2-4 Million

16 Million

Years0

Clinical Diagnosis

20 40 60 80 100

Symptomatic Drugs Only

2000

Years0

Clinical Diagnosis

20 40 60 80 100

2030

Alzheimer’s Disease Predictions

Alzheimer’s Disease Symptomatic Time Course

Autopsy

MCI(12-15%/yr)

MildModerate

Severe

Nursing Home

Diagnosis of AD

3-4 years/stage

Test Result

s

Diagnosis

Alzheimer’s Disease Rx Speculative Timeline

Years0

Gene?Amyloid

depositionCell

damage Autopsy

Clinical diagnosis

LOD?

20 40 60 80 100

Test Result

s

Inflammatoryresponse

Major Theories in AD Causation:

Cholinergic Damage

b-Amyloid Toxicity

Tau Pathology

Genetic Risk

Cholinergic Neuron in Aging

CAT

AChE

Cholineuptake

Solublepeptides

Insolublepeptides

Reactivepeptides

Plaque Theory of Damage in AD

From Outside the Cell

Chaperoneproteins

Sources: Dr. John Trojanowski and Dr. Virginia M.Y. Lee/University of Pennsylvania Medical Center

Beta amyloid peptides,secreted by brain cells, arenormally soluble, and anyexcess is cleared away ...

… but when they become insoluble,they collect in the space between cells, the fibrils herded together bychaperone proteins

The large plaques that form damage brain cells andattract reactive cells, whichcause further damage

Plaque

Neuralcell

Nucleus

Axon

Tangle

Paired helicalfilament

Neuron

Microtubules

Tauproteins

Sources: Dr. John Trojanowski and Dr. Virginia M.Y. Lee/University of Pennsylvania Medical Center

Tau proteins, whichnormally stabilizemicrotubules in brain cells ...

… undergo abnormal chemicalchanges and assemble into spiralscalled paired helical filaments ...

Dendrites

… thus creating tanglesthat disrupt cell functionsand lead to cell death

Tangle Theory of Damage in AD

From Outside the Cell

Donepezil in Mild to Moderate Alzheimer’s Disease

(Winblad B et al. Poster presented at: Therapeutics of Alzheimer’s Disease Conference; 2000; Stockholm)

2

1

0

-1

-2

-30 12 24 36 48 Endpoint

Study Week

MM

SE

, L

east

Sq

uare

s M

ean

Ch

an

ge

from

Base

lin

e S

core

ClinicalImprovement

ClinicalDecline

n = 135n = 137

DonepezilPlacebo

127128

121120

104105

9198

(135)(137)

DonepezilPlacebo

P = 0.053P < 0.001

P = 0.019

P = 0.001 P < 0.001

Galantamine: Mean Change from Baseline in ADAS-Cog Scores

(Raskind MA et al. Neurology, 2000;54:2261-2268.)

40 3 6 9 12

Months of Treatment

Mean

(±

SE

M)

Ch

an

ge f

rom

Base

lin

ein

AD

AS

-Cog

/11

Sco

re

ClinicalImprovement

ClinicalDecline

Placebo/galantamine 24 mgGalantamine 24 mg/galantamine 24 mg

Open-Label Extension

3

2

1

0

-1

-2

-3

-4

-5Double Blind

P < 0.001

P < 0.001

Current View of Cholinergic Therapy

(Tariot PN et al. Neurology. 2000;54:2269-2276; Raskind MA et al. Neurology. 2000;54:2261-2268; Knopman D et al. Neurology. 1996:47:168-117; McLendon BM et al. J Geriatr Psychiatry Neurol.

1999;12:39-48.)

