNA samples at the same time, allowing to obtain
a great amount of data that can be compared directly. On
the other hand, a systematic meta-analytic approach may
provide a quantitative method for combining the results of
various studies on the same topic and for estimating and
explaining their diversity. Finally, a better understanding of
the complex aetiology that underlies AD may be achieved
likely through a multidisciplinary approach that combines
clinical and neurophysiological characterization of AD sub-
types and in vivo functional brain imaging studies 
with molecular investigations of genetic components.
This work was supported in part by the Italian COFIN-
MIUR Program (2000) and by the Alzheimer Project funded
by the Italian Minister of Health (2000).
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