Targets for the Treatment of Alzheimer's Disease

Targets for the Treatment of Alzheimer's Disease

June 1, 2012

Brian S. Appleby, M.D.Cleveland Clinic Lou Ruvo Center for Brain Health

ObjectivesObjectives

1.Describe the pathophysiology underlying Alzheimer's disease (AD)

2.Summarize currently available AD treatments

3.Describe investigational treatments and potential treatment targets

Alzheimer's DiseaseAlzheimer's Disease

Pre-Symptomatic Disease

Mild Cognitive

Impairment(MCI)

Dementia

Amnesia

Aphasia

Apraxia

Agnosia

NeuropathologyNeuropathology

Amyloid plaquesA-beta oligomers

Neurofibrillary tanglesPhosphorylated tau

NeurotoxicityNeurotoxicity

Amyloid precursor protein (APP)

α,β,γ-secretases

a-beta1-40

a-beta1-42

Mesiotemporal Atrophy Mesiotemporal Atrophy

Nucleus Basalis of MeynertNucleus Basalis of Meynert

Ach

Ach

ADAnticholinergicScopolamine

Cholinesterase InhibitionCholinesterase Inhibition

Ach

Ach Ach

Ach

Ach

Ach

Ach

Ach

Ach

AchAch

AchE

Cholinesterase InhibitorsCholinesterase Inhibitors

Medication Mechanism of Action

Donepezil AChE-Inh

Galantamine AChE-Inh

Tacrine AChE-Inh

Rivastigmine

AChE-Inh + Butyl-ChE-Inh

Adverse effects=GI upset & bradycardia

BenefitsBenefits

• Possibly decrease neuropsychiatric symptoms

• Helps maintenance of daily functional ability

• Treatment effect of about 3 years• Approved for use in mild-moderate AD

NO Effect on Survival TimeNO Effect on Survival Time

Suh G, Am J Geri Psych 2011

Switching ChE-Inh?Switching ChE-Inh?

• Tolerability-switch after previous ChE-Inh’s adverse effects have abated

• Lack of clinical efficacy (>2 point decrease of MMSE in first year)

• Not recommended for loss of efficacy past one year of treatment

Massoud F, Int Psychogeriatrics 2011

Farlow MR, Clinical Therapeutics 2010

Farlow MR, Clinical Therapeutics 2010

Donepezil 23mg vs 10mgDonepezil 23mg vs 10mg

• Greater benefits in cognition in moderate to severe AD

• No benefit in functional status• Tolerability issues, 10mg->15mg->23mg

MemantineMemantine

• NMDA antagonist• Approved for use of moderate-severe AD• Mild benefits in cognition and clinician’s

global assessment of change• Not efficacious in mild AD

Treatment TargetsTreatment Targets

Disease Modifying vs. Symptomatic Treatments

Intervention Stage IIntervention Stage I

APPSecretase

ActivityAβ oligomer

species

Variety of small molecule compounds

Intervention Stage 2Intervention Stage 2

Fibrillization Plaque Deposition Neurotoxicity

Anti-propagation strategies

Increase innate clearance mechanisms

Antibody mediatedAnti-inflammatory

mechanisms

Anti-oxidant mechanisms

Targeting tauTargeting tau

• Accompanying and earlier piece to AD• Target hyper-phosphorylation

pathophysiology (formation of p-tau)• Many known ways to inhibit GSK-3β

(a.k.a. lithium, methylene blue)• Applicable to other tauopathies (i.e.

frontotemporal lobar degeneration)

Immunization StrategyImmunization Strategy

Holmes C, Lancet 2008

No Clinicopathologic Correlation

No Clinicopathologic Correlation

No Change in Survival TimeNo Change in Survival Time

Immunotherapy SummaryImmunotherapy Summary

• Early serious adverse effects of cerebral edema

• Works from a pathophysiological perspective

• No effect clinically• ? Need to treat earlier? • ? Are plaques protective “sinks”

Bexarotine (Tg mice)Bexarotine (Tg mice)

*Corresponding clinical improvement

Cramer P, Science 2012

Proteinopathies are “prionoid”Proteinopathies are “prionoid”

Morales R, CNSND-DT 2009

Stop Aggregation/Stop PropagationStop Aggregation/Stop Propagation

Forlorni G, FEBS Letters 2001

One More Challenge…One More Challenge…

2011 Alzheimer’s Disease Facts and Figures

Rank Cause of death 2010 Age-adjusted death rate

% change from 2009

1 Heart disease 178.5 -2.4

2 Cancer 172.5 -0.6

3 Chronic lung disease 42.1 -1.4

4 Cerebrovascular disease 39 -1.5

5 Accidents 37.1 -1.1

6 Alzheimer’s disease 25 +3.3

7 Diabetes 20.8 -1

Adapted from: NVSR, 60(4)

Ashburn TT, Nat Rev Drug Discov 2004

The Power or RepositioningThe Power or Repositioning

Ashburn TT, Nat Rev Drug Discov 2004

SummarySummary

• Pathophysiologic associations are well known; direct neurotoxic mechanisms are becoming better understood

• Only symptomatic treatments currently• Many different targets for future

treatments and many compounds already studied in AD models