The Management of Alzheimer’s Disease and Related Dementias

The Treatment of Alzheimer’s Disease and Disease Progression Modification

Alzheimer’s Disease (AD): Overview

Progressive, degenerative CNS disorder Characterized by memory impairment plus one or

more additional cognitive disturbances Gradual decline in three key symptom domains

– Activities of daily living (ADL)

– Behavior and personality

– Cognition Most common cause of dementia in people

aged 65 and over

Evans DA, Scherr PA, Smith LA, et al. Aging (Milano). 1990(Sept);2(3):298-302; Ernst RL, Hay JW. Am J Public Health. 1994(Aug);84(8):1261-1264; Alzheimer’s Association, 2002

Alzheimer’s Disease: Economic Consequences

Third most expensive disease in the US Costs over $100 billion/year Further $33 billion in lost productivity

and other employer costs 3/4 of patients admitted to residential care

within 5 years of diagnosis

Adapted from Brookmeyer et al, 1998.

8

Delay (Years)

US

Pre

vale

nce

of

AD

(Mil

lio

ns)6

4

2

0204720372027201720071997

0 1 5

Potential Impact of Interventions to Delay Onset of Alzheimer’s Disease

Potential to Increase Diagnosis and Treatment Across Disease Stages

AChE = acetylcholinesterase1Mattson Jack; 2MMI MDAD, 2001; 3On CHeI—midpoint of last year’s treatment by severity rates and rates reported in Reminyl uptake, 2001; 4Decision Resources.

0

200,000

400,000

600,000

800,000

1,000,000

1,200,000

1,400,000

Mild4 Moderate4 Severe4

Number of patients1

Diagnosed2

Treated with AChE inhibitor3

Nu

mb

er o

f P

atie

nts

Disease Stages

Knopman D, Scheider L, Davis K et al. Neurology. 1996(July);47(1):166-177.

Pro

bab

ilit

y o

f R

emai

nin

g a

t H

om

e

Time (Weeks)

80 mg

>80 to 120 mg

>120 to 160 mg

11410085715742281200.4

0.6

0.8

1.0

Long-term Effects of Tacrine on Nursing Home Placement

Hill JW, Futterman R, Duttagupta S, et al. Neurology. 2002(Jan 8);58(1):62-70.

0 5 10 15 20 25

Renal Disease

Cerebrovascular Disease

Peripheral Vascular Disease

Chronic Pulmonary Disease

Diabetes

Diabetes withChronic Complications

Congestive Heart Failure

Annual Cost (Thousands)

Nondemented19,300 matched

ADRD 3,934

Dementia Increases the Costs of Caring for Common Comorbidities in Managed Medicare Settings

Haley WE, Levine EG, Brown SL, et al. Am J Geriatr Soc. 1987(May);35(5):405-411Shaw et al., J Psychosom Res 2003; 54:293-302vonKanel et al., Am J of Cardiol 2001(June);87:1405-1408Grant I, Psychosom Med 1999; 61:420-423

Caregiver Burden in AD

Compared with noncaregiver controls matched by age, gender, race and marital status, caregivers of persons with AD or related disorders require– 46% more physician visits

– 71% more prescribed medications

– Higher diastolic blood pressure

– Hypercoagulable state

– Higher plasma norepinephrine

5% 10% 65% 5% 7% 8%

Dementia with Lewy bodies Parkinson’s disease

Diffuse Lewy body disease Lewy body variant of AD

Vascular dementias and AD

Other dementias Frontal lobe dementia

Creutzfeldt-Jakob disease Corticobasal degeneration

Progressive supranuclear palsy Many others

AD and dementia with Lewy bodies

Vascular dementiasMulti-infarct dementiaBinswanger’s disease

AD

Small et al, 1997; APA, 1997; Morris, 1994.

Differential Diagnosis of Dementia

AP=amyloid plaques; NFT=neurofibrillary tanglesCourtesy of George Grossberg M.D.; St. Louis University.