Proven benefits: – Effective in 6-month trials

Emerging benefits: – Effective for at least 12 months – Slow loss of function – Improve or delay troublesome behaviors – Delay placement in long-term care facility

Alzheimer’s Disease Symptomatic Time Course

Autopsy

MCI(12-15%/yr)

MildModerate

Severe

Nursing Home

Diagnosis of AD

3-4 years/stage

Test Result

s

Diagnosis

Expanding Uses of AChEI’s

Placebo-controlled

Vascular dementia

Lewy body dementia

Adult attention deficit hyperactivity disorder

Supranuclear palsy

Down’s syndrome

Mild cognitive impairment

Multiple sclerosis

Brain injury

Brain tumors

Post–CABG memory loss

Schizophrenia, mania

REM sleep disorder

Parkinson’s Dementia

Autism

Post-ECT confusion

Pre-Surgical Prophylaxis

Open Studies

Therapeutic Targets and Strategies Under Study

, -Secretase inhibitors

Vaccine

Anti-inflammatories

Estrogen preparations

Antioxidants

Statins

NMDA antagonists

Cholinomimetics

Memantine in Mod-Severe AD

0.80 4 12 28

Weeks in Trial

FA

ST

Sco

re

ClinicalImprovement

ClinicalDecline

MemantinePlacebo

0.6

0.4

0.2

0

-0.2

Ch

an

ge

Sco

re

**p = 0.007

Reisberg et al., NEJM 384: 1333-41, 2003

Vitamin E TreatmentPercent Remaining Outside an

Institution

(Sano et al. NEJM 336:1216-1222, 1997)

75

70

65

60

55Placebo Selegeline Vit E Combo

Non

-NH

(%

)

**

ADAS-Cog on GINKGO

(Le Bars et al. JAMA 278 (16): 1327-1332, 1997)

Weeks in Trial

-100 26 52

ClinicalImprovement

ClinicalDecline

GinkgoPlacebo

-8

-6

-4

-2

0

2.0

AD

AS

-Cog

Ch

an

ge S

core

Only 1.4 Point Change!

Indomethacin Trial in AD

(Rogers et al. Neurology 43:1609-1611, 1993)

10

5

0

-5

-10

-15

% C

han

ge f

rom

BL

ADAS MMSE BOSTON TOKEN

NSAID (n = 14, mean = +1.3%) **Placebo (n = 14, mean = -8.4%)

Putative Inflammatory Agents in AD

Interleukin-1 (IL-1)

Interleukin-6 (IL-6)

Senile plaques (SPs)

Neurofibrillary tangles

Tumor necrosis factor (TNF )

NF-B

Microglia

Amyloid

COX-2

Cyclophosphamide Rx in AD:A Pilot Study

Larry Bauer, Coordinator 301-496-3253

Mild-to-Moderate subjects with AD

Ability to give Informed Consent themselves

Willing to undergo 6 monthly infusions

Placebo controlled vs. 2 doses of CYCLO

15 subjects in study to this point

Vaccine Therapy for AD“History & Recent Developments”

AN 1792 (Elan Pharmaceuticals)

- Vaccine that prevents plaque buildup in mice

AN 1792 vaccine administered to

humans causing meningitis-like

reaction (2002)

Alternative vaccine approaches possible

Structure ofPrecursor Molecule

Normal Enzymatic Processing

Alternative Enzymatic Processing

Protease-RegulatingRegion

AmyloidBeta-Region Amino Terminal

MembraneTerminal

Carboxyl

Beta-regionis cut

IntactBeta-fragmentIs released

Amyloid Processing

Alzheimer’s Disease Diagnosis and Treatment: Speculative Timeline

Preventative

Modifying

Symptomatic

Years0

Gene?Amyloid

depositionCell

damage Autopsy

Clinical diagnosis

LOD?

