Minireview
Vol. 266, No. 31, Issue of November 5, pp. 20579-20582, 1991
Molecular Genetics of Alzheimer
Disease Amyloid*
Rudolph E. Tanzi:!:,Peter St. George-Hyslop§, and
JamesF. Gusella
From the Molecular Neurogenetics Laboratory,
Massachusetts General Hospital, Department of Genetics,
Harvard Medical School, Charlestown, Massachusetts
02129
Alzheimer disease is a late onset neurodegenerative disorder
characterized by global cognitive decline. Definitive diagnosis
of Alzheimer disease requires either the autopsy or biopsy
confirmation of specific lesions formed by insoluble protein
aceous fibers in the brain: extracellular deposits of amyloid
in senile plaques and cerebral blood vessels, and intracellular
neurofibrillary tangles in the cytoplasm of neurons (1, 2).
Although intracellular amyloid has been observed in intimate
association with neurofibrillary tangles, the relationship be
tween tangles and senile plaques remains unclear (3).
The etiology of Alzheimer disease is unknown. Although
most cases appear sporadic, epidemiological surveys have
demonstrated an increased risk in first- and second-degree
relatives of Alzheimer disease patients (4-10). A small pro
portion of Alzheimer disease cases occur in families displaying
autosomal dominant inheritance of the disorder. In these
instances, termed familial Alzheimer disease, the disease
seems to be triggered by a genetic defect (Fig. 1). Considerable
controversy surrounds the question of what proportion of
Alzheimer disease is familial (5-100% (7,10», in part because
it is often difficult to assess whether familial aggregation of
Alzheimer disease in late onset pedigrees reflects genetic
inheritance, predisposition, or clustering of a sporadic form
of Alzheimer disease resulting from an environmental origin
or ascertainment bias. Most cases of Alzheimer disease display
onset beyond the age of 65, but in the largest familial Alz
heimer disease kindreds the disorder appears earlier in life
(age 40-50). Familial Alzheimer disease is otherwise clinically
and neuropathologically indistinguishable from cases with
later onset.
Genetic Linkage Studies of Familial
Alzheimer Disease
In addition to Alzheimer disease, senile plaques and neu
rofibrillary tangles are also found in older (over 35 years)
patients with Down syndrome (trisomy 21 (2, 11». Conse
quently, chromosome 21 became one of the first targets of
genetic linkage studies aimed at localizing the familial Alz
heimer disease gene defect. This approach requires tracing
the inheritance of polymorphic genetic markers in families
with the disorder. The advent of recombinant DNA technol-
* Alzheimer disease and chromosome 21-related investigations in
our laboratories are supported by grants from the American Health
Assistance Foundation, the Metropolitan Life Foundation, the Alz
heimer's Association (Mrs. Frank L. Harrington pilot research grant),
and National Institutes of Health Grant HG00317.
:j: Recipient of a French Foundation fellowship.
§ Present address: Tanz Neuroscience Bldg., University of To
ronto, 6 Queen's Park Crescent, Toronto, Ontario M5S lAB, Canada.
20579
THE JOURNAL OF BIOLOGICAL CHEMISTRY
© 1991 by The American Society for Biochemistry and Molecular Biology, Inc.
Printed in U.S.A.
ogy has allowed the direct detection of DNA sequence differ
ences. These may often be assayed as restriction fragment
length polymorphisms and provide an abundant source of
DNA markers. If a genetic marker is located close to a disease
gene on a given chromosome, the two will show a correlated
pattern of inheritance, with a particular marker allele segre
gating (or showing "linkage") with the disorder in an individ
ual family. The significance of an observed pattern of corre
lated inheritance is assessed by "maximum likelihood analy
sis" to calculate a "log of the odds" (LOD)l score. The LOD
score represents loglo of the likelihood of linkage relative to
the likelihood of random segregation for a given data set. An
LOD score in excess of +3 (1,000:1 odds in favor of linkage)
is considered as proof that the genetic marker and the gene
defect reside on the same chromosome and are linked.