Normal AD

AP NFT

Neuropathologic ChangesCharacteristic of AD

PET and Genetic Risk forAlzheimer’s Disease

Small GW, Ercoli LM, Silverman DH. Proc Natl Acad Sci. USA. 2000(May) 23);97(11):6037-6042 .

Normal MemoryNormal Memory

No APOE -4

PET PET ImagingImaging

Genetic Genetic Risk:Risk:

DementiaDementia

APOE -4

-28% -31%-14%-6%

Alzheimer’s Disease Normal ControlDecreasedtemporoparietal

Occipitallobe

Cerebellum 0.00 19.36

Frontallobe

mg/100 g/min

UCI Brain Imaging Center

Silverman DH, Small GW, Chang CY, et al. JAMA. 2001 Nov 7;286(17):2120-2127

PET in the Evaluation of Dementia

284 dementia patients(138 autopsy-confirmed diagnosis)

Sensitivity 93%; specificity 76% Negative PET scan indicated chance of

cognitive progression <20% over 3 years

Rogers and Friedhoff, 1998; *Stern et al, 1994.

–6

0

6

12

180 6 12 14 26 38 50 62 74 85 98

AD

AS

-Co

g S

sco

reM

ean

Ch

ang

e fr

om

Bas

elin

e

Cumulative Weeks from Baseline of the Double-blind Study

Decline in ADAS-Cog scorebased on the natural history ofuntreated patients with moderateAD*

Improvement

DeclineN=133

Model-based Analysis: ADAS-Cog Score Mean Change from Baseline

Flynn et al, 1995; Perry et al, 1978; Rodriguez-Puertas et al, 1997; Whitehouse et al, 1982.

Major Cholinergic Changes in AD

Depletion of acetylcholine (ACh): especially in moderate to severe disease stages

Decline in choline acetyltransferase (ChAT) activity

Loss of cholinergic neurons– Loss of muscarinic (M2) receptors

– Loss of nicotinic receptors (nAChR) AChE Butylcholinesterase (BuChE)

AChE

AcetylCoA

CholineACh

Presynaptic neuron

Synaptic cleft

Postsynapticneuron Acetate

CholineCholine+

+

Glial cell

ACh

AChE

BuChE

BuChE

ChAT

CoA=coenzyme A; MR=muscarinic receptor; NR=nicotinic receptorAdapted from Adem, 1992.

MR1

MR2 NR

MR1 MR2 NR

Normal Cholinergic Function

Cholinesterase Inhibitors

Physicians’ Desk Reference, 2003.

AChCH3

O

ON

H3C

CH3

H 3C

+

Rivastigminemechanism: AChE/BuChE-I

NH3C

CH3

CH3

O N CH3

CH3

O

Donepezilmechanism: AChE-I

H3CO

H3CO

O

CH2

N CH2

.

Galantaminemechanism: AChE-I

O

N

HOOCH3

H3C

NEW

ChE Inhibitors: Overview

Enz et al, 1992, 1993; Samochocki et al, 2000; Svensson and Nordberg, 1997; Yamanishi et al, 1990; Cutler and Sramek, 1998; Inglis, 2002.

AChE Inhibitors

Dual AChE/BuChE Inhibitor

Characteristic Donepezil Galantamine Rivastigmine

Doses per day 1 2 2

Maximum dose (mg/d) 10 24 12

Brain region selectivity No No Yes

Reversibility Reversible Reversible Psuedo-reversible

Nicotinic allosteric modulation No Yes No

Cytochrome P450 metabolism Yes Yes No

Allosteric Nicotinic Receptor Modulation

Samochocki M, Zerlin M, Jostock R, et al. Acta Neurol Scand Suppl. 2000;176:68-73

Response amplitudeto 100 µM ACh

AC

h-I

nd

uce

d C

urr

ent

(pA

)

Concentration (µM)

GalantamineRivastigmineMetrifonateTacrineDonepezil

0

200

400

600

800

1,000

0.001 0.010 0.100 1.000 10.000

NEW

*Darvesh S, Grantham DL, Hopkins DA. J Comp Neurol. 1998(April 13);393(3):374-390. †Mesulam, 2000.

