Public Health and Genetics Information Series
Alzheimer’s Disease
What Is Alzheimer’s Disease?
Alzheimer’s disease (AD) is the leading cause of
dementia, which is the loss of memory, reason, judgment or language so that it
interferes with a person’s life, in those people over 65. AD causes the gradual
loss of brain cells, called neurons. Neurons shrink as the brain ages and
plaques, which are dense, deep deposits of protein, can buildup in neurons.
When neurons die they are not replaced. AD disturbs the metabolism,
communication and repair of neurons, which causes the nerve cells to stop
working and eventually die. This cell death causes changes in memory, judgment,
language skills, personality and behavior. The duration of AD varies from
An excellent review of
Alzheimer’s disease has been created by the Alzheimer’s Disease Education and
Vertical sections through a normal
(right) and a late stage Alzheimer’s brain (left) showing massive tissue
loss and enlargement of cavities. (From, Piecing Together Alzheimer’s by Peter H St George-Hyslop.
Copyright © December 2000 by Scientific American, Inc. All rights reserved)
What Is the Public Health Impact of AD?
Approximately 4 million people in the
What Causes Alzheimer’s Disease?
The exact cause of AD is still unknown however,
researchers are beginning to understand what happens to the brain cells as a
result of AD. The cause of Alzheimer’s disease is most likely a combination of
many factors. Possible risk factors include, but are not limited to: age,
family history of AD, genetic alterations, cardiovascular risk factors,
oxidative damage by free radicals, inflammation, and brain infarction.
The Biology of AD
Alzheimer’s disease brains are characterized by the
presence of beta-amyloid plaques and neurofibrillary tangles. All older people
develop plaques and tangles, but a person with AD develop more.
Neurofibrillary tangles
Microtubules are the internal structural support in
healthy neurons; they guide nutrients and molecules throughout the brain cell.
A protein known as tau helps to make the microtubules stable. In individuals with AD, tau is chemically
changed so that the protein pairs with other tau proteins to cause tangles. The
microtubule therefore disintegrates and the neuron’s support system collapses.
This may result in miscommunication between cells and later, cell death.
Amyloid Plaques
1) APP molecule 2) APP is snipped 3) Plaque develops
Plaques are made up of fragments snipped from a
protein called APP (amyloid precursor protein). The fragments that have been
snipped clump together to form a plaque (see figures above). The plaques
develop in the hippocampus and in the cerebral cortex, which are specific
regions of the brain.
How Are Genes Involved?
About 75 percent of Alzheimer’s disease cases are
classified as sporadic, which means that no other blood relatives are affected.
The precise cause of these cases is not known, but genetics may play a role in
combination with other factors.
The other 25 percent of Alzheimer disease cases can
be classified as hereditary, which means they are caused by altered genes and
tend to occur in families. These hereditary cases are divided into early-onset
AD, where symptoms of AD appear before age 65, and late-onset AD, where
symptoms begin after age 65.
Early-Onset AD
Early-onset AD usually affects individuals between
the ages of 30-60. Early-onset cases
comprise approximately 6-7% of all AD cases worldwide. About 7% of the early-onset cases are
inherited (passed on through generations) and these cases are called Familial
Alzheimer’s disease, or FAD. FAD is
inherited in an autosomal dominant manner, which means only one copy of the
altered gene is necessary to cause the disorder. Generally, a person affected
with an autosomal dominant disease has one affected parent. Researchers have found three genes that are
involved in FAD. A person affected with FAD usually has an alteration in one,
but not all, of these genes:
1. Amyloid precursor protein (APP)- This gene is located on chromosome 21. If an
individual has an alteration in the APP gene their illness is called
Alzheimer’s disease, type I.
2. Presenilin 1 (PSEN1)- This gene is located on chromosome 14. If an individual has
an alteration in the PSEN1 gene their illness is called Alzheimer’s disease,
type 3.
3. Presenilin 2 (PSEN2)- This gene is located on chromosome 1. If an individual has an
alteration in the PSEN2 gene their illness is called Alzheimer’s disease, type
4.
Late Onset AD
The genetic causes of late-onset Alzheimer’s disease
are less defined. A gene that definitely causes late-onset Alzheimer’s disease
has not been identified. However, a gene called apolipoprotein E (APOE) has
been studied as a risk factor for the disease. Particularly, one form (or
allele) of the APOE gene seems to increase an individual's risk for developing
late-onset Alzheimer’s disease.
Late-onset Alzheimer’s disease is also known as Alzheimer’s disease,
type 2. This condition is most common in
individuals over the age of 65. There are several APOE alleles. The epsilon 4
allele (or e4) is associated with an increased risk of late-onset Alzheimer’s
disease. Carrying one APOE e4 allele
nearly doubles an individual’s lifetime risk of AD. An individual who possesses one copy of the
APOE e4 allele may develop Alzheimer’s disease an average of 5-10 years earlier
than an individual without a copy of the APOE e4 allele. However, it is very
important to note that inheriting an APOE e4 allele is not a guarantee that person will definitely develop AD. APOE e4
simply increases the risk of developing late-onset Alzheimer’s disease.
