May 29, 2002 by Terry Grossman
Original link: http://www.kurzweilai.net/predictive-human-genomics-is-here
Thanks to breakthroughs in genomics testing, physicians now
have tools for true preventive medicine. Gene chips and genomics test
panels can predict one’s predisposition towards many serious — and often
preventable — genetic diseases and allow doctors to modify gene
expression through precise, targeted, individualized interventions.
The monumental accomplishment of decoding the human genome is
nearly complete. The results of work of the official
government-sponsored Human Genome Project together with the efforts of
private firms such as Celera and Human Genome Sciences has created a
true inflection point in the curve of medical history. The human genome,
arguably The Rosetta Stone of the human body, is presently undergoing
intense scrutiny by scientists in nearly every country in the world. The
potential benefits of these efforts for improving human health and
well-being are incalculable.
“The greatest payoff from understanding the human genome is likely to
be an illumination of the molecular pathogenesis of disorders that are
currently poorly understood and for which treatments are …frequently
sub-optimal….Genomics offers … the greatest opportunity for development
of targeted therapy since the development of antibiotics,”
1
according to Frank S. Collins, M.D., Ph.D. of the National Human Genome
Research Institute, National Institutes of Health, Bethesda, Md.
Historically, previous medical disciplines have dealt largely with the
after-effects of
an individual’s genetic inheritance. Genomics and these other new
disciplines, on the other hand, look directly at the genes themselves.
They look at an individual’s genetically programmed biochemical pathways
of life under conditions of health and disease. For the first time
ever, physicians have the tools to help their patients employ truly
preventive medicine.
Genomics may help scientists find ways of modifying human biochemistry
long before a genetically predisposed disease has a chance to appear.
2
Rifling through the dusty pages of medical history, however, it seems
axiomatic that our powers for diagnosing diseases has preceded our
ability to offer effective treatment for them. This also seems true on
the new genomics frontier as well.
Testing for genetic diseases
Enter predictive genomics, the identification of the genetic
predisposition of individuals to certain diseases, which is the
diagnostic arm of the new genetics-based paradigm. This field has
already advanced to the point that a number of sophisticated diagnostic
tests are currently available to help predict one’s predisposition
towards many serious (although preventable or modifiable) genetic
diseases.
The fact that proteomics and other therapeutic modalities are still
in their infancy is in keeping with the historical
diagnostics-first-therapeutics-later tradition. Progress in the sister
specialties of proteomics, bioinformatics, and systems biology should
eventually provide ever more effective therapeutic modalities for
patients with these genetic predispositions in the years ahead.
Roger Williams, M.D. in the 1950′s, introduced the concept of
biochemical individuality: that every individual possesses a specific
and unique biochemical blueprint.
3 Until a few years ago,
however, discovering what constitutes our biochemical individuality has
been hit-and-miss at best, the empiric result of decades of careful
trial and error.
For example, after many years of observation, one person may have
noticed that he has more energy when eating protein for breakfast, that
eating strawberries gives him a rash, and that he gets a headache if he
consumes artificial sweeteners. Yet, another person feels sluggish if he
has too much protein for breakfast, but seems to have no problems with
strawberries or artificial sweeteners. Truly, “One man’s meat is another
man’s poison,” for we are all biochemically unique.
As a direct result of data from The Human Genome Project, however, we
have begun to obtain much more information regarding our biochemical
individuality in a rapid, quantifiable and affordable fashion. The tools
of modern science can now accomplish in minutes what once took years of
trial and error. One company, Orchid Diagnostics, currently offers
products and services to help physicians and laboratories perform HLA
genotyping (to assist with matching of donor transplant organs with
recipients), disease susceptibility testing and immunogenetics. Each of
their systems is capable of performing over 500,000 genotype analyses
per day.
4
Genomics testing may soon be able to predict precisely what foods are
best for us, prescribe individualized exercise and other lifestyle
prescriptions, and recommend a personalized list of supplements,
neutraceuticals, and prescription drugs for maximum health and disease
avoidance. This will all be based on an examination of our personal
genetic makeup.