In 1987, two DNA markers on the proximal long arm (q
arm) of chromosome 21, D21S16 and D21S1/D21S11, were
found to display genetic linkage to the disorder in a study of
four large familial Alzheimer disease pedigrees exhibiting an
early age of onset «65 years (12». An example of one of
these pedigrees is shown in Fig. 1. Concurrently, the principal
component of Alzheimer's associated amyloid, flA4, a 42-
amino acid peptide, was found to derive from a larger protein
precursor (the amyloid fl protein precursor, APP) encoded by
a gene (APP) on chromosome 21q (13-16). However, when
the APP gene was directly tested for genetic linkage with
familial Alzheimer disease, several recombinants between
APP and familial Alzheimer disease were observed (17, 18),
suggesting that it was not the site of the primary genetic
defect in familial Alzheimer disease.
Following these reports, several groups endeavored to test
the same chromosome 21 DNA markers in additional familial
Alzheimer disease kindreds. Goate et al. (19) obtained evi
dence supporting the presence of a familial Alzheimer disease
gene defect centromeric to the markers, D21S1/S11 and
D21S16. Another group was able to detect probable linkage
between familial Alzheimer disease and another centromeric
marker, D21S13 (20), closely linked to D21S16. These results
provided further support for the initial finding of a familial
Alzheimer disease gene defect on 21q. On the other hand,
Schellenberg et at. (21) reported the possibility of non-allelic
heterogeneity based on the exclusion of familial Alzheimer
disease from the D21S1/D21S11 region in a set of pedigrees
of predominantly Volga German descent. Pericak-Vance et at.
(22) suggested the possibility of a second familial Alzheimer
disease locus based on the lack of linkage between D21S1/
D21S11 and familial Alzheimer disease in pedigrees mani
festing a relatively late age-of-onset, although an early onset
familial Alzheimer disease pedigree displayed positive linkage
to D21S1/D21S11 and D21S16 in the same study.
An impressive international collaborative effort was
mounted to type 48 familial Alzheimer disease pedigrees for
five DNA polymorphisms at three loci from the proximal half
of chromosome 21q (23). D21S1/D21S11 and D21S16/
D21S13 both gave LOD score values for linkage to familial
Alzheimer disease that were greater than 3.0 supporting the
original finding of linkage to chromosome 21. In addition, the
I The abbreviations used are: LOD, log of the odds; APP, amyloid
f3 protein precursor; KPI, Kunitz protease inhibitor.
20580 Minireview: Molecular Genetics of Alzheimer Disease Amyloid
the defect. Accordingly, a major focus in studies of familial
Alzheimer disease has been the locus encoding the protein
precursor (APP) of the 4.2-kDa peptide, fJA4, which is the
chief component of amyloid in senile plaques and cerebrovas
cular deposits (2). APP mRNA can be alternatively spliced
into three principal transcripts named according to the num
ber of amino acids they encode. The original full-length APP
gene isolated, APP695, is expressed exclusively in the brain
(14, 16) while two larger forms, APP751 and APP770, are
also expressed in peripheral tissues (26, 27). APP751 and
APP770 contain a 56-amino acid domain that interrupts
residue 289 of APP695 (26-28). This domain represents a
Kunitz-type serine protease inhibitor.
