--PART.BOUNDARY.0.23195.emout04.mail.aol.com.809155340
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I apologize for the length of this message, but I found it to be extremely
interesting. Altho' it deals primarily with Alzheimers, PD is also
mentioned, and alot of the info is relevant. WT
ps BARB P. - have there been any listserv digests sent out recently - or
should I check whether I've been cut off somehow?
************************************
>
>
---------------------
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From: [log in to unmask] (Tebay, Wendy)
To: [log in to unmask] (athome)
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Date: 95-08-19 12:51:38 EDT
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------------------------------------------------------------------------
Magazine: The Journal Of NIH Research Title: Alzheimer's Disease As A Model
Of Molecular Gerontology Author: Allen D. Roses Issue: April 1995
Alzheimer's Disease As A Model Of Molecular Gerontology
Allen D. Roses*
Abstract: APOE4, a naturally occurring allele of the gene encoding
apolipoprotein E (ApoE), increases the risk and lowers the age of
developing late-onset Alzheimer's disease (AD). ApoE is the major
apolipoprotein in the nervous system, and it may be necessary for the
growth, maintenance, and repair of axonal membranes and myelin, the fatty
sheath that surrounds axons. ApoE occurs in many cell types outside the
central nervous system (CNS). Within the CNS, ApoE is expressed in
astrocytes and is also located in smaller amounts in the cytoplasm of
neurons in the cerebral cortex. My laboratory group has postulated that the
E4 variant of ApoE may interact abnormally with neuronal cytoskeletal
proteins such as tau, favoring microtubule degradation and the formation of
neurofibrillary tangles, which occur in the brains of people with AD. In
this commentary, I suggest that naturally occurring polymorphisms of genes
other than APOE not only contribute to genetic diversity, but also may
contribute to adult-onset diseases other than AD.
In 1993, we reported that APOE4, a naturally occurring allele of the gene
that encodes apolipoprotein E (ApoE), increases the susceptibility for
developing late-onset Alzheimer's disease (AD)1-6. Since then, many other
groups of investigators have confirmed the finding7-13. The impact of the
APOE4 allele has become more obvious as people who are homozygous (APOE4/4)
or heterozygous (APOE3/4) grow older and develop disease at a significantly
faster rate than their counterparts who carry the APOE2 allele or are
homozygous for APOE3 (APOE2/3, APOE2/4, or APOE3/3).
Now, it is useful to stop and reflect on an interesting and obvious
corollary. A polymorphic difference in a common gene, APOE, has a large
influence on susceptibility to AD, a common late-onset disease3,4. APOE4 is
not a mutant gene that causes AD. Instead, the APOE4 allele increases the
risk and lowers the age of onset of developing AD--with APOE4 homozygotes
at higher risk than heterozygotes. In contrast, the APOE2 allele appears to
decrease the risk and increase the age of onset for AD.
Although there are examples of statistically defined susceptibility factors
in other diseases such as heart disease and cancer, the large genetic
effect of the APOE4 allele on the increased rate of development of AD may
forecast a common theme: Polymorphisms of other common genes may regulate
the rate of disease expression over time in other late-onset neurological
and nonneurological diseases.
During the past decade, we have used many naturally occurring DNA
polymorphisms as research tools to identify and locate genes associated
with particular diseases and to map the human, mouse, and other genomes.
Yet the biological effects of most polymorphisms have been virtually
ignored as factors important for the phenotypic diversity of a species
except when they are mutations for adisease. We tend to use the somewhat
derogatory term "housekeeping genes" for those genes that are expressed in
many tissues (constituitively) and apparently are necessary for sustaining
all cell types--as if these genes are less important than other, more
interesting, organ-specific genes (sometimes called "luxury genes"). Many
widely expressed genes have polymorphic forms. APOE, the gene for
Huntington's disease, and many other genes are expressed in most tissues
and may play a key role in the rate of development of late-onset
diseases14-16. In essence, the polymorphisms at the APOE locus on
chromosome 19 determine the rate of disease development and the age of
clinical onset of AD. I believe there are two important lessons to be
learned independent of the specific role of ApoE in AD.
First, different protein isoforms expressed from polymorphic alleles may
have slightly altered function, with cumulative effects as people age. This
alteration could lead to variable rates of disease onset. It is well
accepted that during embryogenesis, many genes are transiently expressed
and are involved in different stages of the maturation of the organism.
Understanding the regulation of gene expression has, therefore, become an
important problem in developmental biology. However, adults continue to
mature because of other mechanisms that generate genetic diversity. We are
now on the threshold of dissecting not only the genetic diversity that
contributes to adult-onset diseases, but also of identifying factors that
may underlie biological differences among interactions between humans and
their environment.
The relationship between APOE polymorphisms and AD was less important when
people did not live more than 70 years and AD was a less prevalent disease.
But now that we have extended our lifespans, we have also uncovered new
limitations that previously were not subjected to evolutionary pressures or
natural selection. The same APOE4 allele that increases our age-dependent
risk of AD must also convey some selective advantage over the other
variants of APOE to maintain itself in more primitive populations,
including the western Australian aboriginees, Fore tribesmen of New Guinea,
and Yanomami Indians of northwestern Brazil17,18.
The second important observation affects basic neurobiology and emerges
from the sudden focus of attention on ApoE as a factor in brain metabolism
of AD. There is no evidence that ApoE is expressed in brain neurons and,
therefore, the conclusion is that ApoE is not involved in intraneuronal
metabolism. This belief generated immediate and repeated criticism of our
suggestion in 1994 that ApoE3 and ApoE4 interact differently with
microtubule-associated proteins (MAP2 or tau) in neurons in the cerebral
cortex. If ApoE does not get into the neuronal cytoplasm, the reasoning
went, then interactions with the cytoskeletal proteins MAP2 or tau would be
in vitro artifacts without biological significance. But our recent
detection of ApoE in the cytoplasm of normal cortical neurons as well as
its accepted high concentration in astrocytes creates questions about its
normal metabolic function (discussed below) and raises an interesting and
paradoxical scenario19.
AD involves the brain, and the disease is characterized by the loss of
synaptic density and cortical neurons. APOE, the relevant genetic factor,
encodes a 34-kilodalton glycoprotein whose mRNA is not known to be
expressed in neurons. Therefore, there must be specific mechanisms for
neurons to take up extracellular or astrocyte-secreted ApoE. Different
isoforms of a protein that are not made in neurons can nevertheless have a
profound effect on the viability of neurons. Therefore, gene expression in
neurons is not equivalent to disease expression involving neurons. This is
a critical concept that is relevant to many current experiments that
attempt to identify organ-specific candidate genes as the site of mutations
that lead to disease of that organ. Many brain diseases have been assumed
to involve genes uniquely expressed in the brain. In fact, in most cases,
the mutated gene is widely expressed but its clinical effect on late-onset
degeneration appears specific to certain subsets of neurons14-16,20-24.
When does a normal genetic trait become a disease gene?