One often hears of life being compared to a game of cards. An
individual born with a serious genetic disease such as Cystic Fibrosis
or Huntington’s Disease is thought of having been dealt a “bad hand.”
Conversely, the 105-year old we read about who attributes her longevity
to “Eating a jelly donut for breakfast and smoking two packs of
cigarettes every day” would clearly seem to have started life with
exceptionally good cards.
The Mendelian concept of “genetic determinism” – that the genes with
which we are born will determine our fate in an absolute fashion – has
given way to a newer hypothesis of “genomic relativism.” Genes don’t
determine what diseases we will acquire, they merely
predispose us to them. The implications of this simple concept for the future of healthcare and preventive medicine are far-reaching.
While there are a few genes that do condemn an individual to an
almost certain fate (such as the Cystic Fibrosis or Huntington’s Chorea
genes mentioned above), these constitute only a tiny fraction of the
35,000 or so genes that comprise the entirety of the human genome. The
overwhelming majority of the time, our genes merely
predispose
us to disease conditions that will either manifest or not later in life
depending on the lifestyle choices we made earlier on. We end up reaping
later in life what we ourselves sowed in our youth.
Continuing with our gaming analogy, the cards we are dealt represent
our genetic heritage. We call this sum total of our genetic makeup, the
totality of our inherited DNA, our “genotype.”
Our genetic heritage (our starting hand) expresses itself throughout
the course of our lifetimes as a consequence of the environment in which
we live and the lifestyle choices that we make (how well we play). Like
any good card game, it is this combination of luck (genetic makeup)
plus skill (lifestyle choices and environmental factors) that makes for
an exciting outcome. This concept of
genomic relativism is at
once enabling and terrifying. The age-old of battle of predestination
vs. free will is being fought on the front lines of our nuclear DNA. And
it is now looking like very little about our future health is
absolutely predestined or predetermined.
Doctors now realize that almost all human diseases result from the
interaction of genetic susceptibility with
modifiable
environmental factors. In the overwhelming majority of cases, genetic
variations do not cause disease; rather, they influence a person’s
susceptibility to disease as a result of lifestyle choices and
environmental factors. It’s not “nature” vs. “nurture,” but nature
(genetic heritage)
and nurture (lifestyle/ environment).
Compared with looking at one’s “genotype,” it’s more compelling to
watch how the genetic code is translated, i.e., the “phenotype” of one’s
genetic expression, particularly the subtle differences between
individuals. More than 99% of human DNA is identical among all people.
Yet, it is this fraction of one percent that is different that creates
all the variety of life and ensures that no two humans (other than
identical twins who have precisely the same DNA) will be exactly alike.
This fraction of a percent difference in DNA from person to person is
of critical importance. In the course of replicating itself billions
and trillions of times, as it must do to create all the cells and
tissues of the body, our DNA undergoes numerous opportunities for
errors. These mistakes or imperfections in our DNA most commonly take
the form of what are called
point mutations,
deletions or
translocations.
These variations are collectively known as “polymorphisms” (literally,
multiple shapes). Our biochemical individuality derives largely from
these polymorphisms, 100,000 or so of which have been found to date.
Specific genetic polymorphisms that involve only a single nucleotide
(DNA subunit — cytosine, thymine, adenine, or guanine) are the most
common variant, and such “single nucleotide polymorphisms” (SNPs,
pronounced “snips”) are extremely common in the population at large. It
is estimated that 50% of people have at least one of the known SNPs.
By convention, rare single-nucleotide imperfections in the genetic
code are referred to as mutations. When a specific mutation is so common
that it affects more than 1% of the population, it is called a
polymorphism or SNP. These polymorphisms are important because they can
change the manner in which the body functions, and, in some cases,
predispose us (or make us more resistant) to specific diseases.
Individualized healthcare
It is axiomatic of the new theory of genomic relativism that just
because we have a genetic variation that predisposes us to a certain
disease, say heart disease, breast cancer, rheumatoid arthritis or
osteoporosis, it does not mean that we are predestined to get that
disease some day. The fundamental equation of predictive genomics is:
Genetic predisposition + environment + modifiable lifestyle choices = phenotypic expression
Predictive genomics testing signals the beginning of truly
individualized healthcare. Physicians can now begin to evaluate each
patient’s unique genetic predispositions and then develop and implement a
carefully targeted, customized plan for intervention years before
pre-disease imbalances or disease symptoms begin to appear.