The other forms of the APOE gene are e2 and e3. The
most common form of APOE is e3. There has been some evidence that shows the
APOE e2 version may have a protective effect for risk of AD. In addition to Alzheimer’s disease the APOE
gene has been associated with some cardiovascular disorders. Many individuals
with familial hypercholesterolemia have two copies of APOE e2.
Hypercholesterolemia is a condition in which a person has very high levels of
cholesterol and is at high risk for stroke and heart attacks. Hypercholesterolemia
is most likely influenced by more than one gene. Additionally, the e4 allele is a risk factor
for coronary artery disease.
Genetic testing for AD
·
Because of the rarity of APP, PSEN1 and PSEN2 mutations in patients
with late-onset AD, testing for these mutations should be limited to those with
early-onset AD or a strong family history.
·
Relatives of people with documented gene alterations may require
testing for family financial or personal planning.
·
Presymptomatic testing should be carried out with extreme care and only
after genetic counseling so that the individual is aware of the psychological
aspects of testing for an incurable illness.
·
There may also be consequences in employment and health insurance,
which the individual must understand.
·
Additionally, a positive test may indicate other family members at risk
who have not undergone genetic counseling and do not desire genetic testing.
·
APOE e4 testing in individuals that do not show signs of Alzheimer’s
disease should not be conducted at this time.
How is Alzheimer’s Disease Diagnosed?
A definitive diagnosis of AD is available only after
death, when an autopsy may be completed. However, doctors are able to get a
fairly accurate diagnosis in a living person by:
·
A detailed family history
·
Physical and neurological exams and laboratory tests
·
Computerized tomography (CT) scan or magnetic resonance imaging (MRI)
·
Additional neuropsychological testing
Specific criteria have been established by
physicians in order to make a probable diagnosis of AD:
·
Dementia confirmed by clinical and neuropsychological examination
·
Progressive worsening of memory and other mental functioning
·
No disturbances of consciousness (no blacking out)
·
Symptoms began between ages 40-90
·
No other disorders might account for dementia
Furthermore, an early, accurate diagnosis of AD can
assist in helping patients and their loved ones plan for the future. An early
diagnosis allows time to discuss alternatives in care while the patient is able
to participate in such decisions. Early diagnosis also offers the best chance
to treat the symptoms of the disease.
How is Alzheimer’s Disease Treated?
Cholinesterase Inhibitors
In the 1970’s researchers discovered that
acetylcholine levels, a neurotransmitter important in the formation of
memories, fell sharply in individuals with AD. Neurons in specific regions of
the brain utilize acetylcholine. These areas, mainly the hippocampus and the
cerebral cortex, are the parts of the brain which are most severely affected by
AD. This evidence led to the idea that increasing the level of acetylcholine or
hindering the breakdown of acetylcholine might be effective methods for
treatment of AD. Today, the Food and Drug Administration (FDA) has approved
four medications that slow or stop acetylcholinesterase, an enzyme that breaks
down acetylcholine. These medications, called cholinesterase inhibitors, have
been approved for the treatment of mild to moderate AD. These medications,
listed below, are not able to stop the progress of AD however; they do help
patients carry out daily activities.
Tacrine (Cognex®)
Donepezil (Aricept®)
Rivastigmine (Exelon®)
Galantamine (Reminyl®)
Vitamin E
Vitamin E is quite often prescribed as an
Alzheimer’s disease treatment. These supplements may help protect the brain
from free radicals, which are molecules that can damage cell structures and
genetic material. Research shows that vitamin E supplements may provide some
benefit to individuals with AD. A
consultation with a physician should take place before an individual with AD
starts on a vitamin E regimen because of the potential for an interaction with
other medications the patient may be taking.
Alternative Treatments
Alternative treatments include those treatments for
which the safety and effectiveness is not well documented. Furthermore, the purity of these treatments
and the adverse reactions one might experience are not well documented. It is
important to note that these dietary supplements are not strictly regulated by
the Food and Drug Administration (FDA), the governing body which approves
prescription drugs.
Examples of alternative treatments:
- Ginkgo biloba: a plant extract which
is made up of compounds that may have positive effects on cells within the
brain. Ginkgo biloba might have
abilities to protect cell membranes and to regulate the function of
neurotransmitters. On-going
clinical trials are evaluating the use of Ginkgo biloba as an Alzheimer’s
disease treatment. See www.clinicaltrials.gov
for more information.
- Huperzine A: a moss extract with qualities similar to FDA-approved
Alzheimer’s disease medications.
- Phosphatidylserine: a fat which is found in the cell membrane of
neurons. Phosphatidylserine may protect the cell membrane and save the
cells from degeneration.
Clinical Trials
Before a new drug can be put on the market it must
be proven to be safe and effective. This is usually accomplished by clinical
trials, which are research studies to investigate the new medication. The drug
must then be approved by the FDA before it can be prescribed by a doctor. See
this link for additional information: Clinical
Trials Resource Center
Resources
- Alzheimer's Education and Referral
Center
- Genetics
Home Reference
- Alzheimer's Association National
Headquarters
- Nussbaum RL, Ellis CE (2003) Alzheimer’s disease and Parkinson’s
disease. N Engl J Med 348: 1356-64.