A genetic trait can be defined as an inherited variable. A disease is a
morbid constellation of symptoms and signs. Some traits are benign
throughout life, but increased longevity may provide the opportunity for
the effect of other traits to contribute to the development of a disease.
We are now at the threshold of differentiating a disease process from a
genetic variability of neuronal aging.
Figure 1 illustrates the distribution of the age of onset of AD in 72
families with late-onset inherited disease and 198 control subjects (with
sporadic AD) as a function of the five commonly inherited APOE genotypes5.
(APOE2/2 represents less than 0.05 percent of the U.S. population, and
there were not enough data to include it in the figure.) With the caveat
that the APOE4 effect actually starts before 60 years of age12,13, Figure 1
represents the relationship between APOE polymorphisms and the age of onset
of AD. The prevalence of AD in a population depends on the relative APOE
allele frequencies, the longevity of the society, and perhaps ethnic and/or
racial genetic differences in other susceptibility genes.
Several points are readily apparent from these data. The mean age of onset
for individuals in the population with the APOE4/4 genotype (approximately
2 percent of the population) is less than 70 years of age; for APOE2/3
individuals (approximately 10 percent of the population), it is more than
90 years of age. The mean age of onset for APOE3/4 individuals
(approximately 20 percent of the population) is in the mid-70s. Thus, a
difference in the APOE genotype alone stratifies the distribution of age of
onset of AD, with a mean difference of more than 20 years.
There is another fascinating point that can be appreciated from Figure 1.
Even with the "best" genotype, APOE2/3, everyone would get AD if they lived
to 140 years. So what is the relationship of APOE polymorphisms to "aging"?
Other studies of the associations of APOE alleles with longevity have
approached this question in reverse, but with the same general results.
In a 1994 study of 338 French centenarians, Schachter et al.2 found that
the allele frequency of APOE2 in the centenarians was double that of a
non-aged French control group (0.068 to 0.1280) and that the allele
frequency of APOE4 was about half (0.112 to 0.052). The relative
proportions of APOE alleles remaining in the centenarians could be
approximated by using Figure 1 to estimate the alleles left in the
population at age 100.
There are several possible interpretations for these data. The most obvious
is that the process of AD occurs in everyone at a rate influenced by their
APOE genotype. A genetic trait becomes a susceptibility gene for a disease
when the individuals at risk survive long enough for the disease to be
expressed. APOE4 increases risk and lowers the mean age of onset of AD. In
contrast, APOE2 appears to protect against AD until well past current human
lifespans. We are living longer today than at any previous time in human
history. Genetic traits that are beneficial earlier in life may be selected
for during the first 50 years but may generate difficulties in old age.
Thus, time is the variable that has changed most significantly and that has
led to the current epidemic of AD. APOE may be a particularly important
genetic locus for dissecting age- or time-related metabolic processes that
occur in late adult life; the APOE gene may be a window on molecular
gerontology.
Clinicians traditionally measure the duration of disease as dating from the
apparent age of onset. Of course, we realize that the disease processes may
start years before we observe the resulting morbidity. Using sophisticated
laboratory and imaging techniques, we attempt to identify markers of
disease prior to the actual appearance of clinical symptoms26. In fact,
late-onset diseases may well start before development ceases. They may
involve a lifelong process that manifests itself only when signs and
symptoms develop. Late-onset AD is just such a disease.
Two decades ago, when the expected age of survival was about 67 years in
men and 72 years in women, AD was relatively uncommon. But with increased
longevity, processes leading to disease that need more time to develop
begin to appear. An isoform-specific effect of a protein (such as ApoE) on
the distribution of the age of onset of a disease would go unnoticed
without the effect of longer survival. In fact, in primitive populations
where the allele frequency of APOE4 approaches the 0.4 level, which is
frequently observed with AD, the individuals in the population do not live
long enough to develop late-onset disease. For example, the allele
frequency of APOE4 is 0.39 in western Australian aborigines, yet there have
been only rare autopsies in aborigines over the age of 56, and none of
these people had developed AD. These autopsies have been performed during
the past 30 years at the Royal Perth Hospital Department of Neuropathology
(Byron Kakulas, personal communication, 1994)18.
Other diseases that demonstrate time-dependent onset may not develop at a
linear rate, but may accelerate over time. For example, Stanley Prusiner
and his colleagues have demonstrated that the relatively rare prion
diseases--Creutzfeldt-Jakob disease (CJD), Kuru, and
Gerstman-Schenker-Straussler disease--represent a degenerative neuropathy
that may result from an accumulation of the beta-pleated-sheet form of the
prion protein in affected brain regions. The lead time for the conversion
of prion protein from its normal alpha-helix structure to the
beta-pleated-sheet conformation may progress slowly for many years, and
accelerate as more of the (beta}-pleated sheet form accumulates20,27. But
the infectious nature of the prion diseases also illustrates a mechanism
for reducing the time that it takes for the transition to occur:
Transmission of prions can provide protein aggregates that serve as a
seeding function for beta-sheet formation. Once symptoms develop, the
disease course appears to accelerate rapidly, almost resembling a log
function for the relationship of disease to time.
Triplet-repeat diseases, such as Huntington's disease,
dentato-rubropallidal-luyisan atrophy (DRPLA), and myotonic muscular
dystrophy, also suggest a mechanism for regulating the age of onset and the
apparent severity of disease14-16,20-24,28,29. Several genes are known to
have variable numbers of trinucleotide repeats that, when larger than the
normal range, can be associated with variable age of onset diseases. If the
rate of disease development is proportional to the size of the DNA triplet
repeats, then mildly affected patients who carry small numbers of repeats
and develop initial symptoms late in life could never be followed long
enough to develop the full range of disease that develops over decades.
Larger numbers of triplet repeats catalyze the rate of disease so that the
disease starts earlier and can proceed through a longer course of signs and
symptoms.
It is important to understand the role of ApoE and its normally occurring
variants in neuronal metabolism. It is here that the study of the genetics
has delineated a new area of neurobiology. From a practical point of view,
the definition of AD as a universal result of aging could lead to an
important therapeutic strategy. It may be possible to use drugs to mimic
the protective mechanisms of the ApoE2 isoform and thus extend the
distribution of age of onset of AD, which is equivalent to delaying the
disease by 20+ years30. What might happen after age 100 is of little
practical concern because only a small percentage of the population is
likely to survive that long.
The phenotypes of AD can be explained by APOE genotype and time.