Almost all of the most common disabling and deadly degenerative
diseases of our time, including cardiovascular disease, cancer,
Alzheimer’s Disease and adult-onset diabetes,
8 are thought to be the result of interaction between genetic and environmental factors.
By evaluating possible genetic variants in a patient, we will be able to:
- Identify “hidden” gene mutations that may promote chronic disease
- Gain earlier advanced warning of disease susceptibility in each patient
- Determine cumulative risk associated with specific, easily identified mutations
- Intervene much earlier in the pre-disease state
Modify gene expression through more precise, targeted, individualized interventions
- Identify key target areas on which to focus follow-up
- Monitor therapeutic effectiveness of intervention strategies with laboratory testing”5
With clinical insight such as this, physicians will gain a deeper
understanding of disease processes and be able to develop more rapid and
efficacious interventions.
Predictive genomics attempts to identify the most significant single
nucleotide polymorphisms (SNPs) in individuals. This is done to predict
the likelihood that an individual is predisposed to develop a particular
chronic disease or functional imbalance and evaluate the risk that this
disease or imbalance might appear under circumstances of particular
environmental or lifestyle choices.
Predictive genomics may make medical practice in the near future
radically different from the medicine of today. Just as individuals will
no longer be forced to play the poker game of life blindfolded, neither
will their doctors. Rather than having to guess what lifestyle choices
to make, individuals may finally get to look at the owner’s manual for
their particular bodies. Instead of relying on randomized studies
involving large patient populations, doctors will have access to
sophisticated diagnostic and therapeutic tools
individualized for each of their patients.
We may find such freedom enabling, but terrifying as well. The scary
part will be that individuals will be required to take ever-greater
personal responsibility for maintaining their own health and longevity.
The more powerful and dangerous the genetic idiosyncrasies with which an
individual is born, the greater the responsibility on that individual
to modify their environment, diet and lifestyle to attenuate the
expression of that potentially harmful genetic material. As a result,
physicians will move laterally into positions as co-workers or
counselors with their patients, rather than as paternalistic “medicine
men” or even “healers” who possess and dispense wondrous “cures.”
The same SNP that can be harmful to an individual in one environment
can be beneficial to that same individual under different circumstances.
For example, a SNP that has historically afforded individuals a better
chance of survival during periods of famine or near starvation may
render those persons significantly more prone to obesity under
conditions of excess or even adequate calories. The nearly ubiquitous
incidence of obesity among modern day Pima Indians is testimony to the
variegated expression of the same genetic mutation under different
environmental circumstances.
6
The power of predictive genomics to alter medical practice and allow
physicians to practice true preventive medicine seems awesome. However,
despite the signs in the road warning of “Wonders Ahead,” I predict that
only a small percentage of patients who might be helped by predictive
genomics testing will take advantage of its availability within the next
few years.
The inherent conservatism of the medical community as well as the
intrinsic reluctance of the population at large to accept dramatic
changes in their worldview will force a delay in popular implementation
of this paradigm shift. Most physicians and patients will be likely to
continue wandering in the barren but familiar landscape of the
prehistoric genetic desert for a number of years before arriving at The
Promised Land of Predictive Genomics.
The groups most likely to avail themselves more quickly of the new
diagnostic information emanating from Predictive Genomics testing will
include:
- Proactive patients who seek not merely good health, but optimal health and want to bring their risks to an absolute minimum.
- Patients who have a family history of potentially serious diseases
that are easily tested with current technologies, such as heart disease,
Alzheimer’s, colon cancer, osteoporosis, etc.
- Patients who have proven refractory to conventional treatments.
I predict that this radical shift in medical diagnostics will take
several years to filter throughout the medical community and enter
common usage among the general populace. For widespread acceptance to
occur, physicians and patients alike will be forced to take giant
strides in their conceptualizations of why we get sick. The very idea
that patients can be tested
before the fact for the diseases to which they are predisposed represents a very big first step.
