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Aging of the Brain and Alzheimers Disease

D L Price, M Albert, J Troncoso, D R Borchelt
and P C Wong, The Johns Hopkins University,
Baltimore, MD, USA
2007 Elsevier Ltd. All rights reserved.

Introduction
Over the past decade significant advances have been
made in understanding the causes and mechanisms
of dementia syndromes in humans, particularly
Alzheimers disease (AD), the most common cause
of dementia in older adults. Herein, we review the
features of age-associated alterations in memory and
cognition, the biology of AD, and therapies presently available for AD.

organize and plan) measured by the Trail-Making

Test and Self-Ordering Test. Imaging studies,
including magnetic resonance imaging (MRI) (with
measurements of volumes of entorhinal cortex,
hippocampus, banks of superior temporal sulcus,
and caudal anterior cingulate) and positron emission
tomography (with measures of glucose use or
visualization of binding of labeled  amyloid
ligands) can help to predict which of these individuals are entering early stages of AD. Genetics
studies of ApoE status (particularly of E4 allele) can
predict 66% of individuals with memory problems
who will develop AD (see following).
The brains of cognitively intact older individuals
may show senile plaques and neurofibrillary tangles
and loss of subset of neurons, but these lesions are
usually much less frequent and more restricted than
those that occur in cases of AD.

Cognitive and Memory Impairments

in the Elderly
Although many older individuals remain intellectually intact, a significant number of the elderly
show declines in memory and cognitive abilities.
Alterations are often mild, occur relatively late, and
involve speed of learning, complex problem solving,
the ability to retain large amounts of new information, and visuospatial skills. Vocabulary, information storing, and comprehension skills remain
relatively stable into old age. Some older individuals
have mild cognitive impairments (MCI) in which
memory loss exceeds that expected for age, but they
do not meet criteria for AD. Many investigators
regard this syndrome as a transitional state between
the normal functional abilities of older persons and
the syndrome of early AD. Thus MCI is a high-risk
condition for the development of dementia. However, there may be considerable heterogeneity
among subjects with MCI (i.e., interindividual
variability in the rate and severity of progression).
The variable alterations in memory with age makes
it sometimes difficult to determine, after a single
examination, whether an individual with mild ageassociated memory impairments will remain relatively stable or will show progression to severe
dementia. The most accurate approach to analyze
the significance of age-related abnormalities is to
measure cognitive abilities and memory performance
repeatedly in the same patient over a period of time.
Neuropsychologic tests valuable in predicting AD
are delayed recall (recently learned information)
assembled by California Verbal Test and Wechsler
Memory Scale and executive functions (ability to

Alzheimers Disease: Clinical Features,

Diagnostic Studies, and Neuropathology
AD is the most common cause of senile dementia, a
term that refers to a syndrome occurring in older
individuals that results in memory loss and cognitive
impairments of sufficient severity to interfere with
social, occupational, and personal functions. This
type of dementia affects more than 4 million people
in the United States. Because of increased life
expectancy and the postwar baby boom, the older
population is the fastest growing segment of our
society. During the next 25 years, the number of
people with AD in the United States will triple, as
will the cost of treating them. Thus AD is one of
societys major public health problems.
Most individuals with sporadic AD exhibit the
first clinical signs during their seventh decade.
However, some cases develop in midlife; in these
cases a family history of the disease is more likely. In
both the sporadic and familial forms of AD, affected
individuals show abnormalities of memory, problem
solving, executive functions language, calculation,
visuospatial perceptions, judgment, and behavior.
Some patients develop psychotic symptoms, such as
hallucinations and delusions. In these patients,
mental functions and activities of daily living are
increasingly impaired. In the late stages, these
individuals are mute, incontinent, bedridden, and
usually die of intercurrent medical illnesses. Other
causes of dementia include: cerebrovascular disease,
alone or in combination with AD; Lewy body
dementia; Parkinsons disease; alcoholism; drug