APP is an integral membrane-bound protein (14) with the
Kunitz protease inhibitor (KPI) domain located in the large
extracellular portion of the molecule (Fig. 2). While one-third
of the fJA4 domain resides in the transmembrane region of
the molecule, the remaining two-thirds is situated in the
FIG. 1. The Italian familial Alzheimer disease kindred
(FAD4 (12)) and APP genotypes indicating an apparent re extracellular space. The extracellular portion of APP is both
combination event between APP and the familial Alzheimer 0- and N-glycosylated and can be cleaved for release into the
disease gene defect. Affected individuals are shown in red while extracellular space as a large soluble protein (110 kDa) (29,
those without the Alzheimer disease phenotype are shown in blue. 30). The secreted form of APP containing the KPI domain is
Slashed symbols indicate individuals who are deceased. The APP identical to the serine protease inhibitor, protease nexin II
genotypes are shown under each individual for whom DNA is avail (31, 32). Protease nexin II inhibits Factor XIa of the coagu
able for typing. The APP alleles represent a combination of two
EcoRI RFLPs detected by the APP cDNAs, FB68L and HL124 (17). lation pathway, chymotrypsin, and the kallikreins, 7 S nerve
Where the phase of the disease gene with respect to the APP RFLP growth factor 'Y-subunit and epidermal growth factor-binding
can be determined unequivocally, the allele of the marker segregating protein. In peripheral cell cultures, the secreted soluble deriv
with the defect is shown in red. A single apparent recombination atives of APP contain only a portion of the fJA4 peptide while
event is revealed by comparing the four-member sibship of Branch I, the remainder is contained in a membrane-bound C-terminal
generation VI, with the four-member sibship of Branch II, generation fragment (33, 34). Thus, normal processing of APP destroys
V. In the former, the "B" allele of APP is present on the familial
Alzheimer disease chromosome while in the latter the "C" allele of
the integrity of the fJA4 domain, presumably precluding amy
APP is detected. Although the relative phase of the defect and the loid formation and raising the possibility that the generation
APP alleles cannot be assigned with certainty in the other affected of fJA4 and amyloidosis may be the consequence of abnormal
members of each branch, the crossover event +probably occurred in processing of APP.
the multiple generations separating the two branches of the pedigree. The APP gene maps to chromosome 21 at the border of
cytogenetic bands 21q21.3 and 21q22 (35). Consequently, the
Affected Pedigree Member method (24), which examines the presence of fJA4 amyloid deposits in the brains of patients
frequency with which affected family members "share" alleles
of a specific polymorphisms, confirmed the linkage results by
demonstrating a significant association between familial Alz
heimer disease and the three chromosome 21 loci.
This study also revealed that only a subset of the 48
pedigrees contributed positively to the overall data set and
demonstrated that familial Alzheimer disease is genetically
heterogeneous. While some pedigrees with early onset «65
years) displayed positive linkage with chromosome 21, late
onset pedigrees were unlinked. Multipoint analysis aimed at
localizing the gene defect relative to the two linked loci yielded
peak LOD scores of approximately 5.0 for the early onset
pedigrees in two distinct regions of chromosome 21, one
proximal to D21S16/D21S13 (the centromeric region) and
the other distal to D21S1/D21S11 (the APP region). The
presence of two multipoint peaks suggests the possibility that
the genetic defects in different chromosome 21-linked familial
Alzheimer disease kindreds could be at distinct locations on
chromosome 21. However, it could also be due to the con
founding effect that would be caused if a portion of the early FIG. 2. Schematic representation of APP and the mutations
onset pedigrees are, in fact, not linked to chromosome 21. found in the portion of the molecule encoded by exon 17. The
The confirmed existence of non-allelic genetic heterogeneity extracellular portion of the molecule contains a signal peptide (shown
in familial Alzheimer disease has prompted further scanning in white, but actually removed during insertion into the membrane),
of the genome for additional familial Alzheimer disease loci. a cysteine-rich region, an acidic region, and a large glycosylated
To date, a locus on chromosome 19 has been suggested as a region. Between the two latter segments are two domains: encoded
possible predisposing or causative factor in late onset Alz by alternatively spliced exons, the KPI domain and OX-2. The
extracellular portion of APP contains roughly two-thirds of the {3A4
heimer disease, but this remains to be confirmed (25).
region. The remainder of {3A4resides within the membrane-spanning
The Amyloid fJ Peptide Precursor domain; the C-terminal portion of APP is cytoplasmic. The mutations
at positions 693 and 717 (of APP770) represent putative sites for the
An examination of the pathological profile of a genetic defects in HCHWA-D and in an inherited form of Alzheimer disease,
disease can potentially lead to candidate genes for the site of respectively.
 Minireview: Molecular Genetics of Alzheimer Disease Amyloid 20581
It has been suggested that the slightly more hydrophobic
with Down syndrome (trisomy 21) might be most easily ex isoleucine residue replacing the valine at position 717 may
plained by gene dosage. With the exception of one
preliminary and apparently premature report (36),
increased APP gene dosage in the germ line does not
appear to account for the presence of amyloid in Alzheimer
disease or familial Alz heimer disease (37-39).