BuChE neurons are less abundant than AChE neurons BuChE is very rich in cortical and limbic areas (amygdala and

hippocampus) BuChE accumulations in neuritic plaques

Amygdala

Figure 1* Figure 2†

AChEBuChE Hippocampus

Distribution of Cholinesterases in the Healthy Human Brain

Darvesh S, Hopkins DA. J Comp Neurol. 2003;463(1):25-43.

Distribution of Cholinesterases in the Healthy Human Thalamus

Rivastigmine Inhibition of CSF BuChE/AChE: Correlation with CNTB Scores

Cutler et al, 1998; Costa et al, 1999;Giacobini et al, 2002.

*P<.01; **P<.05CNTB=computerized neurophysiological test batteryCSF=cerebrospinal fluid

AUC

Cognitive Performance CNTB BuChE Activity AChE ActivityCNTB summary score -0.65* -0.56*Paired assoc. learning -0.53** -0.22Paired assoc. learning/delayed recall -0.69* -0.36Visual memory -0.52** -0.42

BuChE in CSF

0 2.5 5.0 7.5 10.0 12.5

150

100

50

0

Time (Hours)

Per

cen

tag

e o

f B

asel

ine

mea

n ±

SE

M

Rivastigmine 3 mg po

AChE in CSF

0 2.5 5.0 7.5 10.0 12.5

150

100

50

0

Time (Hours)

Per

cen

tag

e o

f B

asel

ine

mea

n ±

SE

M

Rivastigmine 3 mg po

Relation between Activity and Numbers of Senile Plaques in the Cerebral Cortex

Perry, 1978.

0

20

40

60

80

100

120

140

160

180

200

0 1-5 6-10 11-20 21-30 30-42

Mean Plaque Count

Per

cen

tag

e o

f ac

tivi

ty i

n

gro

up

wit

h n

o p

laq

ues

BuChE

AChE

ChAT

Guillozet et al, 1997.

Compact Plaque Formation

BuChE

Arendt et al, 1992.

0 50 100 150 200

1.50

1.25

1.00

0.75

0.50

Density of A Deposition

G1

nm

ol/

Min

. x

mg

Pro

tein

AChE

Activity of ChEs and -amyloid (A) Deposition in AD Cortex

Davidsson et al, 2001.

50

40

30

20

10

0 Baseline 12 months

AC

hE

Act

ivit

y m

mo

l/m

L/M

in.

P=.0013

800

700

600

500

400

300

200

100

0

10 mg 5 mg 32 mg 24 mg

CS

F A

Ch

E

Pro

tein

Donepezil Galantamine PlaceboTacrine (80–160 mg/day)

0 12 0 12 0 6 0 6 0 12 months

Nordberg et al, 1999.

Long-term CSF Inhibition: Upregulation of AChE by Tacrine, Donepezil, and Galantamine

High-dose rivastigmineLow-dose rivastigmine

Darreh-Shori et al, 2002.

Treatment Length (Months)

Inh

ibit

ion

of

CS

F A

Ch

E (

%)

60

50

40

30

20

10

0

-100 3 6 9 12 0 3 6 9 12

Inh

ibit

ion

of

CS

F B

uC

hE

(%

)

8070605040302010

0-10

Treatment Length (Months)

Long-term CSF Inhibition: Sustained Inhibition of AChE and BuChE by Rivastigmine

Rogers and Friedhoff, 1998; *Stern et al, 1994.

–6

0

6

12

180 6 12 14 26 38 50 62 74 85 98

AD

AS

-Co

g S

core

mea

n C

han

ge

fro

m B

asel

ine

Cumulative Weeks from Baseline of the Double-blind Study

Decline in ADAS-Cog scorebased on the natural history ofuntreated patients with moderateAD*

Improvement

Decline

Model-based Analysis: ADAS-Cog Score Mean Change from Baseline

Baseline 3 6 9 12 18 24 30 36

–6–4–2

02468

1012141618202224

AD

AS

-Co

g S

core

Mea

n C

han

ge

fro

m B

asel

ine

Time (Months)

Estimated decline: Stern equation12 months placeboGalantamine 24–32/24 mg/d

Truyen and Kershaw, 2002; Stern et al, 1994.