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2 Aging of the Brain and Alzheimers Disease

intoxications; infections, such as human immunodeficiency virus (HIV) infection (i.e., acquired immunodeficiency syndrome (AIDS)) and syphilis; brain
tumors; vitamin deficiencies (e.g., B12); thyroid
disease; and a variety of other metabolic disorders.
To make a diagnosis of AD, clinicians rely on:
histories from patients and informants; physical,
neurologic, and psychiatric examinations; neuropsychologic testing; laboratory studies; and a variety of
diagnostic tests, including neuroimaging studies. The
clinical profile, in concert with a variety of
laboratory assessments, allows the clinician to
make a diagnosis of possible or probable AD.
Alterations in levels of specific proteins in the
serum or cerebrospinal fluid, such as the A peptide
and tau, may eventually prove useful in diagnosis.
Levels of A in cerebral spinal fluid (CSF) are
usually low in full-blown AD, while levels of tau
tend to be higher in cases of AD versus controls.
However, values may vary among individuals, and
single measures are not of great diagnostic value.
The presence of the ApoE-4 allele confers risk in
late-onset disease (see following), and ApoE genotyping is a useful research tool but is not helpful for
routine diagnostic purposes. Computerized tomography (CT) or MRI, performed on the majority of
patients with this syndrome, can identify other
potentially treatable diseases and may detect
abnormalities, particularly in the medial temporal
lobe (atrophy of hippocampus and entorhinal
cortex), that may have predictive values for establishing a diagnosis of AD. In AD, positron emission
tomography (PET) and single photon emission
computerized tomography (SPECT) usually show
decreased regional blood flow in the parietal and
temporal lobes with involvement of other cortical
areas at later stages. At present, except for brain
biopsy, no tests definitively establish the diagnosis of
AD in living subjects. It is extremely important for
the physician to exclude other causes of dementia,
because some other types of dementia respond to
specific treatments. However, AD is a disorder for
which no mechanism-based therapies yet exist. Only
symptomatic treatments are available at present (see
following).
AD is characterized by a series of abnormalities in
the brain that selectively involve neurons in the
neocortex, entorhinal area, hippocampus, amygdala,
nucleus basalis, anterior thalamus, and several brain
stem monoaminergic nuclei (in particular the locus
coeruleus and raphe complex). Dysfunction and
death of neurons in these regions and circuits are
reflected by the presence of cytoskeletal abnormalities in these cells (neurofibrillary tangles), loss of
neurons in these regions, the presence of neuritic

plaques in brain regions receiving inputs from these

nerve cells, and reductions in synaptic markers of
these transmitter systems in target fields of these
neurons.
Affected nerve cells often exhibit alterations in the
cytoskeleton. Neurofibrillary tangles (filamentous
inclusions in the cell bodies and proximal dendrites),
contain paired helical filaments (PHF) and 15 nm
straight filaments comprised of hyperphosphorylated isoforms of tau, a microtubule-binding protein.
Other fibrillar tau-related abnormalities include
neuropil threads (in dendrites) and neurites (predominantly in distal axons/terminals). It is likely
that all of these fibrillar inclusions result from
common mechanisms. Because the cytoskeleton is
essential for maintaining cell geometry and for the
intracellular trafficking and transport of proteins
and organelles, it is likely that disturbances of the
cytoskeleton are associated with impaired axonal
transport and thereby they compromise the functions and viability of neurons. Eventually, affected
nerve cells die (possibly by apoptosis), and intracellular neurofibrillary tangles are left behind as
tombstones of the nerve cells destroyed by disease.
As these neurons dysfunction and die, their synapses
degenerate in regions of the brain critical for the
normal functions of cognition and memory.
The brain regions affected by AD contain neuritic,
or senile, plaques comprised of neurites displayed
around extracellular deposits of the A-amyloid
protein (A40 and 42). Fibrillar, amyloid aggregates
are formed of -pleated sheet A peptides that are
birefringent when stained with Congo Red (or
thioflavin) and viewed in polarized light (or fluorescence). A, an 4-kDa -pleated sheet peptide, is
derived from a larger precursor protein, termed the
amyloid precursor protein (APP), encoded by a gene
localized to the mid-portion of the long arm of
human chromosome 21. APP, an integral membrane
glycoprotein, has three principal isoforms of 695,
751, and 770 amino acids, all of which contain the
A sequence. In cell culture, a fraction of cellsurface APP is also internalized to generate A
peptides, which are then secreted. A1-40 and low
levels of A1-42(43) appear in the conditioned
medium of cultured cells and in normal human
cerebrospinal fluid. A1-42(43) appears to be the
pathogenic peptide; these species are more fibrillogenic and toxic than A1-40 and provide a substrate
for amyloid aggregation and deposition. Enriched in
neurons, APP, a single pass transmembrane protein,
is rapidly transported anterograde, along with
enzymes responsible for - and -secretase activities
(see following); it may serve as a kinesin cargo
receptor in axons. APP is delivered to synaptic