The literature frequently refers to the phenotypic manifestations of AD,
beta-amyloid (A-beta) plaques and neurofibrillary tangles, as though they
are relatively invariable. In fact, the brains of people with AD typically
have great variations in their A-beta load. Nevertheless, some
investigators propose that A-beta fibril formation is the central factor in
the development of AD31,32. In the rare beta-PP717 mutation form of the
disease, a transgenic mouse model for increased beta-PP (amyloid precursor
protein) and A-beta production can lead to amyloid plaques and associated
gliosis33. Currently, there is no evidence of behavioral
abnormalities--dementia of AD--in these mice. Whether this mechanism
operates in beta-PP717 AD is uncertain because there is no current evidence
for increased A-beta deposition in patients with this mutation. Late-onset
AD, without beta-PP mutations, may have a wholly distinct pathogenesis. We
generally assume that the same plaques contain A-beta protein as well as
ApoE. Many investigators would be surprised to find that immunostained
serial sections from the cerebral cortices of AD patients may show both
processes, although not necessarily in the same plaques34. In fact, it was
during such studies that we noted ApoE immunoreactivity in cortical neurons
in addition to plaques, blood vessels, and glia. We also found that the
density of immunostained A-beta protein (amyloid load) is related to
different APOE genotypes and to the duration of disease from clinical onset
to death.
This evidence suggests that the isoforms of ApoE affect the rate of
deposition of amyloid and the apparent amyloid load at autopsy9,35.
Adjacent sections of brain from patients with AD stained with multiple
antibodies can illustrate interesting differences. For example, fully
formed plaques have prominent A-beta immunoreactivity, but ApoE
immunoreactivity may be observed in some plaques when A-beta staining is
not observed.
Without rehashing various theories of AD pathogenesis, suffice it to say
that ApoE can occur in neuritic plaques early in their formation, whereas
A-beta deposition typically becomes greater with time as a function of the
type of ApoE that an individual produces: ApoE4 > ApoE3 > ApoE2. Thus, when
we compare microscopic sections of brain from AD patients and from controls
for their APOE genotype and the length of AD disease between onset and
death, we can account for the large differences in A-beta load that others
have reported. Although the A-beta plaque deposition in AD is overwhelming
and impressive, its variability can be explained by the presence of
specific ApoE isoforms. Therefore, the phenotype is consistent with and
dependent on the genotype5.
Similar mutant genotypes may lead to diverse disease phenotypes.
Historically, diseases have been named and classified by their clinical
symptoms and characteristic pathology. If there is one dramatic consequence
of the molecular genetic revolution on contemporary studies of disease, it
is the extreme variations in phenotype that can come from similar genetic
lesions. Perhaps the most striking examples to date are the divergent
phenotypes that result from nearly identical PRPP178 mutations. This mutant
prion gene can cause either CJD or fatal familial insomnia (FFI), two
distinctly different fatal phenotypes21,36. It appears that a small change
in DNA sequence--a polymorphism at codon 129--dictates the phenotype.
(Although the prion protein can aggregate and form amyloid plaques, neither
PRPP178 disease, CJD, or FFI is characterized by prominent plaque
formation.)
Another example of similar genotypes and diverse phenotypes is DRPLA22-24.
A triplet-repeat variation in the same gene causes one set of disease
symptoms in the Japanese cases, which are clinically distinct from the
disease manifestations in African Americans, again pointing to the large
phenotypic effects of small variations in the genetic background.
My view of the future for the study of AD is that, by understanding how
different isoforms of ApoE participate in neuronal metabolism and the
mechanisms of pathogenesis that lead to the synaptic and neuronal loss
characteristic of AD, we can decipher other principles of cerebral
pathology and processes that are currently undefined14-16,20-24,37.
ApoE may be the "vitamin C" of neurons.
As stated above, ApoE is present in neurons of patients with late-onset AD
and in age-matched controls who do not have AD19,34 (see figure 3).
Although ApoE is made in large quantities outside the CNS, where it
contributes to bulk lipid metabolism, the quantity of ApoE that is present
in brain neurons is infinitesimal compared with the quantity in glial
cells19,38,39.
ApoE appears not to be made in neurons, but neurons probably acquire the
protein from astrocytes and require its presence. There must be a currently
undefined, neuron-specific mechanism that allows small amounts of
ApoE--once it is inside a neuron--to escape the intraneuronal endosomal
compartment and enter the cytoplasm. APOE-deficient knockout mice develop
early and severe abnormalities in the morphology of their cortical-neuron
dendrites, presumably as a consequence of having no ApoE in their brains40.
Thus, ApoE is similar to a vitamin, such as vitamin C, in human physiology:
The neuron does not make it but it is necessary for good health.
Our recent studies suggest that the ApoE3 and ApoE2 isoforms may lead to
better brain function over time than ApoE4. Studies of fraternal twins have
revealed lower cognitive performance in normal (non-AD) older adult male
twins who carry the APOE4 allele41. Also, a person's ability to recover
neuropsychological functions after stress, such as cardiopulmonary bypass
surgery, has been related to the presence or absence of an APOE4 allele42.
The neurobiology and hereditary factors that underlie neuropsychological
functioning and responses to environmental stress are only beginning to be
appreciated and studied. The normal metabolic role of small quantities of
cytoplasmic ApoE in neurons and the pathways for regulating the neuronal
intake of ApoE may provide new clues to the study of normal brain function
and response to metabolic stresses5,42.
ApoE seems to function as a neuronal metabolic co-factor for microtubular
maintenance and repair and, possibly, for other physiologic functions, and
it may play akey role in the selective vulnerability that characterizes
some neurodegenerative diseases. The intriguing localization of ApoE to
peroxisomes may suggest that oxygen metabolism is altered in several major
neurodegenerative diseases, including amyotrophic lateral sclerosis,
Parkinson's disease, and the collection of disorders that resemble AD but
that involve different brain pathologies17,43.
It is natural that the impetus for these basic studies should come from
scientists who are interested in the nature of diseases and the
possibilities for treatment. The studies of genes that increase
susceptibility to disease will need to be verified by epidemiological
studies controlled for age, sex, race, and ethnic variables. The
association of the APOE4 allele with more rapid progression to late-onset
AD is a wonderful example of how a previously known genetic variation that
can increase the susceptibility to fatal myocardial infarctions can be
extended to another age-dependent disease44. To understand the epidemiology
of diseases in different populations with variable frequencies of the APOE
alleles, we must focus our attention on the effects of genetic variations
as well as of interactions with diet, exercise habits, education, and other
environmental factors on the rate of disease expression.
Crystal balls do not provide as much light as do data from experiments.
Although this commentary may sound speculative, there is nothing more
conjectural than being asked to write about the future. I think basic
neurobiologists will lead the way in determining the role of ApoE in
neurons and that this information will feed back to investigators who are
interested in brain diseases. The ApoE-isoform-specific metabolism that
--PART.BOUNDARY.0.23195.emout04.mail.aol.com.809155340
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Date: 19 Aug 95 10:50:28 -0700
From: "Tebay, Wendy" <[log in to unmask]>
To: "athome" <[log in to unmask]> (Return requested)
Subject: apoliprotein
Click here to
---------------------------------------------------------------------=
---
Magazine: The Journal Of NIH Research Title: Alzheimer's Disease As A Mod=
el
Of Molecular Gerontology Author: Allen D. Roses Issue: April 1995
Alzheimer's Disease As A Model Of Molecular Gerontology
Allen D. Roses*
Abstract: APOE4, a naturally occurring allele of the gene encoding
apolipoprotein E (ApoE), increases the risk and lowers the age of
developing late-onset Alzheimer's disease (AD). ApoE is the major
apolipoprotein in the nervous system, and it may be necessary for the
growth, maintenance, and repair of axonal membranes and myelin, the fatty=
sheath that surrounds axons. ApoE occurs in many cell types outside the
central nervous system (CNS). Within the CNS, ApoE is expressed in
astrocytes and is also located in smaller amounts in the cytoplasm of
neurons in the cerebral cortex. My laboratory group has postulated that t=
he
E4 variant of ApoE may interact abnormally with neuronal cytoskeletal
proteins such as tau, favoring microtubule degradation and the formation =
of
neurofibrillary tangles, which occur in the brains of people with AD. In
this commentary, I suggest that naturally occurring polymorphisms of gene=
s
other than APOE not only contribute to genetic diversity, but also may
contribute to adult-onset diseases other than AD.