ADAS-Cog: Mean Change from Baseline during up to 36 Months’ Treatment with Galantamine

Time (Months)

Baseline 3 6 9 12 24 36

Number of Patients 165 165 165 165 160 124 81

Withdrawal Design Staggered-start Design

Time

Per

form

ance

Time

Per

form

ance

Randomizedphase

Randomizedphase

Placebophase

Placebophase

Placebo

Active

Placebo

Active

Symptomatic effect

Disease-modifyingeffect

Disease-modifyingeffect

Symptomatic effect

Leber, 1997.

Discrimination between Disease Modification and Symptomatic Benefit

*P<.0012; **P<.0007; ***P<.0001 vs placebo; mean MMSE score=19Rogers SL, Farlow MR, Doody RS, Mohs R, Friedhoff LT. Neurology. 1998(Jan);50(1):136-145

Baseline 6 12 18 Endpoint 30Decline

Improvement

Placebowashout

Weeks on Therapy

AD

AS

-Co

g M

ean

Ch

ang

e fr

om

B

asel

ine

-3

-2

-1

0

1

2

3

4

10 mg/day (n=157)5 mg/day (n=154)Placebo (n=162)

***

***

******

** *

Effects of Donepezil on Cognition

Galantamine 24 mg/ Galantamine 32 mg/ Placebo/Galantamine 24 mg (n=116) Galantamine 24 mg (n=102) Galantamine 24 mg (n=135)

OC analysis; *P=.03 vs placebo/galantamine 24 mgRaskind et al, 2000.

–4

–3

–2

–1

0

1

2

3

4 Baseline 13 26 39 52

AD

AS

-Co

g m

ean

(±

SE

M)

Ch

ang

e fr

om

Bas

elin

e

Double-blind Open-label

Time (Weeks)

*

Improvement

DeclineAll patients receive galantamine

Long-term Effects of Galantamine on Cognition: ADAS-Cog Change from Baseline

Rivastigmine 6–12 mg

Rivastigmine 1–4 mg

Placebo

Projected placebo

*P<.05 vs projected placeboFarlow et al, 2000.

0 12 18 26 38 44 52

Study Week

210

–1–2–3–4–5–6–7–8–9

AD

AS

-Co

g M

ean

Ch

ang

e (±

SE

M)

fro

m B

asel

ine

All patients taking rivastigmine

Long-term Effects of Rivastigmine on Cognition: ADAS-Cog

Doraiswamy et al, 2000.

All patients taking rivastigmine 2–12 mg/d

Study Week

0 26 38 44 52 78 104

–5

0

5

10

15

20

25

30

***

AD

AS

-Co

g M

ea

n C

ha

ng

efr

om

Ba

se

lin

e (

± S

EM

)

*P<.05; ***P<.001 vs projected placeboOC data set Baseline GDS 5

*

*** ***

***

*

*

******

*

Projected placebo

Rivastigmine 6–12 mg/d Placebo treatment up to 26 weeks

Rivastigmine 1–4 mg/d

****** ***

***

*

Effect of Long-term Rivastigmine Therapy on Cognition in Patients GDS ≥5

RDO Population

Mea

n C

han

ge

in A

DA

S-C

og

*

*P<.05

–2

–1

0

1

2

3

4

5

6

7

8

9

6–12 mg/day 1–4 mg/day Placebo

Farlow et al, 2003.

Rivastigmine Effect on Cognitive Function: Return Dropouts at Week 26

Potkin SG et al., Int J Neuropsychopharmacol. 2001;4(3):223-230

Increased frontal cortex

Increased hippocampus

Rivastigmine responders

minus baseline

Increase

Decrease

No change

Placebo

Natural Progression of AD over 6 Months vs the Effects of Rivastigmine

44

42

40

38

36

34

32

30

28

26

24

22

44

42

40

38

36

34

32

30

28

26

24

22

Glu

cose

met

abo

lism

R_FrM

gL_

FrM

gR_C

ingA

L_Cin

gAR_F

rSg

L_Fr

SgR_A

ngL_

Ang

R_Sup

r/Ang

L_Sup

r/Ang

R_Tem

p/M

g

R_Tem

p/M

g

R_FrM

gL_

FrM

gR_C

ingA

L_Cin

gAR_F

rSg

L_Fr

SgR_A

ngL_

Ang

R_Sup

r/Ang

L_Sup

r/Ang

R_Tem

p/M

gR_T

emp/

Mg

Untreated (n=12) Treated (n=11)

Baseline

Brain region Brain region

P<0.05all brain regions

12 months

Nordberg.

