Treatment for Alzheimer’s
Disease
Maenne Okunola
June 2011
UGA COP: Pharm D. Candidate
Preceptor: Dr. Ali Rahimi
Treatment Goal
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Currently there is no current therapy to treat
Alzheimer’s disease. Current therapy is aimed at
prolonging the patient’s cognitive function and
secondary goals include symptomatically treating
psychiatric and behavioral abnormalities
Current therapy has not been shown to prolong life,
cure AD, halt or reverse the pathophysiological
degradation of the disease
Natural Disease Progression
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Alzheimer’s Disease Assessment Scale-Cognition
(ADAS-cog) scores worsen by an average of 4
points over 6 months and 7 points over 1 year
4 points represents a clinically significant change
In clinical practice a Mini Mental Status Examination
(MMSE) is used due to time requirements of the
ADAS-cog
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An untreated patient has an average decline of 2-4 points
per year
Brain Comparison
Ideal Treatment
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Improving symptomatic decline by improving
cognitive function, daily activities, and
behavior
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Current therapy
Arrests the neurodegenerative molecular
process
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Research needed
Treatment Algorithm
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Cholinesterase Inhibitor
NMDA Antagonist
Cholinesterase Inhibitor + NMDA antagonist
Titrate doses to recommended maintenance
therapy as tolerated
Symptomatic approach is used to treat
behavioral symptoms
Cholinesterase Inhibitors
Cholinesterase Inhibitors
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Donepezil (Aricept)- used in mild to severe disease
Galantamine (Razadyne)- used in mild to moderate disease
Rivastigmine (Exelon)- used in mild to moderate disease
Combination of more than one cholinesterase inhibitor is not
recommended
Choice of therapy often selected based on ease of use for the
patient, cost and safety issues
Switching can occur if patients are not tolerating the initial
treatment or a treatment failure
 If MMSE decline is greater than 2-4 points in one year changing
therapy is warranted
Cholinesterase Inhibitors
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Donepezil, Rivastigmine and Galantamine
All show similar efficacy and adverse event profiles with
gastrointestinal complaints being the most common symptom
Dose titration over several months can help tolerability of urinary
incontinence, dizziness, headache, syncope, bradycardia,
muscle weakness, salivation and sweating
Abrupt discontinuation is discouraged due to worsening of
cognition or behavioral problems in some medications
Avoid use with anti-cholinergic medications which is especially
important when trying to treat behavioral abnormalities.
Cholinesterase Inhibitors Mechanism of
Action
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Donepezil- specifically and reversibly inhibits
acetylcholinesterase
Rivastigmine- inhibits both butylcholinesterase and
acetylcholinesterase
Galantamine- selective, competitive, reversible
acetylcholinesterasse inhibitor and also enhances
the action of acetylcholine on nicotinic receptors
Clinical relevance is unknown
NMDA Antagonist
N-methyl-D Aspartate (NMDA)
Antagonist
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Memantine- used in moderate to severe
disease
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Not recommended in early stages of the disease
Only NMDA-antagonist available
Blocks glutamatergic neurotransmission by
antagonizing NMDA receptors
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Glutamate an excitatory neurotransmitter in the
brain
Most common side effects include constipation,
confusion, dizziness, headache, hallucinations,
coughing, and hypertension
Dosage Forms
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Galantamine (Razadyne)- capsule, tablet,
and solution
Donepezil (Aricept)- tablet (oral disintegrating
tablet)
Rivastigmine (Exelon)- capsule, patch, and
solution
Memantine (Namenda)- tablet and solution
Treatment for Non-cognitive Symptoms
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Psychosis
Disruptive behavior
Depression
Environmental interventions then pharmacological therapy
Limited clinical data; therefore, treatment is empirical
General guidelines: reduced doses, close monitoring closely,
slow dose titrations, and careful documentation
Cholinesterase inhibitors and memantine should be considered
as first line therapy in patients with behavior abnormalities in the
beginning stages of AD
Antipsychotics
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Haloperidol
Olanzapine
Quetiapine
Risperidone
Ziprasidone
Treatment of psychosis: hallucinations, delusions,
suspicions
Treatment of disruptive behaviors: Agitation and
aggression
Not FDA approved
Concern with Antipsychotics
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Worsening cognitive impairment, oversedation, falls,
tardive dyskinesia, neuroleptic malignant syndrome,
hyperlipidemia, weight gain, diabetes mellitus,
cerebrovascular accidents
A dose reduction or discontinuation should be
considered periodically in patients
Physical restraints should be limited to patients who
pose imminent harm to themselves or others.
