The Management of
Alzheimer’s Disease
Laurel Coleman, MD
Maine Medical Center
Portland, Maine
Management of Alzheimer’s Disease
Manage
cognitive
symptoms
Manage BPSD
Support
patient/family
Increased
quality of
life for
patient and
family
Pharmacologic Options for AD
• Cognitive enhancers
─ 2 classes
• Cholinesterase inhibitors (ChEIs)
• NMDA-receptor antagonist
─ Do not cure the disease or reverse cognitive
impairment
─ Can improve cognition and functional ability
─ Reduce the rate of decline 9-12 months (ChEIs)
─ Delay in nursing home placement was 17-21
months (ChEIs)
Management of Alzheimer’s Disease:
Cognitive Enhancers
*Available in generic
Drug Name
Dosage form
Dosage range
Donepezil
(Aricept)
Tablet*, orally
5 mg – 23 mg QD
disintegrating tablet*
Minimum
Indication
titration interval
(as tolerated)
4 weeks
5 mg  10 mg
3 months
Mild to
severe
10 mg  23 mg
Galantamine
(Razadyne®)
Tablet/oral solution*
4 mg – 12 mg BID
Extended-release
capsule*
8 mg – 24 mg ER QD 4 weeks
Rivastigmine
(Exelon®)
Capsule*
1.5 mg – 6 mg BID
2 weeks
Patch
Tablet*,
oral solution*
4.6 mg – 9.5 mg QD
5 mg – 10 mg QD
4 weeks
1 week
Memantine
(Namenda®)
4 weeks
Aricept® package insert. Razadyne® package insert. Exelon® package insert.
Mild to
moderate
Mild to
moderate
Mod to
severe
Pharmacologic Options for AD
Common Side Effects
NMDA-receptor
antagonist
Cholinesterase inhibitors
(Donepezil, galantamine, rivastigmine)
•
•
•
•
•
•
•
Nausea
Vomiting
Diarrhea
Weight loss
Loss of appetite
Muscle weakness
Vivid dreams/nightmares
(donepezil)
(Memantine)
•
•
•
•
Dizziness
Headache
Constipation
Confusion
Aricept® package insert. Razadyne® package insert. Exelon® package insert.
Switching ChEIs
Lack or loss of
therapeutic benefit
Immediate switch
No washout needed
Tolerability issues
Washout period of
1-2 weeks before
starting another agent
Noncompliance
Try an alternate
dosage form before
switching
Discontinuation of Therapy
•
Data for optimal duration of treatment as disease
progresses is limited
─
─
•
Consider discontinuation in the following situations:
─
─
─
1.
2.
Modest cognitive and functional benefits associated with continued
therapy with (donepezil) in moderate to severe AD1
Discontinuation associated with adverse behavioral changes and
reduced participation in activites2
Inability to tolerate multiple ChEIs
No improvement or greater than expected decline after one or more
therapeutic trials
End-stage dementia
Howard et al. New Engl J Med. 2012;366:893-903.
Daiello et al. Am J Geriatr Pharmacother. 2009;7:74-83.
Impact of Coexisting Medical
Conditions
2.4 conditions/pt
HTN
82%
DM
39%
CAD 21%
CHF
14%
Stroke 10%
Cognitive
Impairment
Prevalence of coexisting conditions in PWD
Schubert CC, et al. J Am Geriatr Soc. 2006;54(1):104–109.
Impact of Coexisting Medical
Conditions
• PWD in primary care average 5.1
medications/pt1
─ 50% take ≥1 anticholinergic medications
• Medications with anticholinergic activity
─ Impairs cognition acutely (delerium) and
chronically2
• Anticholinergic burden
─ Interfere with the therapeutic effect of ChEIs3
1. Schubert CC, et al. J Am Geriatr Soc. 2006;54(1):104–109.
2. Campbell N, et al. Clin Interv Aging. 2009;4:225–233.
3. Lu C, Tune LE. Am J Geriatr Psychiatry. 2003;11(4):458–461.
Behavioral and Psychological
Symptoms of Dementia (BPSD)
•
•
•
•
Apathy
Depressive symptoms
Anxiety
Agitation/irritability/
aggression
• Psychotic symptoms
─
─
Delusions
Hallucinations
Tampi et al. Clinical Geriatrics. 2011;19:41-46.
