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Apolipoprotein E genotyping in the diagnosis of alzheimer's disease A cautionary view.

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EDITORIALS
Apolipoprotein E
Genotyping in the
Diagnosis of Alzheimer’s
Dis&e: A Cautionary
View
The apolipoprotein E (APOE) gene comes in the following three varieties or alleles: €2, €3, and €4. We all
inherit one allele from each of our parents such that
we are either heterozygous (have two different alleles)
or homozygous (have two copies of the same allele).
APOE is involved in cholesterol transport and the €4
allele has been known for several years to be a risk
factor for coronary artery disease {11.
The more recent association of the APOE4containing genotype with Alzheimer’s disease (AD)
represents a major step forward in our understanding
of this common and important cause of dementia.
APOE4 appears to be a major risk factor for A D that
especially seems to influence age of onset. APOE may
be directly involved in the pathogenesis of amyloid
plaque and/or neurofibrillary tangle formation, but the
precise mechanisms remain to be discovered. The
APOE4/AD association was first recognized by Dr Allen Roses and his colleagues at Duke University and
their initial observations have had tremendous heuristic value as exemplified by scores of studies published
on this topic in the past 2 years 12-41.
An obvious practical question has risen: Is APOE
genotyping useful in the diagnostic evaluation of patients with dementia? Elsewhere in this issue of Annals,
Roses I51 strongly answers this question in the affirmative. However, several important caveats need to be
carefully addressed before APOE is used as a diagnostic test for AD.
Roses [ 5 ] correctly points out that APOE genotypes
should not be used as a predictive test for A D in
asymptomatic individuals. The longitudinal data for
such prediction is simply not available. Furthermore,
an important point to keep in mind throughout this
discussion is that there is not an absolute one-to-one
correlation of the €4 allele with AD. That is, although
€4 correlates with the disease, persons without €4 may
have A D and persons with €4 may never develop the
disease.
Regarding diagnostic testing, it should be noted that
the critical Table 3 in the study by Roses 151 contains
numerous assumptions, estimates, and hypothetical
numbers as duly noted in the fine print of the legend.
For example, no one knows the APOE genotype fre-
2
Annals of Neurology
Vol 38 No 1 July 1395
quencies in a general heterogeneous population of demented persons without AD, and this is crucial missing
information. Such information is being gathered but is
far from complete at the present time. For example,
we do not yet have complete data from different populations regarding the APOE genotype frequencies in
multi-infarct dementia, diffuse Lewy body disease, and
depression, three conditions that form an important
part of the differential diagnosis of dementia [6-101.
A significant increase in the frequency of the €4 allele
in any of these conditions would decrease the value of
APOE testing for AD. The €4 allele apparently is not
associated with dementia in Parkinson’s disease, Creutzfeldt-Jakob disease, or progressive supranuclear palsy
[ 1 1- 131. Also, age, sex, and ethnic background correlate with APOE genotypes in various ways that require
further delineation. The €4 allele, for example, is more
common in Finnish and black African populations and
its frequency decreases with advancing age in all groups
(presumably partly related to mortality from coronary
artery disease) 114-181. The role of the €2 allele is
also not yet clear. Is it a risk factor for A D in some
populations and “protective” in others {161? Further
study is needed.
Because the numbers in Table 3 of the study by
Roses [51 are “rough” estimates, they should have
identified confidence limits. This lack of confidence
limits gives the reader a false sense of security regarding the numbers. For example, in the first row for the
~ 4 / 4genotype, if the control figure in column 5 were
10% instead of 2010, then the percentage of patients
with A D in column 8 would’be about 7794 (instead
of 94%)).Likewise, if the odds of A D before APOE
testing in column 6 were 50% instead of 66%, then
the percentage of patients with A D in column 8 would
be approximately 89%. These are not trivial differences. The important point is that the numbers are
estimates that will change (up or down) as more data
is accumulated.
