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Nervous System
inheritance exhibiting the earliest age (younger than
70 years). The APoE genotype is not, however, an abso-
lute determinant of who will develop AD. Just how these
different APo alleles influence the risk of AD continues
to remain poorly understood.
Manifestations
Alzheimer-type dementia follows an insidious and pro-
gressive course. The hallmark symptoms are loss of
short-term memory and denial of such memory loss,
with eventual disorientation, impaired abstract think-
ing, apraxias, and changes in personality and affect.
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Various stages of the disease have been recognized; all
are characterized by progressive degenerative changes.
The initial changes are often subtle, characterized by a
short-term memory loss that often is difficult to differ-
entiate from the normal memory loss that often occurs
in the elderly, and usually is reported by caregivers and
denied by the person. Although most elderly persons
have trouble retrieving from memory incidental infor-
mation and proper names, persons with AD randomly
forget important and unimportant details. They forget
where things are placed, get lost easily, and have trouble
remembering appointments and performing novel tasks.
Mild changes in personality, such as lack of spontane-
ity, social withdrawal, and loss of a previous sense of
humor, occur during this stage.
As the disease progresses, the person with AD enters
the moderate stage. This stage may last several years
and is marked by a more global impairment of cogni-
tive functioning. During this stage, there are changes
in higher cortical functioning needed for language,
spatial relationships, and problem solving. Depression
may occur in persons who are aware of their deficits.
There is extreme confusion, disorientation, lack of
insight, and inability to carry out the activities of daily
living. Personal hygiene is neglected, and language
becomes impaired because of difficulty in remembering
and retrieving words. Behavioral changes can include
agitation, sleep problems, restlessness and wander-
ing, aggression, and suspiciousness. Some persons may
become hostile and abusive toward family members.
Persons who enter this stage become unable to live
alone and should be assisted in making decisions about
supervised placement with family members or friends or
in a community-based facility.
Severe AD is the last stage of the disease. It is char-
acterized by a loss of ability to respond to the envi-
ronment. Individuals in this stage require total care
and spend most of their time bedridden. Death can
occur as a result of complications related to chronic
debilitation.
Diagnosis andTreatment
Alzheimer disease is essentially a diagnosis of exclusion.
There are no peripheral biochemical markers or tests
for the disease. The diagnosis can be confirmed only
by microscopic examination of tissue obtained from a
cerebral biopsy or at autopsy. The diagnosis is based on
clinical findings.
A diagnosis of Alzheimer disease requires the pres-
ence of dementia established by clinical examination
and documented by results of a Mini-Mental State
Examination, Blessed Dementia Test, or similar men-
tal status test; no disturbance in consciousness; onset
between 40 and 90 years of age, most often after
65 years of age; and absence of systemic or brain disor-
ders that could account for the memory or cognitive def-
icits. Brain imaging, CT scan, or MRI is done to exclude
other brain disease. Metabolic screening should be done
for known reversible causes of dementia such as vita-
min B
12
deficiency, thyroid dysfunction, and electrolyte
imbalance.
There is no curative treatment for Alzheimer dis-
ease.
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Drugs are used primarily to slow the progression
and to control depression, agitation, or sleep disorders.
Two major goals of care are maintaining the person’s
socialization and providing support for the family.
Self-help groups that provide support for family and
friends have become available, with support from the
AD and Related Disorders Association. Day care and
respite centers are available in many areas to provide
relief for caregivers and appropriate stimulation for
the patient.
Although there is no current drug therapy that is
curative for Alzheimer disease, cholinesterase inhibi-
tors have been shown to be effective in slowing the
progression of the disease by potentiating the action of
available acetylcholine.
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These drugs (e.g., donepezil,
rivastigmine, galantamine) inhibit acetylcholinesterase,
preventing the metabolism of endogenous acetylcholine,
and are used in the early stages of the disease for mild
cognitive impairment. Again, such therapy does not halt
the disease but can slow its progression. Memantine, an
N
-methyl-
d
-aspartate antagonist, has been approved by
the FDA for treatment of moderate to severe AD.
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This
medication may act by interfering with the glutama-
tergic excitotoxicity caused by the ischemia (discussed
under mechanisms of brain injury) and amyloid depos-
its associated with the disease, or it may provide symp-
tomatic improvement through effects on the function of
hippocampal neurons. This medication, like the cholin-
esterase inhibitors, modestly delays functional loss.
Other treatments for Alzheimer disease include agents
that are thought to have a neuroprotective effect.
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A
β
seems to exert its neurotoxic effects through a variety
of secondary mechanisms, including oxidative injury
and lipid peroxidation of cell membranes, and inflam-
mation. Several strategies have involved the use of anti-
inflammatory agents and antioxidants (vitamins E and
C). Several, but not all, epidemiologic studies provide
evidence supporting the concept that vitamin E and vita-
min C have a role in delaying the onset of AD. In some,
but not all, trials,
G. biloba
had small but statistically
significant effects compared with placebo in persons
with Alzheimer disease.
Psychotropic medications, such as antipsychotics and
mood stabilizers, may be used to assist in the behavioral
management of the disease. Interventions also include
environmental adjustments, behavioral intervention,
and education and support for caregivers.