In 1993, we reported that APOE4, a naturally occurring allele of the gene=
that encodes apolipoprotein E (ApoE), increases the susceptibility for
developing late-onset Alzheimer's disease (AD)1-6. Since then, many other=
groups of investigators have confirmed the finding7-13. The impact of the=
APOE4 allele has become more obvious as people who are homozygous (APOE4/=
4)
or heterozygous (APOE3/4) grow older and develop disease at a significant=
ly
faster rate than their counterparts who carry the APOE2 allele or are
homozygous for APOE3 (APOE2/3, APOE2/4, or APOE3/3).
Now, it is useful to stop and reflect on an interesting and obvious
corollary. A polymorphic difference in a common gene, APOE, has a large
influence on susceptibility to AD, a common late-onset disease3,4. APOE4 =
is
not a mutant gene that causes AD. Instead, the APOE4 allele increases the=
risk and lowers the age of onset of developing AD--with APOE4 homozygotes=
at higher risk than heterozygotes. In contrast, the APOE2 allele appears =
to
decrease the risk and increase the age of onset for AD.
Although there are examples of statistically defined susceptibility facto=
rs
in other diseases such as heart disease and cancer, the large genetic
effect of the APOE4 allele on the increased rate of development of AD may=
forecast a common theme: Polymorphisms of other common genes may regulate=
the rate of disease expression over time in other late-onset neurological=
and nonneurological diseases.
During the past decade, we have used many naturally occurring DNA
polymorphisms as research tools to identify and locate genes associated
with particular diseases and to map the human, mouse, and other genomes.
Yet the biological effects of most polymorphisms have been virtually
ignored as factors important for the phenotypic diversity of a species
except when they are mutations for adisease. We tend to use the somewhat
derogatory term "housekeeping genes" for those genes that are expressed i=
n
many tissues (constituitively) and apparently are necessary for sustainin=
g
all cell types--as if these genes are less important than other, more
interesting, organ-specific genes (sometimes called "luxury genes"). Many=
widely expressed genes have polymorphic forms. APOE, the gene for
Huntington's disease, and many other genes are expressed in most tissues
and may play a key role in the rate of development of late-onset
diseases14-16. In essence, the polymorphisms at the APOE locus on
chromosome 19 determine the rate of disease development and the age of
clinical onset of AD. I believe there are two important lessons to be
learned independent of the specific role of ApoE in AD.
First, different protein isoforms expressed from polymorphic alleles may
have slightly altered function, with cumulative effects as people age. Th=
is
alteration could lead to variable rates of disease onset. It is well
accepted that during embryogenesis, many genes are transiently expressed
and are involved in different stages of the maturation of the organism.
Understanding the regulation of gene expression has, therefore, become an=
important problem in developmental biology. However, adults continue to
mature because of other mechanisms that generate genetic diversity. We ar=
e
now on the threshold of dissecting not only the genetic diversity that
contributes to adult-onset diseases, but also of identifying factors that=
may underlie biological differences among interactions between humans and=
their environment.
The relationship between APOE polymorphisms and AD was less important whe=
n
people did not live more than 70 years and AD was a less prevalent diseas=
e.
But now that we have extended our lifespans, we have also uncovered new
limitations that previously were not subjected to evolutionary pressures =
or
natural selection. The same APOE4 allele that increases our age-dependent=
risk of AD must also convey some selective advantage over the other
variants of APOE to maintain itself in more primitive populations,
including the western Australian aboriginees, Fore tribesmen of New Guine=
a,
and Yanomami Indians of northwestern Brazil17,18.
The second important observation affects basic neurobiology and emerges
from the sudden focus of attention on ApoE as a factor in brain metabolis=
m
of AD. There is no evidence that ApoE is expressed in brain neurons and,
therefore, the conclusion is that ApoE is not involved in intraneuronal
metabolism. This belief generated immediate and repeated criticism of our=
suggestion in 1994 that ApoE3 and ApoE4 interact differently with
microtubule-associated proteins (MAP2 or tau) in neurons in the cerebral
cortex. If ApoE does not get into the neuronal cytoplasm, the reasoning
went, then interactions with the cytoskeletal proteins MAP2 or tau would =
be
in vitro artifacts without biological significance. But our recent
detection of ApoE in the cytoplasm of normal cortical neurons as well as
its accepted high concentration in astrocytes creates questions about its=
normal metabolic function (discussed below) and raises an interesting and=
paradoxical scenario19.
AD involves the brain, and the disease is characterized by the loss of
synaptic density and cortical neurons. APOE, the relevant genetic factor,=
encodes a 34-kilodalton glycoprotein whose mRNA is not known to be
expressed in neurons. Therefore, there must be specific mechanisms for
neurons to take up extracellular or astrocyte-secreted ApoE. Different
isoforms of a protein that are not made in neurons can nevertheless have =
a
profound effect on the viability of neurons. Therefore, gene expression i=
n
neurons is not equivalent to disease expression involving neurons. This i=
s
a critical concept that is relevant to many current experiments that
attempt to identify organ-specific candidate genes as the site of mutatio=
ns
that lead to disease of that organ. Many brain diseases have been assumed=
to involve genes uniquely expressed in the brain. In fact, in most cases,=
the mutated gene is widely expressed but its clinical effect on late-onse=
t
degeneration appears specific to certain subsets of neurons14-16,20-24.
When does a normal genetic trait become a disease gene?
A genetic trait can be defined as an inherited variable. A disease is a
morbid constellation of symptoms and signs. Some traits are benign
throughout life, but increased longevity may provide the opportunity for
the effect of other traits to contribute to the development of a disease.=
We are now at the threshold of differentiating a disease process from a
genetic variability of neuronal aging.
Figure 1 illustrates the distribution of the age of onset of AD in 72
families with late-onset inherited disease and 198 control subjects (with=
sporadic AD) as a function of the five commonly inherited APOE genotypes5=
=2E
(APOE2/2 represents less than 0.05 percent of the U.S. population, and
there were not enough data to include it in the figure.) With the caveat
that the APOE4 effect actually starts before 60 years of age12,13, Figure=
1
represents the relationship between APOE polymorphisms and the age of ons=
et
of AD. The prevalence of AD in a population depends on the relative APOE
allele frequencies, the longevity of the society, and perhaps ethnic and/=
or
racial genetic differences in other susceptibility genes.
