The document outlines the complexities of Alzheimer's disease (AD), including its pathology, clinical presentation, and the current lack of effective disease-modifying therapies. It emphasizes the importance of identifying therapeutic targets and the necessity for biomarkers to improve trial outcomes. Key treatment approaches discussed include symptomatic therapies and cognitive enhancement, while also highlighting the challenges faced in clinical trials and the evaluation of treatment efficacy.

1. FOCUSED. TRUSTED. GLOBAL.
EXPERTS
Drug Development in Alzheimer’s Disease
Challenges and Opportunities
Samer E. Kaba, M.D.
Medical Director – Neuroscience
Clinical Assistant Professor of Neurology
Emory University

2. FOCUSED. TRUSTED. GLOBAL.
Pathology
o AD is a degenerative disease characterized by:
 Loss of neurons
 Intracellular accumulation of neurofibrillary tangles
 Accumulation of amyloid plaques
 Brain and hippocampal atrophy
o Genetic factors have a definitive role
 Multiple genes identified
o The pathological changes are similar to normal
aging qualitatively, but different quantitatively

3. FOCUSED. TRUSTED. GLOBAL.
Microscopic Changes in AD

4. FOCUSED. TRUSTED. GLOBAL.
Macroscopic Changes in AD

5. FOCUSED. TRUSTED. GLOBAL.
Pathophysiology
o Protein Abnormalities in Alzheimer's Disease
 β-Amyloid
 Tau
o Synapse Related Abnormalities
 Synaptic Failure
 Depletion of Neurotrophin and Neurotransmitters
o Mitochondrial Dysfunction
 Oxidative Stress
 Insulin-Signaling Pathway
 Vascular Effects
 Inflammation

6. FOCUSED. TRUSTED. GLOBAL.
Clinical Presentation
o Cognitive decline
 Short- term memory impairment
 Confusion
 Decreased visuo-spacial orientation
 Reduced comprehension and other verbal skills
o Behavioral changes
 Personality and mood changes
 Sleep disturbance
 Agitation
 Paranoia and hallucinations
 Loco-motor slowing

7. FOCUSED. TRUSTED. GLOBAL.
Therapeutic Targets
o Symptomatic treatments
 Mostly neurotransmitters based
 Existing therapies are all symptomatic
 Can work in different stages of the disease
o Disease modifying therapies
 None is available to date, the race is on…!
 To target the changes leading to progressive tissue
damage and clinical manifestations
 Early treatment is crucial

8. FOCUSED. TRUSTED. GLOBAL.
Symptomatic Therapies
o Cognitive enhancement
 Cholinesterase inhibitors:
• Cognex®
• Aricept®, Excelon®, Razadyne® (formerly Reminyl®)
 NMDA Agonists
• Namenda®
o Behavioral modification
 Antipsychotic drugs
 Antidepressant
 Hypnotics

9. FOCUSED. TRUSTED. GLOBAL.
Current Outcome Measures
in AD Trials:
o Primary outcomes
 Cognition -ADAS-cog
 Global - CIBIC+
o Secondary Outcomes
 Behavioral – NPI or BEHAVE-AD
 ADL – DAD or ADCS-ADL
o Caregiver burden
 Direct relationship to institutionalization of patient
o Pharmaco-economics
 Complex but of increasing interest to governments and
third party payers

10. FOCUSED. TRUSTED. GLOBAL.
Challenges in DM therapies

11. FOCUSED. TRUSTED. GLOBAL.
Disease Modifying Therapy
o No disease modifying therapy for AD is
available yet
o Slow progress because:
 Difficulty in identifying therapeutic targets
 Sub-optimal collaboration with academia
 The lack of adequate animal models of AD
 The limitations of standard clinical endpoints (ADAS-
Cog, MMSI, etc.)
 The need for biomarkers of disease activity and tissue
injury
 Tactical challenges to AD trials

12. FOCUSED. TRUSTED. GLOBAL.
Biomarkers of AD –
A Critical Need
o Providing surrogate measures for evaluating
compounds in early development (go-no-go
decisions)
o Confirming the eligibility of patients for trials
o Selecting homogeneous groups of patients
o Providing more objective endpoints for
confirmatory trials
o Confirming the clinical findings of confirmatory
controlled trials
o Illustrating a positive effect on tissue injury and
disease progression

13. FOCUSED. TRUSTED. GLOBAL.
Biomarkers of AD –Modalities
o Brain imaging
 MRI:
• Volumetric MRI
• Functional MRI,
 Nuclear:
• FDG-PET
• Amyloid imaging (PiB)
o Biological testing
 Tau and P-tau protein in CSF
 Amyloid βA4 in CSF
o Electrophysiology
 Quantitative EEG (Brain Mapping)
 Long latency evoked potentials

14. FOCUSED. TRUSTED. GLOBAL.
Brain Mapping

15. FOCUSED. TRUSTED. GLOBAL.
Volumetric Measurement of Hippocampal
Atrophy

16. FOCUSED. TRUSTED. GLOBAL.
Functional MRI

17. FOCUSED. TRUSTED. GLOBAL.
PET Scan in AD

18. FOCUSED. TRUSTED. GLOBAL.
Outcome Measures
o Cognitive Measures
 ADAS-Cog (Alzheimer Disease Assessment Scale –Cognitive
subscale)
 MMSE (Mini Mental State Examination)
o Functional Rating Scales
 ADCS-ADL (Alzheimer Disease Cooperative Study – Activities of
Daily Living)
o Global ratings of severity and change
 CIBIC/CIBIS (Clinician Interview-based Impression of Change)
 CDR (Clinical Dementia Rating)

19. FOCUSED. TRUSTED. GLOBAL.
ADAS-Cog Limitations
o Ceiling and floor effects
o Non-linear sensitivity
 More sensitive in moderate disease
o Inter-rater and intra-rater variability
 Rater training and drift should be considered in trials
o Change in scores do not always translate into
clinical benefit
o Prone to practice effect
 Should not be administered frequently

20. FOCUSED. TRUSTED. GLOBAL.
Tactical Challenges in AD Trials
o Early disease:
 Patients acceptance / motivation
 The need for long-term follow up
 Competing trials
o Moderate disease
 Finding treatment naïve patients
 Need for reliable caregiver
 Co-morbidities
o Advanced Disease
 Behavioral problems more pronounced
 Institutionalized patients
 Co-morbidities
 Consent issues