20 40 60 80 100

Test Result

s

Inflammatoryresponse

Family “AT RISK” Study:Entry Criteria (Protocol 95-M-96)

Judy Bergeson, Coordinator 301-435-6058

First Degree Relative(s) with AD & Controls

Over 50 Years of Age on Admission

Cognitively Normal at Entry Baseline

APO E Allele, Imaging & CSF Measures

Interested in 8-year Follow-up Commitment

AD Survival Curves for ApoE Genotypes

(Roses Ann. Rev. Med. 47:387-400, 1996)

1.0

0.5

0.0

Pro

port

ion

Un

aff

ect

ed

20 30 40 50 60 70 80 90 100 110Age (years)

S182Mutation

APPMutation

APOE4-4 3-4

3-43-3

2-3

Family “At Risk” StudyPercentage of APO E4+ Subjects

20

% A

PO

E+

40

60

80

Controls At Risk Alzheimer

8%

45%

64%

Amygdala

Temporal Lobe

Hippocampus

FOLLOW-UPsMRI IMAGES IN “AT RISK”

STUDY

Sagital Orientation

sMRI Hippocampal VolumesSpeculative Changes Over Time

Observed

(Adapted from Cohen et al. Neurology 57 (12):2223-2228, 2001)

1.9

1.45

Volu

me

1. 5

1.55

1.6

1.65

1.7

1.75

1.8

1.85

AD Cutoff

Baseline Year1

DiagnosisYear3

APO E4(–)APO E4(+)

Positron Emission Tomography in AD

CONTROL AD PATIENT

Plaque of b-Amyloid Protein in the Brain of an AD Patient

CSF -amyloid1-42 in Older Controls and AD Subjects

(Sunderland et al. JAMA 289: 2094-2103, 2003)

1.200

0

200

400

600

800

1,000

ControlsN=72

ADN=131

Results from Meta-Analysis of CSF-amyloid1-42 Studies: EFFECT SIZE

0.0–1.0 1.0 2.0 3.0 4.0(Sunderland et al. JAMA 289: 2094-2103, 2003)

Neurofibrillary Tangles in AD

CSF tau Levels in Older Controls and AD Subjects

1,600

1,400

1,200

1,000

800

600

400

200

0Controls

N=72AD

N=131

pg

/ml

(Sunderland et al. JAMA 289: 2094-2103, 2003)

Effective Sizes of Results from Meta-analysis of CSF Tau Studies in the World Literature

0.0–1.0 1.0 2.0 3.0 4.0 5.0(Sunderland et al. JAMA 289: 2094-2103, 2003)

Scattergraph of CSF TAU and-amyloid1-42 in AD and Controls

1,600

1,400

1,200

1,000

800

600

400

200

0

CS

F T

AU

0 200 400 600 800 1,000 1,200

CSF -amyloid 1-42

(Sunderland et al. JAMA 289: 2094-2103, 2003)

Alzheimer’s Disease Symptomatic Time Course

Autopsy

MCI(12-15%/yr)

Mild

Moderate

Severe

Nursing Home

Diagnosis of AD

3-4 years/stage

Test Result

s

?

Diagnosis

Alzheimer’s Disease Predictions

2-4 Million

16 Million

Years0

Clinical Diagnosis

20 40 60 80 100

2000

Years0

Clinical Diagnosis

20 40 60 80 100

2030

Symptomatic Drugs Only

Alzheimer’s Disease Diagnosis and Treatment: Speculative Timeline

Preventative

Modifying

Symptomatic

Years0

Gene?Amyloid

depositionCell

damage Autopsy

Clinical diagnosis

LOD?

20 40 60 80 100

Test Results

Inflammatoryresponse

Alzheimer’s Disease Future Goals

2-4 Million

2-3 Million

Years0

Clinical Diagnosis

20 40 60 80 100

SymptomaticAChEIs Drugs

2000

Years0

Clinical Diagnosis

20 40 60 80 100

2030

?GeneTherapy

Secretase Inhib?Statins

NSAIDs, HRT?& ? Vaccine?+ + +

Research to find ways to treat the symptoms of Alzheimer's disease

Research to find ways to predict and prevent Alzheimer's disease

Patient

Early Diagnosis & Treatment: The Race is on!

EarlyDiagnosis

EffectiveTreatment