Several points are readily apparent from these data. The mean age of onse=
t
for individuals in the population with the APOE4/4 genotype (approximatel=
y
2 percent of the population) is less than 70 years of age; for APOE2/3
individuals (approximately 10 percent of the population), it is more than=
90 years of age. The mean age of onset for APOE3/4 individuals
(approximately 20 percent of the population) is in the mid-70s. Thus, a
difference in the APOE genotype alone stratifies the distribution of age =
of
onset of AD, with a mean difference of more than 20 years.
There is another fascinating point that can be appreciated from Figure 1.=
Even with the "best" genotype, APOE2/3, everyone would get AD if they liv=
ed
to 140 years. So what is the relationship of APOE polymorphisms to "aging=
"?
Other studies of the associations of APOE alleles with longevity have
approached this question in reverse, but with the same general results.
In a 1994 study of 338 French centenarians, Schachter et al.2 found that
the allele frequency of APOE2 in the centenarians was double that of a
non-aged French control group (0.068 to 0.1280) and that the allele
frequency of APOE4 was about half (0.112 to 0.052). The relative
proportions of APOE alleles remaining in the centenarians could be
approximated by using Figure 1 to estimate the alleles left in the
population at age 100.
There are several possible interpretations for these data. The most obvio=
us
is that the process of AD occurs in everyone at a rate influenced by thei=
r
APOE genotype. A genetic trait becomes a susceptibility gene for a diseas=
e
when the individuals at risk survive long enough for the disease to be
expressed. APOE4 increases risk and lowers the mean age of onset of AD. I=
n
contrast, APOE2 appears to protect against AD until well past current hum=
an
lifespans. We are living longer today than at any previous time in human
history. Genetic traits that are beneficial earlier in life may be select=
ed
for during the first 50 years but may generate difficulties in old age.
Thus, time is the variable that has changed most significantly and that h=
as
led to the current epidemic of AD. APOE may be a particularly important
genetic locus for dissecting age- or time-related metabolic processes tha=
t
occur in late adult life; the APOE gene may be a window on molecular
gerontology.
Clinicians traditionally measure the duration of disease as dating from t=
he
apparent age of onset. Of course, we realize that the disease processes m=
ay
start years before we observe the resulting morbidity. Using sophisticate=
d
laboratory and imaging techniques, we attempt to identify markers of
disease prior to the actual appearance of clinical symptoms26. In fact,
late-onset diseases may well start before development ceases. They may
involve a lifelong process that manifests itself only when signs and
symptoms develop. Late-onset AD is just such a disease.
Two decades ago, when the expected age of survival was about 67 years in
men and 72 years in women, AD was relatively uncommon. But with increased=
longevity, processes leading to disease that need more time to develop
begin to appear. An isoform-specific effect of a protein (such as ApoE) o=
n
the distribution of the age of onset of a disease would go unnoticed
without the effect of longer survival. In fact, in primitive populations
where the allele frequency of APOE4 approaches the 0.4 level, which is
frequently observed with AD, the individuals in the population do not liv=
e
long enough to develop late-onset disease. For example, the allele
frequency of APOE4 is 0.39 in western Australian aborigines, yet there ha=
ve
been only rare autopsies in aborigines over the age of 56, and none of
these people had developed AD. These autopsies have been performed during=
the past 30 years at the Royal Perth Hospital Department of Neuropatholog=
y
(Byron Kakulas, personal communication, 1994)18.
Other diseases that demonstrate time-dependent onset may not develop at a=
linear rate, but may accelerate over time. For example, Stanley Prusiner
and his colleagues have demonstrated that the relatively rare prion
diseases--Creutzfeldt-Jakob disease (CJD), Kuru, and
Gerstman-Schenker-Straussler disease--represent a degenerative neuropathy=
that may result from an accumulation of the beta-pleated-sheet form of th=
e
prion protein in affected brain regions. The lead time for the conversion=
of prion protein from its normal alpha-helix structure to the
beta-pleated-sheet conformation may progress slowly for many years, and
accelerate as more of the (beta}-pleated sheet form accumulates20,27. But=
the infectious nature of the prion diseases also illustrates a mechanism
for reducing the time that it takes for the transition to occur:
Transmission of prions can provide protein aggregates that serve as a
seeding function for beta-sheet formation. Once symptoms develop, the
disease course appears to accelerate rapidly, almost resembling a log
function for the relationship of disease to time.
Triplet-repeat diseases, such as Huntington's disease,
dentato-rubropallidal-luyisan atrophy (DRPLA), and myotonic muscular
dystrophy, also suggest a mechanism for regulating the age of onset and t=
he
apparent severity of disease14-16,20-24,28,29. Several genes are known to=
have variable numbers of trinucleotide repeats that, when larger than the=
normal range, can be associated with variable age of onset diseases. If t=
he
rate of disease development is proportional to the size of the DNA triple=
t
repeats, then mildly affected patients who carry small numbers of repeats=
and develop initial symptoms late in life could never be followed long
enough to develop the full range of disease that develops over decades.
Larger numbers of triplet repeats catalyze the rate of disease so that th=
e
disease starts earlier and can proceed through a longer course of signs a=
nd
symptoms.
It is important to understand the role of ApoE and its normally occurring=
variants in neuronal metabolism. It is here that the study of the genetic=
s
has delineated a new area of neurobiology. From a practical point of view=
,
the definition of AD as a universal result of aging could lead to an
important therapeutic strategy. It may be possible to use drugs to mimic
the protective mechanisms of the ApoE2 isoform and thus extend the
distribution of age of onset of AD, which is equivalent to delaying the
disease by 20+ years30. What might happen after age 100 is of little
practical concern because only a small percentage of the population is
likely to survive that long.
The phenotypes of AD can be explained by APOE genotype and time.
The literature frequently refers to the phenotypic manifestations of AD,
beta-amyloid (A-beta) plaques and neurofibrillary tangles, as though they=
are relatively invariable. In fact, the brains of people with AD typicall=
y
have great variations in their A-beta load. Nevertheless, some
investigators propose that A-beta fibril formation is the central factor =
in
the development of AD31,32. In the rare beta-PP717 mutation form of the
disease, a transgenic mouse model for increased beta-PP (amyloid precurso=
r
protein) and A-beta production can lead to amyloid plaques and associated=
gliosis33. Currently, there is no evidence of behavioral
abnormalities--dementia of AD--in these mice. Whether this mechanism
operates in beta-PP717 AD is uncertain because there is no current eviden=
ce
for increased A-beta deposition in patients with this mutation. Late-onse=
t
AD, without beta-PP mutations, may have a wholly distinct pathogenesis. W=
e
generally assume that the same plaques contain A-beta protein as well as
ApoE. Many investigators would be surprised to find that immunostained
serial sections from the cerebral cortices of AD patients may show both
processes, although not necessarily in the same plaques34. In fact, it wa=
s
during such studies that we noted ApoE immunoreactivity in cortical neuro=
ns
in addition to plaques, blood vessels, and glia. We also found that the
density of immunostained A-beta protein (amyloid load) is related to
different APOE genotypes and to the duration of disease from clinical ons=
et
to death.