Also, precisely what role does age play? Surely the
APOE genotype has a different diagnostic significance
in a 40-year-old person with dementia versus a 75year-old, but Table 3 does not indicate these differences.
From a practical standpoint, how would APOE genotyping help us in the differential diagnosis of dementia?
Regarding the €4 allele, there are the following three
possibilities in any given patient.
(1) The patient will have no €4 allele. In this case,
the usual diagnostic evaluation will proceed without
change searching for other causes of dementia.
(2) The patient has a single €4 allele. Using the figures in Table 3 of the study by Roses [ 5 ] (remembering these are estimates), the probability the patient has
A D is 50 to 81%. It is unlikely that these odds would
alter the decision to proceed with the usual diagnostic
evaluation, because there is a 17 to 50% likelihood of
some other diagnosis. (The majority of patients will
fall into these first two categories.)
( 3 ) The patient is an ~ 4 / homozygote.
4
This is the
least likely outcome because ~ 4 / homozygotes
4
have a
frequency of only about 2% in the general population
and roughly 10 to 20% in the documented A D population. The figures of Roses (51 indicate that an € 4 4
homozygote with dementia has a 94% probability of
having AD. This is an undeniably strong correlation.
However, accepting these estimates (and the confidence limits here might be at least 90 to 98%), what
should the prudent neurologist do? Obviously, persons
with the ~ 4 / genotype
4
are not protected from other
causes of dementia. Since these would include treatable
causes such as B,, deficiency and hypothyroidism, it is
likely that these and similar tests would be obtained
regardless of APOE genotype. More expensive tests
such as computed tomographic or magnetic resonance
imaging scans would be carefully considered and Roses
[ 5 ] rightly points out that such tests might be difficult
to obtain under so-called managed health care plans.
However, there is nothing to preclude an individual
with the ~ 4 / 4genotype from having a large frontal
meningioma or normal-pressure hydrocephalus as a
cause of dementia. Thus, relatively expensive imaging
tests are still likely to be obtained frequently in this
situation.
The analogy with human immunodeficiency virus
(HIV) testing presents a similar although not identical
scenario. An individual with dementia and a positive
test for HIV may have direct involvement of the central nervous system with the HIV virus as the cause of
the dementing process. However, because other treatable and not treatable causes of the dementia remain
possible (for example, toxoplasmosis and progressive
multifocal leukoencephalopathy, respectively), additional diagnostic testing including expensive imaging
studies are likely to be ordered.
Furthermore, we are learning that there can be unexpected consequences of clinical genetic testing [17}.
For example, if a demented person is discovered to be
an ~ 4 / 4homozygote, each child of that person will
immediately know that he or she also carries at least
one €4 allele. What worries and concerns will this create for such children, and how, when, and by whom
should they be counseled? We must be prepared to
deal with such unanticipated fallout of genetic testing.
In conclusion, the association of APOE4 with A D
is an important and relatively newly discovered phenomenon. A considerable amount of information is
still lacking regarding its role in the pathogenesis of
A D and its influence on individual risks for developing
AD. APOE genotyping should not be used as a predictive test in asymptomatic individuals. Furthermore,
although the presence of an APOE €4 allele increases
the probability that a demented individual has AD, in
most instances the association is not strong enough to
significantly alter the procurement of other differential
diagnostic tests. The strongest association with A D is
in a minority of cases who are ~ 4 / homozygotes.
4
Even
in this situation, however, there will be individuals who
have other causes of dementia and it is not yet clear
how the APOE genotype will influence further diagnostic testing in any consistent practical way. Additional information is badly needed, is in the process
of being obtained, and will undoubtedly change our
perspective of these issues in the next few years.
Thomas D . Bird, M D
V A Medical Center
University of Washington
Seattle. WA
References
1. Davignon J, G r e g RE, Sing CF. Apolipoprotein E polymorphism and atherosclerosis. Arteriosclerosis 1988;8:1-2 1
2. Strittmatter WJ, Saunders AM, Schmechel D, e t al. Apolipoprotein E: high-avidity binding to f3-amyloid and increased frequency of type 4 allele in lare-onset familial Alzheimer disease.