Taking it to the next level and realizing that patients themselves
are largely responsible for their own fates may take an even greater
stretch of the imagination. It will definitely represent a major
paradigm shift in thinking for patients and physicians alike. Such a
drastic alteration in our concept of health and disease–that we are each
largely responsible for our destiny–will make many folks very
uncomfortable indeed.
Testing panels
At this time (mid-2002), several genomics testing panels are
commercially available. Each of these panels tests for a dozen or so
SNPs at a cost of a few hundred dollars per panel. Within a few years,
thanks to the Law of Accelerating Returns,
7 for the same few hundreds of dollars, panels will be available that test for
thousands of genetic predispositions.
We will also soon have access to “DNA chips” that will test for most,
if not all, of the 100,000 or so SNPs currently identified.
8 9
One company, Affymetrix, is currently making gene chips available to
doctors for analyzing our DNA and tracking gene expression in tumors and
other tissue they are sufficiently optimistic about their prospects
that their toll-free number is (800) DNA-CHIP. Affymetrix and other
companies have developed silicon-coated glass wafers that can be
subdivided into over 150,000 distinct locations, so we will be able to
detect polymorphisms on tens of thousands of genes in a matter of
minutes.
The road to these “DNA chips” may have a few hurdles to cross first,
at least before this information is available at low cost. It seems that
a few years ago, the overwhelming majority of information found in DNA
didn’t seem to bear any relationship to the genes themselves and came to
be known as “junk DNA.” Researchers have since learned that these
“non-coding” regions of the DNA are not “junk” at all, but contain vital
information. Many SNPs, in fact, are found in these non-coding DNA
segments.
10
A small Australian biotech company called Genetic Technologies of
Melbourne was among the first to realize that SNPs found outside of the
genes themselves may be just as important as genetic polymorphisms
themselves and registered a number of patents in the 1990′s relating to
this discovery. Genetic Technologies currently seems dedicated to
cashing in on these patents and has threatened to sue companies who try
to use this information without first paying large royalties.
11
Without discussing the legality or morality of such operations,
genomic testing could easily end up be much more costly as a result of
these and similar patents and lawsuits. With our current knowledge and
abilities, however, even if the massive amounts of data that could be
found on DNA chips were available, it would likely produce little beyond
information overload. We need to wait for the bioinformatics scientists
to catch up.
At the present time, because of both the cost considerations and our
limited abilities to make meaningful sense of the data, today’s
clinicians need to apply limiting criteria to determine which
polymorphisms it makes most sense to screen. In so doing, we can
establish which SNPs should be included as part of a comprehensive
preventive health program that incorporates predictive genomic testing.
Presently, the numbers seem quite manageable.
Of the 100,000 SNPs currently identified, only 8,000 seem
relevant
to health. These 8,000 polymorphisms are relevant because they exert a
significant effect on our biochemistry and physiology. Frankly, we don’t
know what the other 92,000 do … at least not yet.
Given our current knowledge of the human genome, only polymorphisms
that exist in a significant percentage of the population are likely to
be identified and evaluated in a cost-effective manner. Polymorphisms of
sufficient
prevalence among the population at large slice the pool down to about 300 SNPs.
It seems both prudent and ethical to test primarily for polymorphisms
whose effects are modifiable through the use of currently available
interventions. Finding out that a patient has a genetic defect that
cannot be modified by any presently available therapy may create as much
anxiety as good (although patients should have the right to know if
they wish). About 100 SNPs are currently
modifiable through interventions such as diet, lifestyle, nutritional supplements, and prescription pharmaceuticals.
In an ideal situation, the effects of our interventions should be easily
measurable through presently available functional laboratory testing. In the year 2002, this brings the total of
relevant,
prevalent,
modifiable and
measurable genetic polymorphisms down to the easily manageable number of a few dozen or so.
Genomic test panels
The more common of these single nucleotide polymorphisms have been
assembled into genomic test panels. Currently, four predictive genomic
panels are commercially available for physician use:
12 a cardiac risk panel, an osteoporosis risk panel, an immune function panel and a detoxification panel.