This evidence suggests that the isoforms of ApoE affect the rate of
deposition of amyloid and the apparent amyloid load at autopsy9,35.
Adjacent sections of brain from patients with AD stained with multiple
antibodies can illustrate interesting differences. For example, fully
formed plaques have prominent A-beta immunoreactivity, but ApoE
immunoreactivity may be observed in some plaques when A-beta staining is
not observed.
Without rehashing various theories of AD pathogenesis, suffice it to say
that ApoE can occur in neuritic plaques early in their formation, whereas=
A-beta deposition typically becomes greater with time as a function of th=
e
type of ApoE that an individual produces: ApoE4 > ApoE3 > ApoE2. Thus, wh=
en
we compare microscopic sections of brain from AD patients and from contro=
ls
for their APOE genotype and the length of AD disease between onset and
death, we can account for the large differences in A-beta load that other=
s
have reported. Although the A-beta plaque deposition in AD is overwhelmin=
g
and impressive, its variability can be explained by the presence of
specific ApoE isoforms. Therefore, the phenotype is consistent with and
dependent on the genotype5.
Similar mutant genotypes may lead to diverse disease phenotypes.
Historically, diseases have been named and classified by their clinical
symptoms and characteristic pathology. If there is one dramatic consequen=
ce
of the molecular genetic revolution on contemporary studies of disease, i=
t
is the extreme variations in phenotype that can come from similar genetic=
lesions. Perhaps the most striking examples to date are the divergent
phenotypes that result from nearly identical PRPP178 mutations. This muta=
nt
prion gene can cause either CJD or fatal familial insomnia (FFI), two
distinctly different fatal phenotypes21,36. It appears that a small chang=
e
in DNA sequence--a polymorphism at codon 129--dictates the phenotype.
(Although the prion protein can aggregate and form amyloid plaques, neith=
er
PRPP178 disease, CJD, or FFI is characterized by prominent plaque
formation.)
Another example of similar genotypes and diverse phenotypes is DRPLA22-24=
=2E
A triplet-repeat variation in the same gene causes one set of disease
symptoms in the Japanese cases, which are clinically distinct from the
disease manifestations in African Americans, again pointing to the large
phenotypic effects of small variations in the genetic background.
My view of the future for the study of AD is that, by understanding how
different isoforms of ApoE participate in neuronal metabolism and the
mechanisms of pathogenesis that lead to the synaptic and neuronal loss
characteristic of AD, we can decipher other principles of cerebral
pathology and processes that are currently undefined14-16,20-24,37.
ApoE may be the "vitamin C" of neurons.
As stated above, ApoE is present in neurons of patients with late-onset A=
D
and in age-matched controls who do not have AD19,34 (see figure 3).
Although ApoE is made in large quantities outside the CNS, where it
contributes to bulk lipid metabolism, the quantity of ApoE that is presen=
t
in brain neurons is infinitesimal compared with the quantity in glial
cells19,38,39.
ApoE appears not to be made in neurons, but neurons probably acquire the
protein from astrocytes and require its presence. There must be a current=
ly
undefined, neuron-specific mechanism that allows small amounts of
ApoE--once it is inside a neuron--to escape the intraneuronal endosomal
compartment and enter the cytoplasm. APOE-deficient knockout mice develop=
early and severe abnormalities in the morphology of their cortical-neuron=
dendrites, presumably as a consequence of having no ApoE in their brains4=
0.
Thus, ApoE is similar to a vitamin, such as vitamin C, in human physiolog=
y:
The neuron does not make it but it is necessary for good health.
Our recent studies suggest that the ApoE3 and ApoE2 isoforms may lead to
better brain function over time than ApoE4. Studies of fraternal twins ha=
ve
revealed lower cognitive performance in normal (non-AD) older adult male
twins who carry the APOE4 allele41. Also, a person's ability to recover
neuropsychological functions after stress, such as cardiopulmonary bypass=
surgery, has been related to the presence or absence of an APOE4 allele42=
=2E
The neurobiology and hereditary factors that underlie neuropsychological
functioning and responses to environmental stress are only beginning to b=
e
appreciated and studied. The normal metabolic role of small quantities of=
cytoplasmic ApoE in neurons and the pathways for regulating the neuronal
intake of ApoE may provide new clues to the study of normal brain functio=
n
and response to metabolic stresses5,42.
ApoE seems to function as a neuronal metabolic co-factor for microtubular=
maintenance and repair and, possibly, for other physiologic functions, an=
d
it may play akey role in the selective vulnerability that characterizes
some neurodegenerative diseases. The intriguing localization of ApoE to
peroxisomes may suggest that oxygen metabolism is altered in several majo=
r
neurodegenerative diseases, including amyotrophic lateral sclerosis,
Parkinson's disease, and the collection of disorders that resemble AD but=
that involve different brain pathologies17,43.
It is natural that the impetus for these basic studies should come from
scientists who are interested in the nature of diseases and the
possibilities for treatment. The studies of genes that increase
susceptibility to disease will need to be verified by epidemiological
studies controlled for age, sex, race, and ethnic variables. The
association of the APOE4 allele with more rapid progression to late-onset=
AD is a wonderful example of how a previously known genetic variation tha=
t
can increase the susceptibility to fatal myocardial infarctions can be
extended to another age-dependent disease44. To understand the epidemiolo=
gy
of diseases in different populations with variable frequencies of the APO=
E
alleles, we must focus our attention on the effects of genetic variations=
as well as of interactions with diet, exercise habits, education, and oth=
er
environmental factors on the rate of disease expression.
Crystal balls do not provide as much light as do data from experiments.
Although this commentary may sound speculative, there is nothing more
conjectural than being asked to write about the future. I think basic
neurobiologists will lead the way in determining the role of ApoE in
neurons and that this information will feed back to investigators who are=
interested in brain diseases. The ApoE-isoform-specific metabolism that
leads to AD will be defined and targeted for pharmacologic therapy. As a
"long-shot" bet, many of my colleagues in AD research who are firmly
engrossed in studying the role of A-beta in AD may come to understand tha=
t
an individual's genotype explains his or her phenotype, not that phenotyp=
e
predicts mechanisms of pathogenesis. The concept of several "Alzheimer's
diseases" will become more apparent; whether and how they are interrelate=
d
will be tested45. Being somewhat of agambler, my "surest bet" is that new=
concepts of basic science of the brain will emerge from controversial dat=
a
that cannot now be explained by prevailing hypotheses.