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Aging of the Brain and Alzheimers Disease

terminals where BACE1 cleaves APP to form Cterminal derivatives; subsequently, the -secretase
complex cleaves at positions 40, 42 and 43 to
generate A peptides (see following). Normally
released at terminals, A42 may serve as a synaptic
modulator. However, elevated concentrations of A
at these synaptic sites, as occurs particularly in the
genetic forms of disease occurring in both transgenic
mice and humans, leads to the formation of A
oligomers and multimers. These putatively toxic
peptide multimers, situated in proximity to
synapses, appear to interfere with synaptic functions, possibly by interacting with a class of
glutamate receptors and eventually lead to neuritic
degeneration of terminals. A species can assemble
into protofilaments and then into the fibrils that are
prominent components of the amyloid cores of
neuritic plaques, which are complex structures
surrounded by astrocytes and microglia.
These cellular abnormalities have profound clinical consequences. Abnormalities that damage the
entorhinal cortex, hippocampus, and other circuits
in the medial temporal cortex are presumed to be
critical in memory impairments. Higher cognitive
deficits, such as disturbances in executive functions
language, calculation, problem solving, and judgment, are believed to be related to pathology in the
neocortex. Alterations in the basal forebrain cholinergic system may also contribute to memory
difficulties and attention deficits. The behavioral
and emotional disturbances may reflect involvement
of the limbic cortex, amygdala, thalamus, and
monoaminergic systems.

Recent Advances in Understanding the

Role of b- and g -Secretase in Processing
of Amyloid Precursor Protein to Form Ab
in Alzheimers Disease
BACE1 and BACE2, encoded by genes on chromosomes 11 and 21, respectively, have been shown to
be transmembrane aspartyl proteases that are
directly involved in the cleavage of APP. BACE1
mRNA is present in a variety of tissues, and BACE1
mRNA levels are high in many regions of brain.
Intriguingly, BACE1 protein is only abundant in the
brain, whereas it is undetectable in other nonneural
tissues, such as the pancreas, where the mRNA is
alternatively spliced to a smaller protein incapable
of cleaving APP. BACE2 mRNA is very low in
neural tissues, except for scattered nuclei in the
hypothalamus and brain stem. The functions of
BACE1 processed peptides generated from APP are
unknown, but it has been suggested that A may

influence synaptic activity. Interestingly, BACE1,

along with APP and components of -secretase
complex, is transported in axons and enriched at
some synapses in several highly plastic structures of
brain (i.e., the mossy fiber pathway originating from
hippocampal granule cells and the glomeruli of
olfactory bulb). These observations are consistent
with the idea that A released in synaptic fields may
influence synaptic plasticity.
BACE1 preferentially cleaves APP at the 1 and
11 sites of A in APP and is critical for the
generation of A. BACE1-deficient mice show no
overt developmental phenotype. In cultures of
BACE1-/- neurons, the secretion of A1-40/42 and
A11-40/42 is abolished. Thus BACE1 is the
principal neuronal -secretase and makes proamyloidogenic cleavages. In contrast, BACE2 makes
antiamyloidogenic cleavages at 19/20 of A.
Thus BACE2 acts more like -secretase. Although
BACE1 is critical for amyloidogenesis in brain,
BACE2 does not appear to play a significant role
in APP processing in neurons. In contrast to the
ubiquitous expression of BACE1 mRNA in a variety
of tissues, BACE1 protein is abundantly expressed in
the brain but is undetectable in other nonneural
tissues, such as the pancreas. Although BACE1
protein is expressed at comparable levels in most
brain regions, BACE1-specific immunoreactivities
are particularly localized in the hippocampus.
-Secretase activity is essential for the regulated
intramembraneous proteolysis of a variety of transmembrane proteins dependent upon a multiprotein
catalytic complex, including PS and several other
transmembrane proteins. It is not clear whether PS1
itself acts as an aspartyl protease, functions as a
cofactor critical for the activity of -secretase, or
exerts its influence by playing a role in trafficking of
APP or other essential proteins critical for enzyme
activity to the proper compartment for -secretase
cleavage. The concept that PS1 may act as an
aspartyl protease or may be a critical cofactor
essential for the activity of -secretase is suggested
by several observations: PS1 is isolated with secretase under specific detergent-soluble conditions;
PS1 is selectively cross-linked or photoaffinity
labeled by transition state inhibitors; substitutions
of aspartate residues at D257 in TM6 (although
controversial) and at D385 in TM7 have been
reported to reduce secretion of A and ultimately
cleavage of Notch1 in vitro; and cells in which PS1
has been targeted show decreased levels of secretion
of A. Recent work is focused on roles of different
proteins in the multiprotein catalytic complex,
including (Nct), Aph-1, and Pen-2 domain. Studies
of NCT null (NCT -/-) mice and NCT -/- fibroblasts