The Cardiovascular Risk Panel identifies
genetic single nucleotide polymorphisms associated with increased risk
of developing coronary artery disease, other vascular diseases,
Alzheimer’s Disease, and hypertension. Risk factors measured include
markers for inflammation, folic acid defects, iron storage problems,
blood coagulation abnormalities, and cholesterol regulation defects, as
well as cardio-protective markers. The information from such profiling
will provide the ability to predict heart disease decades before
symptoms appear.
13
The Osteoporosis Risk Panel identifies SNPs
associated with increased risk of developing bone loss. Risk factors
include defects in calcium and vitamin D metabolism, parathyroid hormone
action, abnormal collagen synthesis, and chronic inflammation.
The Immune Panel identifies SNPs associated
with increased risk of developing immune dysfunction. Risk factors
include altered production and activity of cytokines such as
interleukins and Tissue Necrosis Factor-alpha (TNF-a) that may lead to
inflammation and altered immunity. These SNPs have been associated with
increased risk of asthma, rheumatoid arthritis, some types of cancers
and other diseases.
The Detoxification Panel identifies SNPs
associated with increased risk of developing detoxification defects,
especially with increased exposure to environmental and other toxins.
Risk factors include altered liver detoxification processes, including
defects in glutathione conjugation (the detoxifier molecule mentioned in
the sidebar below). Defects in the body’s detoxification pathways have
been associated with increased risk for certain cancers, chronic
fatigue, multiple chemical sensitivity, and alcoholism.
Some patients may feel it worthwhile to screen with all four panels,
while others may prefer to pick and choose one or more of the panels
they feel are most relevant to them.
The testing procedure itself is very simple. Cells are collected
either by using a mouth rinse solution collected at the patient’s home
or from a simple blood draw in the physician’s office.
Many patients are understandably concerned about the confidentiality
of their genomics testing results. Manufacturers of the genomics test
panels have made the sage decision to address these issues before
problems occur and have concluded that genomics test results require a
higher level of security and confidentiality than other test results. At
the testing facility, genomics testing results are protected by a
security code that is disclosed only to the patient’s attending
physician.
14
It would be tragic for genomics test results to be used by agencies
such as insurance companies and HMOs to discriminate unfairly against
individuals who have been proactive in seeking to achieve better health.
So in most medical offices, copies of genomics test results are not
included with the patient’s regular medical records, but are kept in a
separate secure location. This is done to ensure that such information
is not routinely available to insurance companies who do not yet have
sufficient experience with genomics testing to understand the full
implications of these results.
* * *
Just as I was preparing to finish this article (in fact, I had only
these concluding paragraphs to complete), I got the results of my own
genomics profile back from the lab. As is often the case where hopes and
dreams in life collide with reality, the outcome of my tests was less
ideal than I had hoped, but not as bad as I had feared. I found out that
I am among the 30% of the population who carries the Apo E4 gene. While
I haven’t lost sleep over this information, I have found these results
disturbing. This information has introduced a light chop onto the calm
waters of my inner tranquility.
Luckily, though, I have the more common and less risky E3/E4
genotype, not the distinctly more malevolent E4/E4. Yet, I now live with
the knowledge that my chances of developing Alzheimer’s Disease at some
point in my life are 2-3 times average. From a purely statistical point
of view, the chance that a man my age with the E3/E4 genotype will
develop AD within the next 30 years is 14%.
All things considered, I am still glad I took this test. I found I
had other genetic risk factors as well. Now knowing precisely what some
of these risks are has stimulated me to be even more vigilant in my
health maintenance efforts. To help reduce my chance of developing
Alzheimer’s Disease and some other diseases for which I find I am at
above average risk, I plan to reduce my consumption of saturated fat
significantly. I plan to eat more fish. I will also make some
modifications to the nutritional supplements I take.
But, knowing that all of the genetic risks that have been identified
for me are just that — risks and not diseases — gives me hope, and also
tools to keep some of these dreaded maladies at bay. So, I am very glad
that I took this test.
Predictive Genomics testing is here and it is available today. It can
provide previously unknowable genetic information personalized to each
individual. For additional information on specific single nucleotide
polymorphisms (SNPs), see the site run by
The National Center for Biotechnology Information. Another excellent resource is
Office of Genomics and Disease Prevention of The Center for Disease Control (CDC).