Proc Natl Acad Sci USA 1993;90:1977-1981
3. Corder EH, Saunders AM, Strittmatter WJ, e t al. Gene dose of
apolipoprotein E type 4 allele and the risk of Alzheimer’s disease
in late onset families. Science 1993;261:921-923
4. Roses A. Apolipoprotein E affects the rate of Alzheimer disease
expression: P-amyloid burden is a secondary consequence dependent o n APOE genorype and duration of disease. J Neuropatho1 Exp Neurol 1994;53:429-437
5. Roses AD. Apolipoprotein E genotyping in the differential diagnosis, not prediction, of Alzheimer’s disease. Ann Neurol 1995;
38:6-14
6. Noguchi S, Murakami K, Yamada N. Apolipoprotein E genotype and Alzheimer’s disease. Lancet 1993;342:737-738
7. Frisoni GB, Calabresi L, Geroldi C, et al. Apolipoprorein E €4
allele in Alzheimer’s disease and vascular dementia. Dementia
19943:240-242
8. Galasko D, Sairoh T, Xia Y, et al. The apolipoprotein E allele
€4 is overrepresented in patients with Lewy body variant of
Alzheimer’s disease. Neurology 1994;44:950-195 1
9. Pickering-Brown SM, Mann DAM, Bourke JP. Apolipoprotein
E4 and Alzheimer’s disease pathology in Lewy body disease
and in other P-amyloid-forming diseases. Lancet 1994;343:1155
(Letter)
10. Harringron CR, Louwagie J , Rossau R, e t al. Influence of apolipoprotein E genotype on senile dementia of the Alzheimer and
Lewy body types. Am J Pathol 1994;145:1472-1483
11. Koller WC, Glatt SL, Hubble JP, et al. Apolipoprotein E genotypes in Parkinson’s disease with and without dementia. Ann
Neurol 1995;37:242-245
12. Marder K, Maestre G , Cote L. The apolipoprotein €4 allele
in Parkinson’s disease with and without dementia. Neurology
1994;44:1330- 133 1
13. Schneider JA. Gearing M, Robbins RS, et al. Apolipoprorein E
genotype in diverse neurodegenerative disorders. Ann Neurol
1995 (In press)
14. Hallman DM, Boerwinkle E, Saha N , et al. The apolipoprotein
E polymorphism: a comparison of allele frequencies and effects
in nine populations. Am J Hum Genet 1991;49:338-349
IS. Hendrie HC, Hall KS, Hui S, et al. Apolipoprotein E genotypes
Editorial: Bird: Apolipoprotein E Genotyping 3
16.
17.
18.
19.
and Alzheimer’s disease in a community study of elderly African
Americans. Ann Neurol 199537:118-120
Maestre G, Ottrnan R, Stern Y,er al. Apolipoprotein E and
Alzheimer’s disease: ethnic variation in genotypic risks. Ann
Neurol 1995;37:254-259
Davignon J, Bouthillier D, Nestruck AC, er al. Apolipoprotein
E polymorphism and atherosclerosis: insight from a study in
octogenarians. Trans Am Clin Climatol Assoc 1987;99:100-110
Rebeck GW, Perk ‘IT, West HL, et al. Reduced apolipoprotein
€4 allele frequency in the oldest old Alzheimer’s patients and
cognitively normal individuals. Neurology 1994;44:15 13- 1516
Bird TD, Bennett RL. Why do D N A testing! Practical and
ethical implications of new neurogenetic tests. Ann Neurol
1995 (In press)
The Plastic Brain
Not so very long ago, the wiring of the adult human
brain was thought to be fixed. Axonal processes have
complex paths through the neuropil and make specific
connections onto just the right places on elaborate dendritic networks in order to convey appropriate information and permit function. These connections are set
up during development, which itself is dazzlingly complex. It was difficult to conceive how these connections
could be altered and not confuse the workings of the
brain. Yet it is now clear that the brain is a dynamically
changing structure. Humans are constantly learning,
and the essence of learning is change. In addition, the
brain adjusts in reaction to alterations of the body such
as amputation of a limb, and it undergoes plastic
changes in reaction to brain injury. Such changes are
necessary, for example, for recovery after stroke. The
human motor system has been a good model for studies of brain plasticity. It is accessible for study with
functional imaging using positron emission tomography (PET) and transcranial magnetic stimulation
(TMS). TMS can accurately localize the primary motor
cortex devoted to a body part and measure both its
excitability and its extent [l, 2).