If AD is a universal corollary of long life with variations in APOE
genotype being responsible for the proportion of individuals who will
develop AD during their life span, then nothing needs to be replaced by
gene therapy. Indeed, we need to enhance or inhibit by 10-15 percent the
rate of relevant critical reactions to push the curve of age of AD onset =
to
the right. If genotype does predict phenotype, then we must describe the
genetically relevant mechanisms that are specifically affected by differe=
nt
ApoE isoforms--and then determine how to slow the processes down. The AD
drugs of the future will target genetically relevant processes, rather th=
an
the phenotypic consequences of the disease.
Acknowledgment
Without the far-sighted thinking of Dr. Zavin Khachaturian and the Nation=
al
Institute on Aging (NIA), the support for the discovery of APOE as a
susceptibility locus for Alzheimer's disease would not have occurred. NIA=
funding of the Joseph and Kathleen Bryan Alzheimer's Disease Research
Center and the Leadership and Excellence in Alzheimer's Disease (LEAD)
Award provided most of the financial support. The critical element of the=
LEAD Award--not having to undergo competitive review for seven
years--provided an opportunity to go in new directions, rather than pursu=
e
safe renewals.
References
1. W.J. Strittmatter, K.H. Weisgraber, D.Y. Huang, L.M. Dong, G.S.
Salvesen, M.A. Pericak-Vance et al., "Binding of human apolipoprotein E t=
o
synthetic amyloid beta peptide: isoform-specific effects and implications=
for late-onset Alzheimer disease," Proc. Natl. Acad. Sci. USA 90, 8098
(1993).
2. A.M. Saunders, W.J. Strittmatter, D. Schmechel, P.H. St. George-Hyslop=
,
M.A. Pericak-Vance, S.H. Joo et al., "Association of apolipoprotein E
allele epsilon 4 with late-onset familial and sporadic Alzheimer's
disease," Neurology 43, 1467 (1993).
3. E.H. Corder, A.M. Saunders, W.J. Strittmatter, D.E. Schmechel P.C.
Gaskell, G.W. Small et al., "Gene dose of apolipoprotein E type 4 allele
and the risk of Alzheimer's disease in late onset families," Science 261,=
921 (1993). (See "Comments" section.)
4. E.H. Corder, A.M. Saunders, N.J. Risch, W.J. Strittmatter, D.E.
Schmechel, P.C. Gaskell Jr. et al., "Protective effect of apolipoprotein =
E
type 2 allele for late onset Alzheimer disease," Nat. Genet. 7, 180 (1994=
).
5. A.D. Roses, "Apolipoprotein E affects the rate of Alzheimer disease
expression: beta-amyloid burden is a secondary consequence dependent on
APOE genotype and duration of disease," J. Neuropathol. Exp. Neurol. 53,
429 (1994). (See "Comments" section of this review paper.)
6. A.M. Saunders, K. Schmader, J.C. Breitner, M.D. Benson, W.T. Brown, L.=
Goldfarb et al., "Apolipoprotein E epsilon 4 allele distributions in
late-onset Alzheimer's disease and in other amyloid-forming diseases,"
Lancet 342, 710 (1993). (See "Comments" section.)
7. G. Lucotte, F. David, S. Visvikis, M.B. Leininger, G. Siest, M.C. Babr=
on
et al., "Apolipoprotein E-epsilon 4 allele and Alzheimer's disease," Lanc=
et
342, 1309 (1993). (letter)
8. J. Poirier, J. Davignon, D. Bouthillier, S. Kogan, P. Bertrand, and S.=
Gauthier, "Apolipoprotein E polymorphism and Alzheimer's disease," Lancet=
342, 697 (1993). (See "Comments" section.)
9. G.W. Rebeck, J.S. Reiter, D.K. Strickland, and B.T. Hyman,
"Apolipoprotein E in sporadic Alzheimer's disease: allelic variation and
receptor interactions," Neuron 11, 575 (1993).
10. D.S. Borgaonkar, L.C. Schmidt, S.E. Martin, M.D. Kanzer, L. Edelsohn,=
J. Growdon et al., "Linkage of late-onset Alzheimer's disease with
apolipoprotein E type 4on chromosome 19," Lancet 342, 625 (1993). (letter=
)
11. A. Ueki, M. Kawano, Y. Namba, M. Kawakami, and K. Ikeda, "A high
frequency of apolipoprotein E4 isoprotein in Japanese patients with
late-onset nonfamilial Alzheimer's disease," Neurosci. Lett. 163, 166
(1993).
12. K. Okuizumi, O. Onodera, H. Tanaka, H. Kobayashi, S. Tsuji, H.
Takahashi et al., "ApoE-epsilon 4 and early-onset Alzheimer's," Nat. Gene=
t.
7, 10 (1994). (letter)
13. C.M. van Duijn, P. de Knijff, M. Cruts, A Wehnert, L.M. Havekes, A.
Hofman et al., "Apolipoprotein E4 allele in a population-based study of
early-onset Alzheimer's disease," Nat. Genet. 7, 74 (1994).
14. S.H. Li, G. Schilling, W.S. Young III, X.J. Li, R.L. Margolis, O.C.
Stine et al., "Huntington's disease gene (IT15) is widely expressed in
human and rat tissues," Neuron 11, 985 (1993).
15. S.E. Andrew, Y.P. Goldberg, B. Kremer, H. Telenius, J. Theilmann, S.
Adam et al. "The relationship between trinucleotide (CAG) repeat length a=
nd
clinical features of Huntington's disease," Nat. Genet. 4, 398 (1993). (S=
ee
"Comments" section.)
16. O.C. Stine, N. Pleasant, M.L. Franz, M.H. Abbott, S.E. Folstein, and
C.A. Ross, "Correlation between the onset age of Huntington's disease and=
length of the trinucleotide repeat in IT-15," Hum. Mol. Genet. 2, 1547
(1993).
17. D.E. Crews, M.I. Kamboh, C.J. Mancilha, and B. Kottke, "Population
genetics of apolipoprotein A-4, E, and H polymorphisms in Yanomami Indian=
s
of northwestern Brazil: associations with lipids, lipoproteins, and
carbohydrate metabolism," Hum. Biol. 65, 211 (1993).
18. F.M. van Bockxmeer, "ApoE and ACE genes: impact on human longevity,"
Nat. Genet. 6, 4 (1994).
19. S.H. Han, G. Einstein, K.H. Weisgraber, W.J. Strittmatter, A.M.
Saunders, V.M. Pericak et al., "Apolipoprotein E is localized to the
cytoplasm of human cortical neurons: a light and electron microscopic
study," J. Neuropathol. Exp. Neurol. 53, 535 (1994).
20. S.B. Prusiner, "Molecular biology of prion diseases," Science 252, 15=
15
(1991).
21. R. Medori, H.J. Tritschler, A. LeBlanc, F. Villare, V. Manetto, H.Y.
Chen et al., "Fatal familial insomnia, a prion disease with a mutation at=
codon 178 of the prion protein gene," N. Engl. J. Med. 326, 444 (1992).
(See "Comments" section.)
