Current Issues In The Diagnosisand Treatment of Alzheimer’s

Malgorzata Franczak, MD Associate Professor of Neurology

Medical College of Wisconsin Director of the Normal Pressure Hydrocephalus Program

Director of the Community Engagement

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Diagnosis of Alzheimer’s Disease

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In 2011 The National Institute on Aging and The Alzheimer’s Association proposed new

criteria and guidelines for diagnosing Alzheimer’s Disease

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Three stages of Alzheimer’s Disease A. Preclinical AD

B. Mild Cognitive Impairment due to AD

C. Dementia due to AD

Biomarkers tests A. Biomarkers showing levels of beta-amyloid accumulation

in the brain

B. Biomarkers showing that neurons in the brain are injured

or actually destroyed

Preclinical Alzheimer’s Disease

1. Individuals have no symptoms

2. Measurable changes in the brain, CSF and/or blood that indicate the earliest signs of disease are found

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Cognitive ContinuumCognitive Continuum

NormalNormal

Mild CognitiveMild CognitiveImpairmentImpairment

DementiaDementia

CP926864- 9

1. Memory complaint, preferably corroborated by

an informant

2. Memory impairment documented according to

appropriate reference values

3. Essentially normal performance in non memory

cognitive domains

4. Generally preserved activities of daily living

5. Not demented

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Mild Cognitive Impairment (MCI)

100

0

88

12

76

24

64

36

52

48

0 12 24 36 48

Months

Alzheimer'sdisease

MCI

Copyright restrictions may apply.

Petersen, R. C. et al. Arch Neurol 2009;66:1447-1455.

Hypothetical temporal ordering of neuropathological processes in the course of Alzheimer disease and corresponding imaging and biomarker measures

Psychosocial Management

Cognitive drug management

Behavioral drug management

Medical management

Maintain quality of life

Maximize function

Enhance cognition

Treat mood and behavior problems

Educate and counsel caregiver to alleviate stress Regular office visits Frequent telephone contact with family members Coordination of multidisciplinary team

Treatment GoalsTreatment Goals

FDA-approved drugs commonly used for the treatment of AD Aricept® (donepezil hydrochloride)

Indicated for mild, moderate, or severe dementia of the Alzheimer’s type

Exelon® (rivastigmine tartrate) and EXELON®PATCH (rivastigmine transdermal system) Indicated for mild to moderate dementia of the Alzheimer’s type Indicated for mild to moderate Parkinson’s disease dementia (PDD)

Razadyne® (galantamine hydrobromide) Indicated for mild moderate and advanced dementia of the

Alzheimer’s type

Namenda® (memantine hydrochloride) is an NMDA receptor antagonist Indicated for moderate to severe dementia of the Alzheimer’s typeAricept® is a registered trademark of Eisai Incorporated; Razadyne® is a registered trademark of Ortho-McNeil Neurologics Incorporated; Namenda® is a registered trademark of Forest Pharmaceuticals Incorporated.

Adapted with permission from Winblad et al. Neurology. 2001;57:489-495.See Appendix for study description and safety information (Nordic).

12 24 520

P=.019

P<.001

P=.001

36 Endpoint

P<.001

Clinicalimprovement

Clinicaldecline

-3.0

-2.5

-2.0

-1.5

-1.0

-0.5

0.0

0.5

1.0

Study week

MM

SE

ch

ang

e fr

om

bas

elin

e

Aricept (n=142)Placebo (n=144)

P=.0004

P=.0019

Adapted with permission from Feldman et al. Neurology. 2001;57:613-620.See Appendix for study description and safety information (Moderate to Severe AD [MSAD]).

Endpoint

P<.0001

Clinicalimprovement

Clinicaldecline-2

-1

0

1

2

3

0 12 24

Study week

MM

SE

ch

ang

e fr

om

bas

elin

e

Aricept (n=144)Placebo (n=146)

Tpmx\82250816\Alzheimer’s.v2 - 196/27/02 13:47

GAL-USA-9: Change FromGAL-USA-9: Change FromBaseline in ADAS-cog/11 ScoresBaseline in ADAS-cog/11 Scores-6-4-202468

10121416

Mea

n C

hang

e Fr

om B

asel

ine

Mea

n C

hang

e Fr

om B

asel

ine

± S

E in

AD

AS-

cog/

11 ±

SE

in A

DA

S-co

g/11

BaselineTime (months)Time (months)

3 6 9 12 18 24 30 36

18202224

1. Torfs K et al Poster presented at the Sixth International Stockholm/Springfield Symposium on Advances in AlzheimerTherapy, April 2000. 2. Stern RG et al. Am J Psychiatry. 1994;151:3. 3. Data on file. Janssen Pharmaceutica.

Estimation of decline–Stern Equation2

12-month Placebo1

Galantamine 24-32/24 mg3

Reprinted with permission from Rogers SL et al. Eur Neuropsychopharmacol. 2000;10:195-203.

20

30

40

50

60

-10

0

10

14 26 38 50 62 74 86 98 110 124 136 146 158 170 182 194 206 213 230 242 254

Weeks

Donepezil-treated group95% confidence intervalHistorical control

Mea

n c

han

ge

(± S

E)

fro

mb

asel

ine

in A

DA

S-c

og

sco

res

Mohs et al. Neurology. 2001;57:481-488.See Appendix for study description and safety information (Preservation of Function).