Mutations in APP
If the APP gene actually harbored the defect leading to
familial Alzheimer disease, one would expect to observe no
crossovers between the two loci in a direct two-point genetic
linkage test. When tested in the four original familial Alz
heimer disease families used to demonstrate linkage to chro
mosome 21 and other pedigrees, multiple recombination
events were observed between APP and familial Alzheimer
disease in affected individuals (12, 13) (see example in Fig.
1). The presence of at least one crossover in each of the four
families indicated that the APP gene is most likely not the
site of the defect in any of these pedigrees. Maximum likeli
hood analysis indicated that the APP gene was at least 8 cm
away from the familial Alzheimer disease defect (12).
The recent demonstration that familial Alzheimer disease
is genetically heterogeneous renewed the possibility that the
APP gene might still be the site of the defect in some
familial
Alzheimer disease pedigrees, especially those displaying
link
age to chromosome 21 and no crossovers with APP. Goate
et
al. (40) re-examined APP genetic linkage in six familial Alz
heimer disease families and found two pedigrees with no
crossovers between APP and the disorder. When a portion
of
exon 17 of the APP gene from affected individuals in these
two pedigrees was sequenced, a conservative amino acid
change was discovered. Exon 17 was chosen on the basis of
the recent report that a mutation in this exon, which encodes
the fJA4 region, represents the gene defect in the rare Dutch
disorder, hereditary cerebral hemorrhage with amyloidosis
(HCHWA-D, Ref. 41) (see Fig. 2). In HCHWA-D, fJA4-type
amyloid accumulates in large amounts in cerebral vessels
and
ultimately leads to stroke and death by the fifth or sixth
decade of life (42).
The apparent missense mutation in exon 17 discovered in
familial Alzheimer disease caused the substitution of an iso
leucine for a valine at residue 717 (according to APP770
sequence) within the transmembrane region immediately C
terminal to the fJA4 domain. This base substitution co-segre
gated with familial Alzheimer disease in two separate pedi
grees but was absent from eight other familial Alzheimer
disease families and from 200 normal chromosomes analyzed
(40). Although it has now been found in four additional
familial Alzheimer disease kindreds (43), the vast majority of
familial Alzheimer disease pedigrees of both early and late
onset do not exhibit this mutation (40, 44, 45). While it is
conceivable that this alteration could represent a very rare,
neutral polymorphism, it seems far more likely that, at least
in some cases, mutation at the APP locus does cause familial
Alzheimer disease.
In all but one of the six families reported with this
mutation,
a distinct neuropathological profile has been seen (40, 43,
46) including cortical diffuse Lewy bodies and abundant
congo philic amyloid angiopathy leading in some cases to
stroke.
This latter feature is reminiscent of the phenotype of patients
with Dutch HCHWA-D in which dementia sometimes
follows cerebral strokes. Thus, the two known APP
mutations might be viewed as allelic forms of the same
disease characterized by prominent vascular involvement.
alter the anchoring of APP in the membrane (40).
Alongthese lines, an interesting comparison may be
drawn with the dominant mutation, deg-l(u38), which
results in neuronal degeneration in Caenorhabditis elegans
(47). This mutation ultimately leads to death with late onset
long after neuronal synapses have been formed. The deg-l
gene appears to encode a membrane-associated protein; it
has been suggested that a mutation in this gene might lead
to compromised membrane integrity and cell lysis. A similar
phenotype is observed with mutations in the mec-4 gene
which is a close homologue of the deg-I gene (48).