Antidepressants
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Citalopram
Escitiolopram
Fluoxetine
Paroxetine
Sertraline
Venlafaxine
Trazadone
Treatment of depression: poor appetite, insomnia, hopelessness,
anhedonia, withdrawal, suicidal thoughts, agitation, or anxiety
As many as 50% of AD patients suffer from depression
Anticonvulsants
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Carbamazepine
Valproic Acid
Treatment of agitation or aggression
Standard of treatment
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None exists
Duration of treatment ranges from clinician to
clinician. May be months to years
No clear standard of care for dosing from clinical
trials
No clear standard of when to discontinue therapy in
very severe stages of AD
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Many clinicians do discontinue therapy when the patient
becomes bed ridden
Key Non-pharmacological Methods
Education
Preparation
Communication
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Educating patient and family at the time of diagnosis
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Discussion of the course of illness
Expectations from treatment
Legal and financial planning including a durable power of
attorney
Quality of life issues
Re-enforcing the importance of communication between
the patient and family members
Decreasing environmental triggers and personal discomfort
Non-Pharmacological Interventions
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Physical well-being
Increased overall well being
Stimulation oriented treatments: recreational
activity, art therapy, music therapy, pet
therapy and aromatherapy may be useful, but
lack of sufficient evidence to validate
effectiveness but used in clinical practice
Caregivers
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Find time to rest, relax and tend to personal
affairs because stress will impact the health
and quality of life of both the patient and the
caregiver
Help patients to discover a structured level of
autonomy using reminders and explanations
Be aware of signs and symptoms of decline
Knowing when to institutionalize a patient
Interventions
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Patients should be assessed every 3-6
months
Patients may need to stop driving even at
mild levels of treatment
Sleep disturbances common in people with
dementia, proper sleep hygiene should be
implemented before beginning
pharmacological therapy
Behavioral Management
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Sleep disturbances
Wandering
Urinary Incontinence
Agitation
Aggression
May be useful to try this before beginning
drug therapy
Epidemiological Correlations
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Brain Vascular Health
Lipid lowering agents
Non inflammatory
agents
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Vitamin B 6, B12 and
B12 deficiency
Hyerhomocysteinemia
Brain Vascular Health
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New studies have evidence brain vascular disease
plays an important role in the progression of dementia
Brain vascular disease may accelerate deposition of
beta amyloid plaques and increase amyloid toxicity to
neurons and the neural synapses
Brain vascular health includes managing blood
pressure, glucose, cholesterol and homocysteine.
 Elevated homocysteine levels correlate with
decreased performance on cognitive tests
Importance of stating physically, mentally, and socially
active
Folate, Vitamin B12, Vitamin B6
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Defects in these vitamins are associated with
neurological and psychological dysfunction
In elderly patients there is increased concern
of satiety, atrophic gastritis, and decreased
function of the olfactory functions
Increased homocysteine has a direct
correlation with a deficiency and these vitamins
Estrogen Therapy
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Epidemiological studies post menopausal
women who took estrogen replacement
therapy had a lower incidence of AD
Studies did not show an improvement in
behavioral or functional outcomes when
estrogen used to treat cognitive decline
Estrogen has a risk of stroke and other
cardiovascular events
Anti-inflammatory Agents
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Epidemiological studies suggest patients on
anti-inflammatory agents have a lower
incidedence of AD
Treatment less than 2 years proved beneficial
in some patients
Clinical studies does not show evidence of
cognitive benefit and tolerability was an issue
Lipid Lowering Agents
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Epidemiological studies and AD show a correlation
between higher midlife total cholesterol rates and
AD
Correlation between people on lipid lowering therapy
and lower incidences' of AD