For further information about Predictive Genomics, please see the website for the genomics division of
Great Smokies Diagnostic Laboratory16 or visit
my website (Terry Grossman MD).
Genetic engineering disciplines
As a direct outgrowth of the Human Genome Project, a number of new
scientific disciplines have been created to help interpret and
capitalize on the voluminous amounts of data that is being generated
each day.
- Genomics is the study of the composition of genetic material itself (the DNA in our genes and chromosomes)
- Proteomics is the study of proteins, both those
found naturally in the body and those created in the laboratory. Given
the capitalist imperative, in the private sector at least, there is a
bias in this field towards the production of proprietary protein
molecules that may have value in helping maintain optimal health as well
as treating disease
- Bioinformatics is the new discipline assigned the task of developing techniques to gather and process all of this new information
- Systems Biology is the study of how all of these
systems work together to form the inordinately complex, ineffably
elegant, and indescribably beautiful entity we call life
Genomics testing for cardiovascular conditions
I want to offer one practical example of the type of information
available through genomics testing. We will examine one specific marker
that is part of the Cardiovascular Genomics Profile — the apolipoprotein
E (Apo E) polymorphisms. We will first discuss the specific risks and
benefits associated with the different Apo E polymorphisms. Then, we
will discuss how this information can result in lifestyle
recommendations, which can help an individual modify the phenotypic
expression of the more dangerous genotypes.
Apolipoproteins are carrier proteins responsible for the transport of
lipids such as fat and cholesterol throughout the bloodstream. Since
fat and cholesterol are oily substances that are not water-soluble, they
require specific carrier molecules to help move them from place to
place in the body.
One important lipid carrier protein, Apolipoprotein E, comes in three
main polymorphic flavors — Apo E2, Apo E3 and Apo E4. These three
lipoproteins differ in the amino acids found at locations 112 and 158.
Apo E2 has the amino acid cysteine at each of these loci, while Apo E4
substitutes arginine in each location. The most common type, Apo E3, has
one of each, cysteine at site 112 and arginine at site 158.
17
These subtle differences produce significant variations in how Apo E
performs its duties of pick up and delivery of lipid bundles. One
isoform, Apo E2, performs its job of clearing cholesterol from the
arteries quite well, while Apo E4 is much less efficient.
Every person possesses two copies of the Apo E gene, one inherited
from each parent. There are, thus, six possible combinations: E2/E2,
E3/E3, E4/E4, E2/E3, E2/E4 and E3/E4.
It is known that individuals who possess one or two copies of the E4
polymorphism have an increased incidence of elevated cholesterol,
triglycerides and coronary heart disease.
18 Of even greater
clinical significance, however, is the correlation between the presence
of Apo E4 and the incidence of Alzheimer’s Disease (AD). The effect of
this polymorphism on AD is actually quite dramatic.
Individuals who do not have any copies of the Apo E4 allele have only
a 9% risk of developing AD by age 85. People with one copy of the gene
(the E3/E4 genotype carried by over 25% of the population) have a 27%
chance that they will develop AD by the same age. For individuals who
possess two copies (E4/E4), the risk of developing Alzheimer’s increases
to 55% by the age of 80.
19
Furthermore, the age at which dementia is diagnosed is much younger,
depending on the number of copies of Apo E4 carried: 84 years old if one
has no copies of E4, 75 years if one copy and a mean age of 68 years in
E4/E4 homozygotes.
20
Pathological examination of brain tissue of Alzheimer’s patients
reveals three main types of abnormalities: extracellular amyloid
plaques, intracellular neurofibrillary tangles, and vascular amyloid
deposits. It is probably no coincidence that Apo E4 has been
immunochemically linked to each of these types of deposits.
The Apo E2 gene, on the other hand, appears to confer some degree of
protection against development of AD, and patients with at least one
copy of the E2 allele have a 40-50% reduction in their Alzheimer’s risk.
