Alzheimer’s Disease:

Clinical Management

Jeffrey Cummings, MD, ScD

Cleveland Clinic Lou Ruvo Center for Brain Health

DisclosuresDr. Cummings has provided consultation to Acadia, Avanir,

BiOasis, Bracket, Eisai, Genentech, Lilly, Lundbeck, Medavante, Otsuka, QR, Roche, Takeda and Toyama pharmaceutical and assessment companies.

Dr. Cummings has stock options in Prana, Neurokos, ADAMAS, MedAvante, QR pharma.

Dr. Cummings owns the copyright of the Neuropsychiatric Inventory.

This lecture will include reference to unapproved medications and diagnostics.

AD: Clinical Management

Medications

Cognitive enhancing agents

Treatment of neuropsychiatric symptoms

Brain health; non-pharmacologic

interventions

Clinical trials

MEDICATIONS

AD: Medications

Cognitive enhancers

Cholinesterase inhibitors

Donepezil (Aricept™)

Rivastigmine transdermal system (Exelon

Patch™)

Galantamine (Razadyne™)

Memantine (Namenda™)

Namzaric™ (donepezil 10 mg+ memantine 28

mg)

Cognitive Enhancers:

A Clinical Strategy

Accurate Dx

of AD

AD Dementia: mild, moderate,

severe

Donepezil

5mg

Monitor for tolerability: diarrhea,

night mares, muscle cramps

Donepezil

10 mg

Monitor for tolerability: diarrhea,

night mares, muscle cramps

Cognitive Enhancers:

A Clinical Strategy

WatchIf donepezil tolerated; watch at

10 mg dose for 6-12 months

Rivastigmine

Transdermal

If donepezil not

tolerated; switch

to patch; 4.6 mg

Rivastigmine

Transdermal

If tolerated;

advance to 9.5

mg

Cognitive Enhancers:

A Clinical Strategy

ChE-I

Optimized

Observe for clinical worsening

or progression to moderate AD

Memantine

10 mg

Monitor for tolerability: drowsy,

headache, dizziness

Memantine

20 mg

Monitor for tolerability: drowsy,

headache, dizziness

Cognitive Enhancers:

A Clinical Strategy

ChE-I/

Memantine

Observe for clinical worsening

or moderate/severe AD

High Dose

Donepezil

23 mg or 2x 10 mg; monitor for

tolerability: diarrhea, night

mares, muscle cramps

If on rivastigmine patch;

advance to 13.3 mg patch

Cognitive Enhancers:

A Clinical Strategy

End dosing

20 mg donepezil or 13.3 mg rivastigmine

patch; plus

20 mg memantine

Donepezil

Single 23 mg dose or 2 x 10 mg dose

Give in the morning to avoid dream-related

issues

Cognitive Enhancers:

A Clinical Strategy

Rivastigmine

Main tolerability issue is skin reaction

Discontinue when redness extends beyond

the patch boundaries or there is pruritus

Redness can be treated with steroid cream

Make sure patch is changed daily (previous

patch removed)

Make sure location is rotated and not re-used

more often than every two weeks

Cognitive Enhancers:

A Clinical Strategy

Memantine

20 mg (10 BID) or 28 mg QD

Namzaric™

Fixed combination of 10 mg donepezil and 28

mg memantine

Can be substituted when doses stable

Do not use 2 cholinesterase inhibitors together

(e.g, pill and patch)

Cognitive Enhancers:

A Clinical Strategy

Donepezil

Ask about “loose stools” not just “diarrhea”;

patients and caregivers tend to under-report

bowel changes

Anorexia is a subtle GI symptom; ask about

weight loss and eating habits

Expectations

45% of patients improve on ChE-I

80% of patient have a delay in decline on

ChE-I

Cognitive Enhancing Agents:

Setting ExpectationsC

og

nitio

n

Time

Improve

(45%)

Delay

(80%; 6-9

months)

Continued

benefit above

placebo

Parallel slope

Cognitive Enhancers:

A Clinical Strategy

Contraindications

Donepezil should not be used in patients with

bradycardia (HR < 40 bpm) or sick sinus

syndrome

Treatment of Neuropsychiatric

Symptoms in AD

Cognitive enhancers

Psychotropic agents

There are no drugs approved for any psychiatric

symptom in AD

All prescribing for psychiatric/behavioral

symptoms in AD is “off label”

Treatment of Neuropsychiatric

Symptoms in AD

Cognitive Enhancer Neuropsychiatric

Symptom

Cholinesterase inhibitors Apathy

Hallucinations

Depression

Memantine Irritability

Agitation

Treatment of Neuropsychiatric

Symptoms in AD

NP Symptoms Agents to Be

Considered

Dose

Depression Citalopram 10 - 20 mg

Sertraline 50 - 200 mg

Duloxetine 20 mg BID – 30 mg

BID

Psychosis (delusions

+/- hallucinations)