Mutations in both the mec-4 and deg-
1(u38) genes involve the same residue, Ala-442, in the
hydro phobic domain of the protein (48). Substitutions of
Thr or Val for Ala are sufficient to induce degeneration
apparently via steric hindrance. Driscoll and colleagues (48)
have found that cell viability is maintained if the amino
acid in position
442 contains a side chain no larger than a sulfhydryl on the
fJ carbon. Interestingly, Ala-442 is predicted to be contained
in a fJ turn structure close to or within the hydrophobic
membrane-spanning domain. Likewise, both mutations iden
tified in APP occur in the hydrophobic fJA4 domain either
close to or within the trans-membrane domain. The APP717
mutation associated with familial Alzheimer disease replaces
a valine with an isoleucine. The latter residue possesses a
larger nonpolar R group. By analogy to the proposed action
of Ala-442 mutations in C. elegans, the APP717 substitution
could be envisioned to disrupt membrane integrity resulting
in the release of unprocessed APP. Consequently, the fJA4
domain would not undergo "normal" cleavage and become
potentially amenable to amyloid formation.
An alternative explanation for the role of the APP717
mutation in familial Alzheimer disease pathogenesis involves
the disruption of a putative regulatory stem-loop structure in
APP mRNA (49). The mutation site is flanked by 26 nucleo
tides capable of forming a stem-loop structure which contains
the consensus sequence CAGUGAcharacteristic of the iron
responsive elements that regulate translation of ferritin and
transferrin receptor in response to iron concentration (50).
The putative iron-responsive element in APP is situated
precisely at residues 40-42 of the fJA4 domain. The destabi
lizing effect imparted on the stem-loop structure by the
APP717 substitution could, by analogy to ferritin and trans
ferrin receptor, affect translational regulation of APP result
ing in either altered levels of APP protein or abnormally
truncated products. Either the overproduction of APP or the
production of truncated APP moleculescontaining intact
(3A4 domains and lacking cytoplasmic portions could
conceivably lead to amyloid formation.
Summary
It is not yet clear whether linkage of familial Alzheimer
disease to chromosome 21 could be explained entirely by
mutations in APP. Goate et al. (40) have raised the possibility
that reports of recombination between APP and familial
Alzheimer disease in chromosome 21-linked pedigrees may
have been in error because of factors such as mistyping,
misdiagnosis, non-paternity, and phenocopy. The largest
fam ily used in the original report of linkage of familial
Alzheimer disease to chromosome 21 (12) is shown in Fig. 1.
It yields a peak LOD score of 2.94 at 15 cM with the
proximal chromo some 21 marker D21S52 located
approximately 15 cm from APP. This early onset (40-50
years) familial Alzheimer dis ease pedigree contains two
branches in which different APP alleles appear to segregate
with Alzheimer disease. Since it is highly unlikely that all
affected individuals in each branch were mistyped and/or
misdiagnosed, this obligate crossover
20582 Minireview: Molecular Genetics of Alzheimer Disease Amyloid
event implies several possibilities. 1) APP is not the site of
the defect in this familial Alzheimer disease pedigree for
which there is suggestive but not significant evidence for
linkage to chromosome 21; or 2) APP is the site of the
defect, and the
apparent crossover event is due either to intragenic recombi
nation within the relatively large APP gene (approximately
180 kilobases) or to the introduction into this pedigree of a
second familial Alzheimer disease gene. The complete se
quencing of all exons and the promotor of APP in affected
individuals of this pedigree should resolve whether APP is
the site of the gene defect in this family.
Continued linkage analysis of familial Alzheimer disease
pedigrees with highly informative polymorphisms (e.g.
simple sequence repeats) for APP and other chromosome
21 loci
should not only allow the identification of familial
Alzheimer
disease kindreds potentially harboring APP mutations but
also resolve the issue of whether a familial Alzheimer
disease gene defect distinct from APP is also located on
chromosome
21. In view of the complex genetic nature of inherited Alz
heimer disease, an extensive collaborative effort of multiple
groups to methodically screen familial Alzheimer disease
fam ilies with loci spanning the human genome will
probably be
necessary to accelerate the localization and identification of
both causative and predisposing familial Alzheimer disease
gene defects. However, given the important role played by
APP and the presence of a potentially causative mutation in
this gene in a few familial Alzheimer disease families, at
tempts to define genetic, biochemical, and environmental
factors affecting expression of the APP gene and the
process ing of its product, including the possibility of
additional mutations in the APP gene, offer a alternative
approach to unraveling the enigmatic etiology of Alzheimer
disease.
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