•
•
•
•
•
Disinhibition
Euphoria
Loss of appetite
Sleep disturbances
Stereotyped
behaviors (eg,
pacing, wandering,
rummaging, picking
Managing BPSD
• Identify triggers
─
─
─
Observe symptom timing and frequency
Look for environmental triggers, eg noise, lighting
Investigate potentially treatable causes, eg pain
• Make adjustments
─
─
─
Address medical causes
Adapt environment
Adapt caregiving
• Modify as needed
Managing BPSD
Nonpharmacological Interventions
•
•
•
•
Use the “3 Rs”—repeat, reassure, redirect
Simplify the environment, task, routine
Anticipate unmet needs
Allow adequate rest between stimulating
events
• Use cues
• Encourage physical activity
• Other interventions
Managing BPSD:
Pharmacologic Interventions
Drug class
Chemical name
Dosage
range (mg)
Side effects of class
Antipsychotics
Aripiprazole*
Haloperidol
Risperidone*
Quetiapine*
Olanzapine*
2.5-15
0.5-5
0.25-2
25-200
2.5-15
Sedation, EPS, NMS,
metabolic syndrome, QTc
prolongations, increased
risk of CVE and mortality
Antidepressants
Fluoxetine
Citalopram
Paroxetine
Sertraline
Trazadone
10-80
10-60
10-50
25-200
25-200
Anxiety, headaches,
sedation, GI symptoms,
sexual dysfunction
Mood stabilizers
Carbamazepine
Divalproex
sodium
Oxcarbazepine
100-400
250-1000
300-600
Sedation, gait and balance
issues, falls, liver
dysfunction,
hyperammonemia,
thrombocytopenia
*2nd-generation
antipsychotics
Adapted from Tampi et al. Clin Geriatr. 2011;19:31-32.
Alzheimer’s Disease
Education of Patient
and Family
Education of Patient and Family
• Safety issues:
─
─
─
─
─
Home environment
Driving
Medication adherence
Financial exploitation
Elder abuse
• Address future needs: financial planning,
advanced directives, power of attorney
Education of Patient and Family
Medications
• Define treatment success
─ Symptomatic benefit in
• Cognition
• Physical function and ADLs
• Behavior
─ Increases time to nursing home placement
• Discuss length of therapy
─ Adequate trial is 6 months
Cummings JL. Am J Geriatr Psychiatry. 2003;11(2):131–145.
Doody RS, et al. Arch Neurol. 2001;58(3):427–433.
Impact on Caregivers
Tasks Change Over Time
Early stage
Mid stage
•
•
•
Help with
IADLS, eg,
paying bills and
preparing meals
Cope with mood
swings and
reluctance to
engage
•
Help with ADLS,
eg, dressing and
toileting
Cope with
increased
memory loss,
sleep
disturbances,
wandering, loss
of driving
Late stage
•
•
Help with all
personal care
Cope with
unresponsiveness
and end-of-life
issues
Education of Patient and Family
Alzheimer’s Association
•
24/7 Nationwide Helpline
─
─
•
www.alz.org
─
•
800.272.3900
Information and referral in 170 languages
Current reliable information for healthcare professionals, people
with dementia, family members and caregivers
300 local offices
─
─
─
─
─
Information and referral
Support groups
Care consultation
Safety services
Education, local conferences
Clinical Trials
•
>120 clinical studies in
the US are recruiting
participants
─
•
Slow recruitment is a
barrier to discovering
new treatments
Alzheimer’s Association
TrialMatch™
─
─
─
─
Connect potential
participants with
appropriate clinical studies
Access via phone or online
Confidential
Free
Understanding prevention research
• Much evidence comes from large
epidemiological studies that show
associations, not proof
• Study results apply to populations, not
individuals
• Large randomized studies for many
prevention strategies unlikely
─ Cost prohibitive
Prevention
Factors with a consistent association
•
•
•
•
•
•
•
Heart-head connection
Preventative drug treatments
Physical exercise
Diet
Social connections
Intellectual activity
Head trauma prevention
Prevention
Factors with a consistent association
Increased risk of AD
• Conjugated equine
estrogen with
progesterone*
• Diabetes
• Depression
• Smoking
*Moderate evidence,
all other factors had low evidence
Decreased risk of AD
• Physical activity
• Mediterranean diet
• Cognitive engagement
The Future of Alzheimer’s Disease
• Earlier recognition
─ Dependent on reliable biomarkers
• New medications
─ Current medications only address symptoms
─ New medications in development
• Disease-modifying therapy
• Combination disease-modifying and symptomatic
therapy
• Prevention
Alzheimer's Disease Progression
Beta-amyloid and neurofibrillary
tangle formation begins in
pre-clinical phase
Pre-Clinical
Cell death
MCI
Probable AD
TIME
Asymptomatic
Aβ=Beta-amyloid
AD=Alzheimer’s disease
MCI=Mild cognitive impairment
Clear cognitive
deficits
Mild cognitive
deficits
Adapted from Shaw et al. Nature Reviews Drug Discovery. 2007;6:295-303.
Targets for Future Therapies
• A
─ -secretase inhibitors
─ -secretase inhibitors
─ Monoclonal antibodies
• Tau protein
• Inflammation
• Insulin resistance
Emerging Treatments for AD
 A production
 A  aggregation
 A  clearance
 tau aggregation
or phosphorylation
Cholinergic
drugs
Other
Clinical Trials
Failed
Phase 2
Moving to
Phase III
Phase III
AN-1792
ACC-01
Lu AE58054
Solanezumab
Bapineuzumab
Crenezumab
EVP-6124
IVIg
Dimebon
Rosiglitazone
Semagacestat
Tarenflurbil
Tramiprosate