21
Apo E2 is not perfect, however, as some forms of heart disease are more
common in patients with this polymorphism. All things considered, Apo
E2 is a pretty good deal, however, and it is not unlikely that our 105
year-old smoker mentioned above was born with one or two copies of Apo
E2. The Apo E3 form is the most common, by far, (over 50% of the
population is E3/E3) and affords some protection against both heart
disease and Alzheimer’s.
In a large study of 12,709 male twins who were 62-73 years old, the
odds of developing AD was 17.7 for genotype E4/E4 versus E3/E3 (i.e., an
almost 18-fold increased risk) and 13.8 for E4/E4 versus all remaining
genotypes. By contrast, the odds ratio for heterozygous E3/E4 was only
2.76 versus E3/E3 and 2.01 versus all other genotypes.
22
Although the Apo E4 allele is a potent risk factor for AD and may be
associated with other forms of dementia, the good news is that most
people who carry the Apo E4 gene still do not develop dementia, and
about one-half of people diagnosed with AD do not possess any copies of
the Apo E4 gene.
23 In some studies, it has been reported that
the proportion of patients with dementia that is attributable to the
Apo E4 allele is estimated to be only 20%.
24
Free radical damage appears to play a key role in the creation of
insoluble beta-amyloid, one of the hallmarks of AD pathophysiology.
Therefore, particularly for individuals who discover they carry the Apo
E4 gene, special efforts to limit free radical damage seem prudent.
25
Patients who have been identified as Apo E4 carriers would be advised
to begin taking aggressive free radical damage control measures, i.e.,
anti-oxidant and other therapies, as early in life as possible.
The following practical recommendations are suggested for patients
carrying the Apo E4 genotype (although they could also be of value for
anyone):
- Vitamin and herbal agents which directly interact
with free radicals such as vitamin C, vitamin E, alpha lipoic acid and
coenzyme Q 10 should be taken daily.
- Pharmacological agents that may help reduce free radical production in the brain include the monoamine oxidase-B inhibitor, selegilene,26 and the hormones, melatonin and estrogen (women only). Low-dose aspirin therapy (81 mg daily) may be prudent as well.27
For patients unable to lower their lipid levels despite dietary
strategies, the nutrient policosanol is of value. For patients who still
require a prescription drug, lorelco (available through compounding
pharmacies) seems to work better than other cholesterol lowering agents,
although some specific precautions must be followed when this
medicationis used.
- Neutraceutical agents such as phosphatidylserine in
fairly large doses – such as 300 mg/day taken on a long-term basis –
has been shown to slow cognitive decline in Alzheimer’s dementias.28 Acetyl-l-carnitine seems to have value as well.
- Lifestyle changes including stress management and regular aerobic exercise have been found to be of value in preventing the incidence of AD. 29,30
- Dietary modifications are warranted since we recall
that Apo E4 is also associated with elevated lipid levels. Suggestions
include an aggressive low-fat diet to help keep cholesterol levels down,
while lowering simple carbohydrates in the diet (such as sugars and
refined flour products) is often of benefit to individuals with high
triglycerides.
1 Collins, FS, Guttmacher AE. Genetics moves into the medical mainstream. JAMA. 2001 Nov 14;286(18):2322-4
2 Flower J, Dreifus LS, Bove AA, Weintraub WS. Technological Advances and the Next 50 Years of Cardiology. J
Amer Coll Cardiol, 35:(4):1082-1091.
3 Williams, Roger J. Biochemical Individuality : The Basis for the Genetotrophic Concept. New York: Keats, 1998.
4 http://www.orchid.com/products/lsg/products/uht.asp
5 http://www.genovations.com/overview.html
6 Coleman DL. Diabetes and obesity: thrifty mutants?
Nutr Rev 1978 May;36(5):129-32.
7 Kurzweil, Ray. The Age of Spiritual Machines. New York: Viking, 1999, p.30.
8 Francis Collins, American College of Cardiology Annual Scientific Session, New Orleans, March 1999.
9 Wu, Corinna. “The Incredible Shrinking Laboratory,”
Science News, 15 (8/15/98): 154, pp 104.
10 Roth FP, Hughes JD, Estep PW, Church GM. Finding DNA
regulatory motifs within unaligned noncoding sequences clustered by
whole-genome mRNA quantitation
Nature Biotechnology 1998; 16: 939-45.
