The Management of Alzheimer’s Disease

Laurel Coleman, MDMaine Medical Center

Portland, Maine

Management of Alzheimer’s Disease

Managecognitive

symptoms

Manage BPSD

Support patient/family

Increased Increased quality of quality of

life for life for patient and patient and

familyfamily

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)

Drug Name  Dosage form Dosage range Minimum titration interval (as tolerated)

Indication

Donepezil(Aricept)

Tablet*, orally disintegrating tablet*

5 mg – 23 mg QD 4 weeks5 mg 10 mg

3 months10 mg 23 mg

Mild to severe

Galantamine(Razadyne®)

Tablet/oral solution*

Extended-release capsule*

4 mg – 12 mg BID

8 mg – 24 mg ER QD

4 weeks

4 weeks

Mild to moderate

Rivastigmine(Exelon®)

Capsule*

Patch

1.5 mg – 6 mg BID

4.6 mg – 9.5 mg QD

2 weeks

4 weeks

Mild to moderate

Memantine(Namenda®)

Tablet*, oral solution*

5 mg – 10 mg QD 1 week Mod to severe

*Available in generic

Aricept® package insert. Razadyne® package insert. Exelon® package insert.

Management of Alzheimer’s Disease: Cognitive Enhancers

Cholinesterase inhibitors(Donepezil, galantamine, rivastigmine)

NMDA-receptor antagonist(Memantine)

• Nausea• Vomiting• Diarrhea• Weight loss• Loss of appetite• Muscle weakness• Vivid dreams/nightmares

(donepezil)

• Dizziness• Headache• Constipation• Confusion

Aricept® package insert. Razadyne® package insert. Exelon® package insert.

Pharmacologic Options for ADCommon Side Effects

Switching ChEIs

Lack or loss of therapeutic benefit

Tolerability issues

Noncompliance

Immediate switchNo washout needed

Washout period of 1-2 weeks before

starting another agent

Try an alternate dosage form before

switching

Discontinuation of Therapy

• Data for optimal duration of treatment as disease progresses is limited─ 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

• Consider discontinuation in the following situations:─ Inability to tolerate multiple ChEIs─ No improvement or greater than expected decline after one or

more therapeutic trials─ End-stage dementia

1. Howard et al. New Engl J Med. 2012;366:893-903. 2. Daiello et al. Am J Geriatr Pharmacother. 2009;7:74-83.

Impact of Coexisting Medical Conditions

Cognitive Impairment

2.4 conditions/ptHTN 82%DM 39%CAD 21%CHF 14%Stroke 10%

Schubert CC, et al. J Am Geriatr Soc. 2006;54(1):104–109.

Prevalence of coexisting conditions in PWD

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

• Disinhibition• Euphoria• Loss of appetite• Sleep disturbances• Stereotyped

behaviors (eg, pacing, wandering, rummaging, picking

Tampi et al. Clinical Geriatrics. 2011;19:41-46.

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 BPSDNonpharmacological 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 InterventionsDrug class Chemical name Dosage

range (mg)Side effects of class

Antipsychotics Aripiprazole*HaloperidolRisperidone*Quetiapine*Olanzapine*

2.5-150.5-50.25-225-2002.5-15

Sedation, EPS, NMS, metabolic syndrome, QTc prolongations, increased risk of CVE and mortality

Antidepressants FluoxetineCitalopramParoxetineSertralineTrazadone

10-8010-6010-5025-20025-200

Anxiety, headaches, sedation, GI symptoms, sexual dysfunction

Mood stabilizers CarbamazepineDivalproex sodiumOxcarbazepine

100-400250-1000300-600

Sedation, gait and balance issues, falls, liver dysfunction, hyperammonemia, thrombocytopenia

Adapted from Tampi et al. Clin Geriatr. 2011;19:31-32.

*2nd-generation antipsychotics

Alzheimer’s Disease

Education of Patientand 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 FamilyMedications• 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 CaregiversTasks Change Over Time

Early stage•Help with IADLS, eg, paying bills and preparing meals•Cope with mood swings and reluctance to engage

Mid stage•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 FamilyAlzheimer’s Association• 24/7 Nationwide Helpline

─ 800.272.3900─ Information and referral in 170 languages

• www.alz.org─ 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

PreventionFactors with a consistent association• Heart-head connection• Preventative drug treatments• Physical exercise • Diet• Social connections• Intellectual activity• Head trauma prevention

PreventionFactors with a consistent association

Increased risk of AD• Conjugated equine

estrogen with progesterone*

• Diabetes• Depression• Smoking

Decreased risk of AD• Physical activity• Mediterranean diet• Cognitive engagement

*Moderate evidence, all other factors had low evidence

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

TIMEPre-Clinical MCI Probable AD

Asymptomatic

Cell death

Alzheimer's Disease Progression

Adapted from Shaw et al. Nature Reviews Drug Discovery. 2007;6:295-303.

Aβ=Beta-amyloidAD=Alzheimer’s diseaseMCI=Mild cognitive impairment

Beta-amyloid and neurofibrillary tangle formation begins in pre-clinical phase

Clear cognitive deficits

Mild cognitive deficits

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 phosphorylationCholinergic drugsOther

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