Glucose Metabolism in Cortical Association Areas for AD Patients with and without Rivastigmine Treatment

Cortex Hippocampus Cortex Hippocampus0

100

200

Ch

E A

ctiv

ity

% o

f R

esp

ecti

ve

Co

ntr

ol

Val

ues

±

SE

M

AD Brain Region

AChE BuChE

AChE and BuChE Activities in Human Postmortem AD Brain

Perry EK, et al. Neuropathol Appl Neurobiol. 1978;(4):273-277

BuChE staining in plaques, tangles, dystrophic neurites, and glia in AD

BuChE staining primarily glial in nondemented

Guillozet AL, Smiley JF, Mash DC, Mesulam MM. Ann Neurol. 1997(Dec);42(6):909-918

Selective Association of BuChE with Amyloid Plaques in Cortex AD

200

150

100

50

0Sec

rete

d

-AP

P L

evel

s in

R

at

CS

F (

Co

ntr

ol

± S

EM

%)

Nonlesion Nucleus basalis lesion

Control Phenserine CymserineBuChEIAChEI

Haroutunian V, et al. Brain Res Mol Brain Res. 1997;46(1-2):161-168

AChE and BuChE Inhibitors Decrease Endogenous -APP Levels in Rats

12

10

8

6

4

2

0

–20 0.7 0.8 0.9 1.0

MM

SE

Dec

lin

e/Y

ear

BuChE Level in Medial Temporal Cortex

R=0.88 P<.002

N=9Perry et al, in press.

Disease Progression: Rate of Cognitive Decline in DLB Correlated with BuChE Levels at Autopsy

Buerger et al, 2002.

10

0

–10

–20

An

nu

al

MM

SE

Dec

reas

e

CSF p-tau231 (pg/mL)

0 300 600 900 1,200 1,500 1,800 2,100RHO=-.30P<.01

Correlation between CSF [Phospho-tau] and MMSE Decrease in MCI

1,300

1,100

900

700

500

300

100

CS

F t

au L

evel

(pg

/mL

)

Control Tacrine Rivastigmine

Stefanova et al, 2003.

P=.005* P=.16

P=.04*

Baseline

Followup (12 months)

CSF Tau Levels in Treated and Untreated AD Patients

50% cases of moderate AD remain undiagnosed 70% cases of mild AD remain undiagnosed

Physician would have been consulted sooner if caregiver or others had known aboutprescription medication

Physician would have been consulted sooner if caregiver or others had known about early signs

Harris Interactive Inc., 2001.

Greater Awareness May Lead to Earlier Diagnosis and Treatment

Summary

Both AChE and BuChE can contribute to the loss of ACh, which underlies many of the symptoms in AD

Inhibition of CSF AChE and BuChE with rivastigmine correlates with clinical benefits

BuChE increases with severity of AD BuChE may play a role in plaque maturation and APP

processing Both AChE and BuChE are pharmacological targets Lack of upregulation with rivastigmine implies that cognitive

benefits are sustained during long-term treatment Increased AChE protein following galantamine and

donepezil is of uncertain clinical importance

Summary (cont’d)

AD is an expensive illness in human and economic terms for patient and care givers

Diagnosis is often not made, especially in early and mild AD Frequently treatment is not initiated or sustained Early treatment pays off; delaying treatment has long-term

consequences Functional imaging can aid in early diagnosis of dementia Moderately ill patients can robustly respond to tx Cholinesterase inhibitors attenuate symptomatic decline

and may modify disease progression