11 http://www.newscientist.com/news/print.jsp?id=ns99992280
12 These tests are available through Great Smokies Diagnostics Laboratory www.gsdl.com.
13 “Genomic Medicine and Novel Molecular Therapies in
Cardiovascular Medicine,” Victor Dzau, Bishop Lecture, American College
of Cardiology Annual Scientific Session, New Orleans, March 1999.
14 http://www.genovations.com/patient_privacy.html
15 Bickeboller H, et al. Apolipoprotein E and Alzheimer disease: genotype-specific risks by age and sex.
Am J Hum Genet 1997 Feb;60(2):439-46.
16 Additional contact information for Great Smokies
Diagnostic Laboratory/Genovations™ is 63 Zillicoa Street; Asheville, NC
28801 Ph: 1-800-522-4762 (8AM – 8PM EST) ; Fax: 1-828-252-9303 ; e-mail:
cs@gsdl.com.
17 This is an oversimplification. For all of the many Apo E
amino acid substations possible, please visit the National Library of
Medicine website:
http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?107741#MAPPING
18 Eto M, et al. Familial hypercholesterolemia and apolipoprotein E4.
Atherosclerosis 1988 Aug; 72(2-3):123-8.
19 Myers RH, Schaefer EJ, Wilson PW, D’Agostino R, Ordovas
JM, Espino A, Au R, White RF, Knoefel JE, Cobb JL, McNulty KA, Beiser A,
Wolf PA. Apolipoprotein E epsilon4 association with dementia in a
population-based study: The Framingham study.
Neurology 1996 Mar;46(3):673-7
20 Kamboh MI. Apolipoprotein E polymorphism and susceptibility to Alzheimer’s disease.
Hum Biol 1995 Apr; 67(2):195-215.
21 Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA,
Mayeux R, Myers RH, Pericak-Vance MA, Risch N, van Duijn CM. Effects of
age, sex, and ethnicity on the association between apolipoprotein E
genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer
Disease Meta Analysis Consortium.
JAMA 1997 Oct 22-29;278(16):1349-56
22 Breitner JC, Jarvik GP, Plassman BL, Saunders AM, Welsh
KA. Risk of Alzheimer disease with the epsilon4 allele for
apolipoprotein E in a population-based study of men aged 62-73 years.
Alzheimer Dis Assoc Disord 1998 Mar;12(1):40-4.
23 Myers RH, Schaefer EJ, Wilson PW, D’Agostino R, Ordovas
JM, Espino A, Au R, White RF, Knoefel JE, Cobb JL, McNulty KA, Beiser A,
Wolf PA. Apolipoprotein E epsilon4 association with dementia in a
population-based study: The Framingham study.
Neurology 1996 Mar;46(3):673-7.
24 Slooter AJ, Cruts M, Kalmijn S, Hofman A, Breteler MM, Van
Broeckhoven C, van Duijn CM. Risk estimates of dementia by
apolipoprotein E genotypes from a population-based incidence study: the
Rotterdam Study.
Arch Neurol 1998 Jul;55(7):964-8.
25 Retz W et al. Free radicals in Alzheimer’s disease.
J Neural Transm Suppl 1998;54:221-36.
26 Rosler M, et al. Free radicals in Alzheimer’s dementia: currently available therapeutic strategies.
J Neural Transm Suppl 1998;54:211-9.
27 Pasinetti GM. Cyclooxygenase and inflammation in Alzheimer’s disease: experimental approaches and clinical interventions.
J Neurosci Res 1998 Oct 1;54(1):1-6.
28 Engel RR, et al. Double-blind cross-over study of
phosphatidylserine vs. placebo in patients with and without
apolipoprotein E4.
Atherosclerosis. 1990 Sep;84(1):49-53.
with early dementia of the Alzheimer type.
Eur Neuropsychopharmacol 1992 Jun;2(2):149-55
29 Khalsa, Dharma Singh and Stauth, C.
Brain Longevity. New York: Warner Books, 1997.
30 Fletcher GF.The antiatherosclerotic effect of exercise and development of an exercise prescription.
Cardiology Clinics 1996; 14 (1): 85-95.
