Laurel Coleman, MD Maine Medical Center Portland, Maine The Management of Alzheimer’s Disease

Management of Alzheimer’s Disease

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 months (ChEIs) Pharmacologic Options for AD

Aricept® package insert. Razadyne® package insert. Exelon® package insert. *Available in generic Drug Name Dosage formDosage range Minimum titration interval (as tolerated) Indication Donepezil (Aricept) Tablet*, orally disintegrating tablet* 5 mg – 23 mg QD 4 weeks 5 mg  10 mg 3 months 10 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 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 QD1 weekMod to severe Management of Alzheimer’s Disease: Cognitive Enhancers

Dizziness Headache Constipation Confusion NMDA-receptor antagonist (Memantine) Nausea Vomiting Diarrhea Weight loss Loss of appetite Muscle weakness Vivid dreams/nightmares (donepezil) Cholinesterase inhibitors (Donepezil, galantamine, rivastigmine) Pharmacologic Options for AD Common Side Effects

Switching ChEIs

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 AD 1 ─ Discontinuation associated with adverse behavioral changes and reduced participation in activites 2 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: Daiello et al. Am J Geriatr Pharmacother. 2009;7: Discontinuation of Therapy

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

PWD in primary care average 5.1 medications/pt 1 ─ 50% take ≥1 anticholinergic medications Medications with anticholinergic activity ─ Impairs cognition acutely (delerium) and chronically 2 Anticholinergic burden ─ Interfere with the therapeutic effect of ChEIs 3 1. Schubert CC, et al. J Am Geriatr Soc. 2006;54(1):104– Campbell N, et al. Clin Interv Aging. 2009;4:225– Lu C, Tune LE. Am J Geriatr Psychiatry. 2003;11(4):458–461. Impact of Coexisting Medical Conditions

Disinhibition Euphoria Loss of appetite Sleep disturbances Stereotyped behaviors (eg, pacing, wandering, rummaging, picking Tampi et al. Clinical Geriatrics. 2011;19: Apathy Depressive symptoms Anxiety Agitation/irritability/ aggression Psychotic symptoms ─ Delusions ─ Hallucinations Behavioral and Psychological Symptoms of Dementia (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

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 Nonpharmacological Interventions

Adapted from Tampi et al. Clin Geriatr. 2011;19: Drug classChemical nameDosage range (mg) Side effects of class Antipsychotics ( * 2 nd -generation antipsychotics) Aripiprazole*2.5-15Sedation, EPS, NMS, metabolic syndrome, QTc prolongations, increased risk of CVE and mortality Haloperidol0.5-5 Risperidone* Quetiapine* Olanzapine* AntidepressantsFluoxetine10-80Anxiety, headaches, sedation, GI symptoms, sexual dysfunction Citalopram10-60 Paroxetine10-50 Sertraline Trazadone Mood stabilizersCarbamazepine Sedation, gait and balance issues, falls, liver dysfunction, hyperammonemia, thrombocytopenia Divalproex sodium Oxcarbazepine Pharmacologic Interventions

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

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. Education of Patient and Family Medications

Late stage Help with all personal care Cope with unresponsiveness and end-of-life issues Late stage Help with all personal care Cope with unresponsiveness and end-of-life issues Mid stage Help with ADLS, eg, dressing and toileting Cope with increased memory loss, sleep disturbances, wandering, loss of driving Mid stage Help with ADLS, eg, dressing and toileting Cope with increased memory loss, sleep disturbances, wandering, loss of driving Early stage Help with IADLS, eg, paying bills and preparing meals Cope with mood swings and reluctance to engage Early stage Help with IADLS, eg, paying bills and preparing meals Cope with mood swings and reluctance to engage Impact on Caregivers Tasks Change Over Time

24/7 Nationwide Helpline ─ ─ 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 Education of Patient and Family Alzheimer’s Association

>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 Clinical Trial Recruitment

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 Understanding prevention research

Heart-head connection Preventative drug treatments Physical exercise Diet Social connections Intellectual activity Head trauma prevention Prevention Factors with a Consistent Association

Physical activity Mediterranean diet Cognitive engagement Decreased risk of AD Conjugated equine estrogen with progesterone* Diabetes Depression Smoking *Moderate evidence, all other factors had low evidence Increased risk of AD Preventing Alzheimer’s Disease and Cognitive Decline

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 The Future of Alzheimer’s Disease

Alzheimer’s Disease Progression

A  ─  -secretase inhibitors ─  -secretase inhibitors ─ Monoclonal antibodies Tau protein Inflammation Insulin resistance Targets for Future Therapies

Emerging Treatments for AD

Phase II: ACC-01 Crenezumab Moving to Phase III: Lu AE58054 EVP-6124 Phase III: Solanezumab IVIg Failed: AN-1792 Bapineuzumab Dimebon Rosiglitazone Semagacestat Tarenflurbil Tramiprosate Clinical Trials