22. S. Nagafuchi, H. Yanagisawa, K. Sato, T. Shirayama, E. Ohsaki, M. Bun=
do
et al., "Dentatorubral and pallidoluysian atrophy expansion of an unstabl=
e
CAG trinucleotide on chromosome 12p," Nat. Genet. 6, 14 (1994).
23. J.R. Burke, M.S. Wingfield, K.E. Lewis, A.D. Roses, J.E. Lee, C.
Hulette et al., "The Haw River Syndrome: dentatorubropallidoluysian atrop=
hy
(DRPLA) in an African-American family," Nat. Genet. 7, 521 (1994).
24. R. Koide, T. Ikeuchi, O. Onodera, H. Tanaka, S. Igarashi, K. Endo et
al., "Unstable expansion of CAG repeat in hereditary
dentatorubral-pallidoluysian atrophy (DRPLA)," Nat. Genet. 6, 9 (1994).
25. F. Schachter, D.L. Faure, F. Guenot, H. Rouger, P. Froguel, G.L.
Lesueur et al., "Genetic associations with human longevity at the APOE an=
d
ACE loci," Nat. Genet. 6, 29 (1994).
26. G.W. Small, J.C. Mazziotta, M.T. Collins, L.R. Baxter, M.E. Phelps,
M.A. Mandelkern et al., "Apolipoprotein E type 4 allele and cerebral
glucose metabolism in relatives at risk for familial Alzheimer disease,"
JAMA (in press).
27. S.B. Prusiner, "Genetic and infectious prion diseases," Arch. Neurol.=
50, 1129 (1993).
28. H.G. Harley, J.D. Brook, S.A. Rundle, S. Crow, W. Reardon, A.J. Buckl=
er
et al., "Expansion of an unstable DNA region and phenotypic variation in
myotonic dystrophy," Nature 355, 545 (1992). (See "Comments" section.)
29. A.D. Roses, "Myotonic dystrophy," in The Molecular and Genetic Basis =
of
Neurological Disease, R.N. Rosenberg, S.B. Prusiner, S. DiMauro, R.L.
Barchi, and L.M. Kunkel, Eds. (Butterworth-Heinemann, Boston, 1993), pp.
633-646.
30. W.J. Strittmatter, K.H. Weisgraber, M. Goedert, A.M. Saunders, D.
Huang, E.H. Corder et al., "Hypothesis: microtubule instability and paire=
d
helical filament formation in the Alzheimer disease brain are related to
apolipoprotein E genotype," Exp. Neurol. 125, 163 (1994) (review).
31. J. Hardy and D. Allsop, "Amyloid deposition as the central event in t=
he
aetiology of Alzheimer's disease," Trends Pharmacol. Sci. 12, 383 (1991)
(review).
32. D.J. Selkoe, "Alzheimer's disease: a central role for amyloid," J.
Neuropathol. Exp. Neurol. 53, 438 (1994). (See "Comments" section of this=
review paper.)
33. D. Garnes, D. Adams, R. Alessandrini, R. Barbour, T. Carr, J. Clemens=
et al., "Alzheimer-type neuropathology in transgenic mice overexpressing
V717F beta-amyloid precursor protein," Nature 373 523 (1995).
34. S.H. Han, C. Hulette, A.M. Saunders, G. Einstein, V.M. Pericak, W.J.
Strittmatter et al., "Apolipoprotein E is present in hippocampal neurons
without neurofibrillary tangles in Alzheimer's disease and in age-matched=
controls," Exp. Neurol. 128, 13 (1994).
35. D.E. Schmechel, A.M. Saunders, W.J. Strittmatter, B.J. Crain, C.M.
Hulette, S.H. Joo et al., "Increased amyloid beta-peptide deposition in
cerebral cortex as a consequence of apolipoprotein E genotype in late-ons=
et
Alzheimer disease," Proc. Natl. Acad. Sci. USA 90, 9649 (1993).
36. L.G. Goldfarb, R.B. Petersen, M. Tabaton, P. Brown, A.C. LeBlanc, P.
Montagna et al., "Fatal familial insomnia and familial Creutzfeldt-Jakob
disease: disease phenotype determined by a DNA polymorphism," Science 258=
,
806 (1992).
37. T.T. Warner, G.G. Lennox, I. Janota, and A.E. Harding,
"Autosomal-dominant dentatorubropallidoluysian atrophy in the United
Kingdom," Mov. Disord. 9, 289 (1994).
38. J.F. Diedrich, H. Minnigan, R.I. Carp, J.N. Whitaker, R. Race, W. Fre=
y
II et al., "Neuropathological changes in scrapie and Alzheimer's disease
are associated with increased expression of apolipoprotein E and cathepsi=
n
D in astrocytes," J. Virol. 65, 4759 (1991).
39. J. Poirier, A. Baccichet, D. Dea, and S. Gauthier, "Cholesterol
synthesis and lipoprotein reuptake during synaptic remodelling in
hippocampus in adult rats," Neuroscience 55, 81 (1993).
40. E. Masliah, M. Mallory, N. Ge, M. Alford, I. Veinbergs, and A.D. Rose=
s,
"Neurodegeneration in the central nervous system of apoE-deficient mice,"=
Exp. Neurol. (submitted for publication).
41. T. Reed, D. Carmelli, G.E. Swan, J.C.S. Breitner, K.A. Welsh, G.P.
Jarvik et al., "Lower cognitive performance in normal older male twins
carrying the apolipoprotein Ee4 allele," Arch. Neurol. 51, 11 (1994).
42. B. Tardiff, M. Newman, A. Saunders, W. Strittmatter, L.R. Smith, A.
Roses et al., "Apolipoprotein E allele frequency in patients with cogniti=
ve
defects following cardiopulmonary bypass," Circulation 90, 1 (1994).
43. R.L. Hamilton, J.S. Wong, L.S. Guo, S. Krisans, and R.J. Havel,
"Apolipoprotein E localization in rat hepatocytes by immunogold labeling =
of
cryothin sections," J. Lipid Res. 31, 1589 (1990).
44. P.W.F. Wilson, R.H. Myers, M.G. Larson, J.M. Ordovas, P.A. Wolf, and
E.J. Schaefer, "Apolipoprotein E alleles, dyslipidemia, and coronary hear=
t
disease: the Framingham offspring study," JAMA 272, 1666 (1994).
45. A.D. Roses, "The Alzheimer diseases," in Current Neurology, S.H. Appe=
l,
Ed. (Mosby-Year Book, Chicago, 1994), pp. 111-141.
*Alzheimer's Disease Research Center, Bryan Research Building, Room 227,
Duke University Medical Center, Durham, NC 27710-2900. Comments intended
for publication should be addressed to Advice and Dissent, The Journal Of=
NIH Research, 1444 I St., N.W., Suite 1000, Washington, DC 20005.
Allen D. Roses is the Jefferson Pilot Professor of Neurobiology and
Neurology in the Departments of Medicine and Neurobiology, Bryan
Alzheimer's Disease Research Center, Duke University Medical Center,
Durham, N.C.
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