Alzheimer’s Disease:Advances and Hope

Trey Sunderland, M.D. Chief, Geriatric Psychiatry BranchNational Institute of Mental Health

Bethesda, Maryland

Diagnosis and Treatment of

Alzheimer’s Disease:Today and Tomorrow

What is the course of Alzheimer’s

Disease?

When does AD

really start?

What is the cause of AD?

FrontalCortex

HippocampusBasal

NucleusNucleus ofDiagonal Band

MedialSeptal Nucleus

OccipitalCortex

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

Neurofibrillary Tangles in AD

FDA Approved Therapy:

Acetylcholinesterase Inhibitors (AChEI)

Rivastigmine in Mild to Moderate Alzheimer’s Disease

(Messina J et al. Poster presented at: 3rd International Meeting of College of Psychiatric and Neurologic Pharmacists; April 6-9, 2000; Washington, DC.)

-2

0

2

4

6

80 12 26 38 44 52

Weeks of Treatment

Mean

Ch

an

ge

from

Base

lin

e i

n A

DA

S-C

og

Sco

re

ClinicalImprovement

ClinicalDecline

6-12 mg/d1-4 mg/dPlacebo/RivastigmineProjected Placebo

All patients taking 2-12 mg/d

Metrifonate Effects on NPI

(Cummings et al. AAN Abstract, 1998)

4

NP

I C

han

ge f

rom

BL

3

2

1

0

-1

Total Hal Depr Apathy Abe

0.8

0.6

0.4

0.2

0

-0.2

PlaceboMetrifonate

Therapeutic Conundrums: Questions

How long to treat? Do they slow progression?

Are they effective in all stages of AD?

Are they effective only in Alzheimer’s disease?

Cholinesterase inhibitors

Current &

Potential AD

Therapies:

Memantine in Moderate-to-Severe Alzheimer’s Disease

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

Memantine Placebo

NCompletersAge (Yrs)Educ (Yrs)MMSEGDS Stage: 5 6

126 (35M/91F)97 (77%)

75.5 ± 8.212.3 ± 3.17.8 ± 3.8

47% 53%

126 (47M/79F)84 (67%)

75.8 ± 7.312.9 ± 3.18.1 ± 3.6

49% 51%

Effect of Lovastatin on Serum A

* P = 0.02 ** P = 0.03

-75

Controlled-Release Lovastatin

-50

-25

25

50

75

% C

han

ge i

n S

eru

m A

0

Placebon = 15

10 mgn = 20

20 mgn = 19

40 mgn = 20

60 mgn = 20

***

Proportion Remaining Unaffected According to Duration of Estrogen

Use

(Tang MX et al. Lancet, 1996;348:429-432)

0.065 70 75 90

Age of Onset (Years)

0.2

0.4

0.6

0.8

1.0

Pro

port

ion

Fre

e o

f A

D

Survival Analysis Plot of Distribution by Age

80 85 95

>1 Year (mean 13.6 years)<1 Year (mean 4 months)Never

Duration of estrogen

Anti-inflammatory

Approaches

Alzheimer’s DiseaseInflammatory Mechanisms

APP

Non-Fibrillar -A4

-A4 Deposits

IL-1, IL-6

Activated Microglia

NeuronalDegeneration

NIMH Study(Protocol 01-M-0128)

Vaccine Therapy?

Anti-Amyloid Therapy?

Gamma secretase inhibitors

Beta secretase inhibitors- Drug(s) that blocks enzyme that triggers plaque

Future Therapies:

?Multidrug Approaches?

Would YOU want

Preventative Therapy?

RISK vs. BENEFIT

Analysis Needed

(Protocol 95-M-96)

Family “AT RISK” Study:Biological Measures

APO E Genotyping (Baseline)

Structural MRI (1.5 Tesla Machine)

CSF Tap (i.e., -amyloid, Tau, etc.)

What is this object?

Family “AT RISK” Study:Biological Measures

APO E Genotyping (Baseline)

Structural MRI (1.5 Tesla Machine)

CSF Tap (i.e., -amyloid, Tau, etc.)

Family “AT RISK” Study:Biological Measures

APO E Genotyping (Baseline)

PET Scans

CSF Tap (i.e., -amyloid, Tau, etc.)

Family “AT RISK” Study:Biological Measures

APO E Genotyping (Baseline)

Structural MRI (1.5 Tesla Machine)

CSF Tap (i.e., -amyloid, Tau, etc.)

CSF -amyloid1-42 in AD

Good Consistency

Across 18 Studies

Family “AT RISK” Study:Biological Measures

APO E Genotyping (Baseline)

Structural MRI (1.5 Tesla Machine)

CSF Tap (i.e., -amyloid, Tau, etc.)

CSF Tau in AD

Excellent Consistency

Across 35 Studies!

-amyloid1-42 + Tau

92% Specificity

89% Sensitivity

What about Normal

People “At Risk”?

Will the therapies be

available soon enough?

Future Therapies:

Multidrug Approaches

Alzheimer’s Disease Predictions

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