Changes of the human motor system have been
demonstrated with motor learning. The size of the motor cortex devoted to the muscles moving the reading
finger of a blind person who reads Braille is larger than
the same muscle on the contralateral side and to similar
muscles in subjects who cannot read Braille E3). There
are increases in the size of motor representation of
muscles that participate in learning a task on the piano
[4). The motor area for involved muscles increases
during implicit learning of a motor sequence [ S ] .
Patients who have undergone hemispherectomy often recover motor function on the side of the body
contralateral to the hemiparesis. In this case, motor
commands must be issued from the remaining cortex
ipsilateral to the body part. The development of ipsilat4 Annals of Neurology Vol 38 No 1 July 1995
eral control in this circumstance has been demonstrated with both TMS and PET E2, 6). In patients who
have suffered hemiparesis from stroke and recovered,
the involvement of the ipsilateral motor cortex is also
likely important and has been demonstrated with PET
17, 81.
After amputation of a body part, the motor cortex
previously devoted to that body part typically does not
remain silent. Plastic changes reorient that portion of
cortex to more proximal body regions [S]. Similar
findings are seen with spinal cord injury [lo). In the
current issue, Mano and colleagues 111) show that the
biceps region of the motor cortex can be directed to
the spinal cord neurons of intercostal nerves in patients
with brachial plexus avulsion after the intercostal nerve
is anastomosed to the musculocutaneous nerve. Moreover, they have shown that eventually the biceps can
be controlled separately from respiration, demonstrating that control of the spinal neurons has been completely altered as a result of the brain plasticity.
How can such dramatic changes occur? There are a
number of mechanisms operative. Some of the changes
can be quick. One such mechanism is a change in synaptic strength by processes such as long-term potentiation. Another is a change in the balance of excitation
and inhibition. This process depends on the fact that
neurons or neural pathways have a much larger region
of anatomical connectivity than their usual territory of
functional influence. Some zones may be kept in check
by tonic inhibition. If the inhibition is removed, the
region of influence can be quickly increased. An example of rapid changes is the expansion of proximal muscle regions after transient deafferentation of the forearm using a blood pressure cuff [12, 131. These
changes can be found within minutes.
Over longer periods of time, there can be anatomical
changes. Increases in synaptic density will strengthen
a preexisting weak connection. Like those changes due
to balance of excitation and inhibition, such changes
depend on preexisting connections. Preexisting connections, however, have only a limited sphere of influence and are likely measured in millimeters.
Can axons sprout and make new connections over
long distances? This would seem to be very difhcult to
accomplish, yet the evidence is mounting that it does
occur. Pons and colleagues showed such long-distance
plasticity in the so-called Silver Spring monkeys that
had a limb deafferented for many years 114). Now
Mano and colleagues [ 11) make a similar observation
in humans. They have demonstrated that the biceps
motor cortical region has gained control of thoracic
motor neurons. It is unlikely that such divergent motor
regions would have been connected even by silent anatomical connections. This has required plastic changes
over a distance of 2 to 4 cm, a longer distance than
preexisting anatomical connections are known to oc-
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