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4 Aging of the Brain and Alzheimers Disease

have shown that NCT is an integral member of the

-secretase complex. Partial decreases in the level of
NCT significantly reduce the secretion of A, and
NCT may be a valuable therapeutic target for AD.
Aph-1 and Pen-2 are novel transmembrane proteins:
Aph1 has seven predicted transmembrane domains;
whereas Pen-2 has two predicted transmembrane
regions. These proteins interact with sel-12/PS and
aph-1/nicastrin, and their inactivation with RNAi
methods in Drosophila cells decreases -secretase
cleavages of APP and Notch and reduces levels of
processed PS. For these reasons, Aph-1 and Pen-2
are now believed to be critical components of
-secretase complex.

Genetics of Alzheimers Disease

Five principal risk factors exist for AD: (1) age, (2)
mutations in the presenilin 1 (PS1) gene on
chromosome 14, (3) mutations in the presenilin 2
(PS2) gene on chromosome 1, (4) mutations in the
APP gene on chromosome 21, and (5) ApoE alleles
positioned on the proximal long arm of chromosome 19. The presence of any of the mutations in
genes encoding APP, PS1, or PS2 causes the
disorder to occur earlier in the third through sixth
decades. Specific ApoE alleles appear to predispose
to later onset AD and some cases of late-onset
familial AD. Approximately 510% of cases of AD
exhibit clinical syndromes in mid-life (early onset)
and are inherited in an autosomal dominant manner.
In a small fraction of early-onset families, missense mutations have been identified in the APP gene
on chromosome 21. In all cases mutations invariably
occur within or immediately proximal to the A
region. In several families the normally occurring
valine residue at position 717 (of APP-770) is
replaced with either Ile, Gly, or Phe. Cells that
express APP with mutations at position 717 secrete
increased levels of A1-42,43. These longer A
forms have a propensity to nucleate rapidly into
amyloid fibrils. In two large, related, early-onset AD
families from Sweden, a double mutation at codons
670 and 671 results in a substitution of the normal
Lys-Met dipeptide to Asn-Leu. Cells that express
this mutant polypeptide and secrete approximately
six- to eightfold higher levels of A. In a hereditary
disease associated with A deposition around blood
vessels and cerebral hemorrhage, an APP mutation
at position 693 leads to a Glu-Gln substitution
(corresponding to amino acid 22 of A). This
mutation is associated with the A peptide species
that are more prone to aggregate into fibrils. Thus
some of the mutations linked to AD can change the
processing of APP and influence the biology of A

by increasing the production of A peptides or the

amounts of the longer, more toxic A42 or by
promoting fibril formation. In those pedigrees in
which missense mutations in either APP or PS genes
promote the formation of the more toxic form of
A, it is highly likely that A is central to the
pathogenesis of disease.
Nearly 50% of cases of early-onset familial AD
are linked to the PS1 gene (chromosome 14), which
encodes a 467-amino-acid polypeptide containing
between seven and nine transmembrane domains.
Two mutations in the PS2 gene, which encodes a
protein homologous to PS1, cause autosomal dominant AD in two familial AD pedigrees. Approximately 50% of PS1 mutations occur within or
immediately adjacent to predicted transmembrane
domains. Mutant PS1 and PS2 influence APP
processing in a fashion that results in the elevated
production of A1-42/43. In cultured cells and
brains (human, monkey, and mouse), PS1 accumulates as an N-terminal 28-kDa fragment and a
C-terminal 18-kDa fragment, providing strong
support for the idea that PS1 is subject to endoproteolytic processing in vivo. In view of the paucity of
accumulated full-length PS, it has been suggested
that PS fragments may be functional units. As
indicated previously, it is believed that PS are critical
components of the -secretase complex. PS are
highly homologous to sel-12, a gene product that
plays a role in the determination of cell fates during
development, suggesting roles for PS in these
processes. Recent work indicates that -secretase
cleaves APP and Notch-1, generating intracellular
domains that traffic to the nucleus where they are
involved in transcriptional activation. The results of
studies of PS1 and Nct are consistent with the
concept that they are components of -secretase and
the phenotype of knockout mouse embryos are the
result of failed Notch1 signaling. Mutant PS1 and
PS2 influence APP processing in a fashion that
results in the elevated production of A1-42/43.
An allele of ApoE, a glycoprotein that carries
cholesterol and other lipids in the blood, has been
implicated as a risk factor for the disease in AD. At
the single ApoE locus, three alleles are expressed:
ApoE2, ApoE3, and ApoE4. The ApoE3 allele is
most common in the general population (frequency
of 0.78), whereas the allelic frequency of ApoE4 is
0.14. However, in clinic-based studies, patients with
late-onset disease (>65 years of age) have an ApoE4
allelic frequency of 0.50; thus the risk for AD is
increased by the presence of apoE4. The mechanisms whereby the ApoE allele type elevates the risk
for late-onset disease are not known but may reflect
differences in the abilities of ApoE isoforms to bind