0 50 100 150 200 250 300 350

Median time to functional decline (days)

Placebo(n=217 at baseline)

Aricept 10 mg(n=214 at baseline)

P<.002

208 days

357 days

Aricept 23 mg

Screened 2186

Randomized 1467

Donepezil 10 mg 471

Donepezil 23 mg 963

Completed Withdrawn 399 72

Completed Withdrawn 687 278

Reason for withdrawalAE 8.1%Lack of efficiency 0.1Other 7

Reason for withdrawalAE 18.6%Lack of efficiency 0Other 9.1

10 mg 23 mg

Diarrhea 8.3 5.3Nausea 11.8 3.4Vomiting 2.5 9.2Anorexia 1.7 5.3

Aricept 23 mg GI Adverse events

0 6 12 18 24 Weeks of Drug Treatment

Aricept 23 mgAricept 10 mg

0

SIB Change

from BaselineLS mean

(±SE)

1

2

1

2

4

EXELON Patch is applied once daily

Exelon Patch prescribing information. Novartis Pharmaceuticals Corporation, East Hanover, NJ, 2007.

*Dose should be increased after a minimum of 4 weeks only if initial dose is well tolerated. When switching from oral rivastigmine, apply the first patch on the day following the last oral dose.

4 WEEKS4 WEEKS**4 WEEKS4 WEEKS**

EXELON Patch 9.5 mg/24h

EXELON Patch 4.6 mg/24h

Initial Rx Maintenance Rx

Daily Rivastigmine Oral Dosage

Daily EXELON Patch Dosage

<6 mg 4.6 mg/24 h

6 to 12 mg 9.5 mg/24 h

Safety population.

Exelon Patch prescribing information. Novartis Pharmaceuticals Corporation, East Hanover, NJ, 2007.

Pat

ien

ts r

epo

rtin

g a

dve

rse

even

ts,

%

Nausea Vomiting

23%

7%5%

17%

6%3%

25

20

15

10

5

0

30

35

EXELON Capsule 12 mg/d(n=294)

EXELON Patch 9.5 mg/24h

(n=291)

Placebo(n=302)

EXELON Capsule 12 mg/d(n=294)

EXELON Patch

9.5 mg/24h(n=291)

Placebo(n=302)

Severe Impairment Battery

ADCS-ADL

Developers: Merz,Lunbeck,Forest Non competitive low affinity NMDA

receptor (like amandatine) Trials in AD VaD MCI in the EU Available since January 2004 One month titration to10mg bid Indication for advanced AD MMSE < 14

The Memantine Group Exhibited Significantly Superior Cognitive The Memantine Group Exhibited Significantly Superior Cognitive Function Compared With the Placebo Group Function Compared With the Placebo Group

*.

Mea

n C

han

ge F

rom

Ba

selin

ein

SIB

Sco

re

-12

-10

-8

-6

-4

-2

0

2

4 12 28

Imp

rove

me

nt

Week

Memantine

Placebo

0 End Point

De

terio

ratio

n

126126126126 117117

119119106106107107

83839696 124124

123123

*P=.002†P<.001

P<.001

n =n =n =n =

P=.068

Memantine in Moderate to Severe AD StudyMemantine in Moderate to Severe AD Study

Memantine-Treated Patients Demonstrated Significantly Less Memantine-Treated Patients Demonstrated Significantly Less Functional Deterioration vs Placebo Functional Deterioration vs Placebo

Mea

n C

han

ge F

rom

Ba

selin

e in

AD

CS

-AD

L 19 S

core

126126126126 117117

119119106106107107

84849797 124124

123123

4 12 28Week

0 End Point

Imp

rove

me

nt

De

terio

ratio

n

-7

-5

-4

-3

-2

-1

0

1

-6Memantine

Placebo

*P=.003

†P=.02

n =n =n =n =

P=.106

P=.145

Memantine in Moderate to Severe AD StudyMemantine in Moderate to Severe AD Study

*OC analysis. †LOCF analysis Adapted with permission 2004 from: Reisberg B, Doody R, Stöffler A, Schmitt F, Ferris S, Möbius HJ. N Engl J Med.

2003;348:1333-1341. Copyright © 2003 Massachusetts Medical Society. All rights reserved.Data on file, Forest Laboratories, Inc.

Namenda XR 28 mg

AChEI1

2

4

4 8 12 16 20 24 weeks

3

-1

0

Time course of the change from baseline in SIB score for patients completing 24 weeks of treatment.

Namenda XR 28 mg

Time course of the CIBIC-Plus score for patients completing 24 weeks of treatment.

Namenda XR 28 mg

AChEI

4 8 12 16 20 24 weeks

Mean (± SEM) CIBC-Plus Score

3.8

3.6

4.2

4

4.4

Gastrointestinal Disorders Diarrhea 4 5 Constipation 1 3 Abdominal pain 1 2 Vomiting 1 2 Infections and infestations Influenza 3 4 Investigations Weight, increased 1 3 Musculoskeletal and connective tissue disorders Back pain 1 3

Adverse reactions observed with a frequency of ≥ 2% and occurring with a rate greater than placebo Adverse reaction

Placebo (n = 335) % NAMENDA XR 28mg (n = 341) %

Fish oils Coconut oil B complex vitamins Ginko Biloba Prevagen

Figure 2.  Dynamic biomarkers of the Alzheimer's pathological cascadeAβ is identified by CSF Aβ42 or PET amyloid imaging. Tau-mediated neuronal injury and dysfunction is identified by CSF tau or fluorodeoxyglucose-PET. Brain structure is measured by use of structural MRI. Aβ=β-amyloid. MCI=mild cognitive impairment.

Prevent build up of plaque (anti-amyloid)o slow or prevent amyloid production by inhibiting clipping

enzymes or by vaccine therapyo slow aggregation into plaqueso dissolve plaqueso increase clearance

Prevent build up of paired helical filaments (tau focused)o slow or prevent tau aggregation and dysfunctiono dissolve paired helical filaments

Prevent brain cell dysfunction and deatho slow or prevent oxidative stress, inflammation, reduced

blood flowo increase levels of protective molecules in braino maintain viable connections between cells