Quetiapine 25 – 200 mg/d

Risperidone 0.5 – 2 mg/d

Pimavanserin 34 mg/d

Treatment of Neuropsychiatric

Symptoms in AD

NP Symptoms Agents to Be

Considered

Dose

Agitation Citalopram 10 - 20 mg/d

Quetiapine 25 – 200 mg/d

Risperidone 0.5 – 2 mg/d

Nuedexta 10/20 mg BID

Apathy Methylphenidate 10 - 20 mg/d

Modafinil 100 – 200 mg/d

Treatment of Neuropsychiatric

Symptoms in AD

NP Symptoms Agents to Be

Considered

Dose

Sleep/insomnia Zolpidem 2.5 - 5 mg HS

Trazodone 25 - 50 mg HS

Sleep/irregular sleep-

wake rhythm disorder

(ISWRD)

Suvorexant 10 – 20 mg HS

Treatment of Neuropsychiatric

Symptoms in AD: Caveats

Apathy is often mis-identified as

depression

Consider apathy before prescribing an

antidepressant

Psychosis

Pimavanserin is approved for psychosis of

Parkinson’s disease

Treatment of Neuropsychiatric

Symptoms in AD: Caveats

Agitation

Citalopram

Reduced agitation in a trial

QTq prolongation observed at 30 mg

1 point decease in MMSE score

Risperidone and quetiapine

Parkinsonism/tardive dyskinesia

Weight gain/metabolic syndrome

1 point decrease in MMSE score

Treatment of Neuropsychiatric

Symptoms in AD: Caveats

Agitation

Neudexta (DM/Q)

Anti-agitation affect observed in Phase II

trial

Currently in Phase III trial

Approved for pseudobulbar affect (PBA)

Not approved for agitation

Treatment of Neuropsychiatric

Symptoms in AD: Caveats

Apathy

Distressing to caregivers

Methylphenidate

Decreased appetite and weight loss

Insomnia

Modafinil

Insomnia

Treatment of Neuropsychiatric

Symptoms in AD: Caveats

Sleep

Avoid benzodiazepines

Avoid benadryl/OTC sleep aids

Anticholinergic effects worsen cognition

Insomnia

Zolpidem

Irregular sleep-wake rhythm disorder (ISWRD)

Goal: improve night-time sleep and day-time

wakefulness

Orexin antagonists (suvorexant)

Treatment of Neuropsychiatric

Symptoms in AD: Caveats

Start low; go slow; but do not under-dose

Treat 6-12 months before slow withdrawal

Most NPS are recurrent

Relapse following tx withdrawal is common

Psychotropic side effects are common

Psychotropic drug-drug interactions are common

Psychotropics benefit patient and caregiver

quality of life when well used

BRAIN HEALTH

30% of AD is Attributable to Modifiable

Risk Factors

AD – Alzheimer’s diseaseBarnes D, Yaffe K. Lancet

Neurol 2013; 10: 819-828

Increase Alzheimer’s

Disease

Decrease Alzheimer’s

Disease

• Education

• Exercise

• Diet/nutrition

• Socialization/brain

fitness

• Sleep

• Age

• Genes (ApoE 4)

• Female sex

• Diabetes

• Obesity

• Hypertension

• Depression/stress

• Head injury

• Smoking

FINGER Study

Finnish Geriatric Intervention Study to

Prevent Cognitive Impairment and

Disability (FINGER)

1200 person; randomized 1:1 to

intervention or not

60-77 years old

Had dementia risk factors and normal or

nearly normal cognition

Ngandu T, et al. Lancet 2015; 385: 2255-2263

FINGER Study

Tx: diet, exercise, cognitive training,

vascular risk monitoring

2 year intervention

Now being replicated in US

US Pointer Study (Alz Assn)

FINGER Study: Less Decline

in Cognition

Ngandu T, et al. Lancet 2015; 385: 2255-2263

NTB – Neuropsychological

Test Battery

FINGER Study: Less Decline in

Processing Speed

Ngandu T, et al. Lancet 2015; 385: 2255-2263

Customized Intervention

Food & Nutrition

Medical Health Mental Fitness

Physical Fitness

Sleep & Relaxation

Social Interaction

Clinical Trials

Volunteers needed for our army of citizen

scientists

Refer for clinical trials

Altruism

Help for future victims including family

Alliance with referring clinician

Only way to develop new therapies for AD

SUMMARY

Comprehensive Management

Exercise

Nutrition

Sleep

NP sxCog

Enhance

Clinical Trials

Control CVD

Summary

Cognitive enhancers

Cholinesterase inhibitor

Memantine

Improve some; delay decline in most

Psychotropic agents

Not approved

Can be helpful when used judiciously

Brain health important (healthybrains.org)

Refer to clinical trials