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Aging of the Brain and Alzheimers Disease

A and possibly influence aggregation, deposition,

and/or clearance.

Animal Models of Aging

and Alzheimers Disease
Both spontaneously occurring and genetically produced diseases in animals have now been used to
model features of AD. Rhesus monkeys, Macaca
mulatta, with an estimated life span of more than 35
years, show cognitive and memory deficits that
appear at the end of the second and the beginning
of the third decades of life. These animals develop
virtually all of the brain abnormalities (amyloid
deposits, scattered tangles, and mild reductions in
transmitter markers) observed in older humans and,
to a lesser degree, patients with AD.
The ability to introduce wild-type or mutant
transgenes into mice provides an opportunity to
determine whether the overexpression of wild-type
or mutant APP or PS transgenes causes behavioral
abnormalities, A deposition, and reductions in
synaptic/transmitter markers. These studies are
reviewed in Animal Models of A amyloidogenes.

Therapies for Alzheimers Disease

At present no cure exists for this devastating illness.
Available treatments for AD are symptomatic in
nature, many present-day therapies focus on treating
associated conditions, such as depression, agitation,
sleep disorders, hallucinations, and delusions. One
of the principal therapeutic targets has been the
functions of basal forebrain cholinergic system,
which is severely damaged in AD. Several strategies
have been developed to influence this neurotransmitter system. Unfortunately, precursor loading (i.e.,
choline, lecithin) and muscarinic agonist approaches
to improve cholinergic functions have not proved to
be very effective. Recently, several acetylcholinesterase inhibitors, including rivastigmine, have been
approved in the United States for the treatment of
AD. These drugs are sometimes associated with side
effects and they have, at best, a very modest effect
on cognitive functions and the ability to perform
activities of daily living. Clinical trials have begun to
test the efficacies of anti-inflammatory compounds,
estrogens, plant extracts, and antioxidants without
great benefit. In an anti-glutaminergic approach in
one small trial, Memantine, an N-methyl-D-aspartate
(NMDA) receptor antagonist, has been suggested to
reduce the rate of clinical deterioration of patients
with moderate to severe AD.

When mice harboring mutant genes linked to

familial AD were injected with 42 peptide and
Freunds adjuvant, the levels of  and the plaque
burden were reduced. Subsequently a phase 1
human clinical trial was completed with no evidence
of adverse events. However, in a phase 2 trial with a
significantly larger number of patients, there were at
least 15 individuals who suffered adverse events,
consistent with meningoencephalitis. The trial was
stopped. Autopsy findings of one of these patients
were interpreted to indicate that there were reductions in the numbers of  plaques in the cortex,
but there was persistent pathologic neurofibrillary
and  angiopathy, as well as T-lymphocyte
meningoencephalitis.
At this writing many pharmaceutical companies
are using high throughput screening and molecular
modeling to identify inhibitors for - and -secretase
activities. It is anticipated that these mechanismbased therapies may be available at the time of the
next revision of this article.
See also: Alzheimers Disease; Alzheimers Disease,
Molecular Genetics of; Aging of the Brain; Cognition in
Aging and Age-Related Disease; Learning and Memory;
Dementia; Acetylcholine [Classic Paper].

Relevant Website
http://www.alzforum.org

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6 Aging of the Brain and Alzheimers Disease
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