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Pravastatin and lovastatin but not simvastatin were
associated with a lower incidence of AD
More trials are needed to address the impact of cognitive
benefit, the duration of treatment, class effect, and optimal
dosing for its role in AD
Role of therapy should remain for people with
indications for their use
Therapies in the Pipeline
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Vitamin E
Atomexetine
IGIV 10%
Thiazolidinediones
(anti-inflammatory
effects)
Over 900 studies
occurring now phase 14 and
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Ginkgo Biloba
Huperzine A
Semagacestat
(LY450139)
Coenzyme Q10
Acupuncture
Over 100 studies phase
3
Vitamin E
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Antioxidant- may be useful because of the
accumulation of free radicals associated with AD
Favorable side effect profile and low cost
Impaired hemostasis, fatigue, nausea, diarrhea,
abdominal pain, and thinning of the blood
Increased mortality in older patients
Doses above 400 international units per day should
be avoided in patients with AD
May be beneficial in combination with Selegeline:
Phase III study-PREADVISE- examining anti-oxidant
effects of Selegeline
Ginkgo Biloba
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Increased blood flow, decreased viscosity of the
blood, antagonizing platelet activating factor
receptors, increased tolerance to anoxia, inhibiting
monoamine oxidase, anti-infective properties,
preventing damage of membranes caused by free
radicals
If used for dementia should be used as soon as
deterioration of cognitive functioning occurs
Side effects are typically mild and rare
Herbal products are typically poorly standardized
Huperzine A
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An alkyloid isolated from the Chinese club moss,
Huperzia serrata
Reversibly inhibits acetylcholinesterase and is
administered orally in doses 50-200 mcg 2-4 times
daily
May be more promising for symptomatic treatment
of Alzheimer’s disease
Promising product from clinical studies, but lack of
product purity
Concurrent use with other available cholinesterase
inhibitors should be avoided
Semagacestat (LY450139)
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Inhibiting the enzyme gamma-secretase lowers the
production of beta amyloid. Semagacestat
(LY450139) a functional gamma-secretase inhibitor
lowers the beta amyloid in the blood and spinal fluid
in humans.
Effect of LY450139 a gamma-secretase inhibitor on
the progression of Alzheimer’s disease as compared
with Placebo- Currently Phase III
60 mg orally titrated up to 140 mg
Immune Globulin Intravenous (Human),
10% (IGIV, 10%)
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A Randomized, Double-Blind, Placebo-Controlled,
Two Dose-Arm, Parallel Study of the Safety and
Effectiveness of Immune Globulin Intravenous
(Human), 10% (IGIV, 10%) for the Treatment of Mild
to Moderate Alzheimer's Disease – Phase III trial
The purpose of this study is to determine whether
IGIV, 10% treatment, administered at two different
doses results in a significantly slower rate of decline
of dementia symptoms in subjects with mild to
moderate (AD).
Approved in 2005 for primary immunodeficiency
Coenzyme Q10
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A natural antioxidant in the body
Role of therapy currently being explored, but
limited clinical trials in humans for AD
Helpful links
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www.aoa.gov
www.nia.nih/gov/alzheimers
www.alzforum.org
www.aarp.gov
www.thefamilycaregiver.org
www.ec-online.net
Economic Impact
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US health care cost is greater than $100 billion
Annual cost for caring for an individual with
advanced AD is approximately $50,000
According to CDC, there is 231,900 patients in
nursing homes with AD which accounts for 15.5% of
the nursing home population
4th leading cause of death in adults
Resources
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http://www.gammagardliquid.com/aboutgammagard-liquid/dosage-administration.html
http://www.nlm.nih.gov/medlineplus/druginfo/natural/
1003.html
cdc.gov
www.ncbi.nlm.nih.gov
www.novartis.com
www.alz.org
www.clinicaltrials.gov
Resources
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National Guideline Clearinghouse (NGC). Guideline
synthesis: Management of Alzheimer's disease and
related dementias. In: National Guideline Clearinghouse
(NGC). Rockville (MD): 2006 Nov (revised 2010 Sep).
[cited 2011 June 13]. Available: http://www.guideline.gov.
Dipiro J,Talbert R, Yee G., Matzke G, Wells B, Posey L.
Pharmacotherapy: A Pathophysiologic Approach. 7th.
New York: McGraw-Hill, 2008. 1051-1066
B Vitamins, Homocysteine, and Neurocognitive Function
in the Elderly. American Journal of Clinical Nutrition.
February 2000;71(2):614s-620s. Accessed June 15,
2011.