1. Alzheimer’s Disease Landscape
James R. Burke, MD, PhD
Professor of Medicine (Neurology)
Duke University Medical Center
9th June 2012

2. Alzheimer’s Disease Most common cause of dementia Clinical Pathology
Insidious onset of cognitive decline- prominent memory problems.
Pathology
Brain atrophy
Amyloid plaques
Neurofibrillary tangles

3. Etiology
Age
Genetics
Autosomal Dominant - rare, early-onset forms- All are related to mutations in amyloid pathway.
Late-onset AD- Apolipoprotein E- susceptibility gene. Individuals who inherit APOE 4 form are at increased risk of AD
Kawas C et al. Neurology 2000;54:
AD Roses Sci Am Sci Med 1995, 2:16-25

4. Epidemiology Risk Factors for AD Age Genetics Education Head trauma
Medical conditions:
Hypertension, Diabetes mellitus, Hypercholesterolemia, Obesity, Smoking
1950
1980
2000
2020
>65 yrs
<65 years
Source: U.S. Census Bureau

5. World-wide incidence of AD Ziegler Graham et al
World-wide incidence of AD Ziegler Graham et al., 2008 Alz & Dementia
AD incidence higher in US, Canada, and Europe
What accounts for differences in disease rates?
Obesity, diabetes, smoking,
hypertension?
Lifestyle?
Genetics?   
 CCMS
Systematic review ( ) AD incidence studies (n=27)

6. Pathology/Pathophysiology: Biomarkers and pathology precede symptoms
12. Clinical presentation of ulcerative colitis
Bloody diarrhoea is the classical presenting symptom of ulcerative colitis, although a small number of patients have constipation. Other less frequent symptoms include fever, cramping abdominal pain, weight loss and general malaise. Where inflammation affects mainly the rectum and sigmoid colon, patients may complain of frequency, urgency, tenesmus, and pain, which is relieved by defecation.
Braak and Braak 6

7. Diagnosis History of insidious onset memory problems
Impairments on cognitive testing- especially delayed memory
No focal deficits on neurologic examination
Neuroimaging- atrophy and absence of significant cerebrovascular disease

8. Clinical features of AD
MCI due to AD- Forgetful, repetitive questions. No impairment in ADLs (2-5 years)
Mild AD- Disoriented for date/time, word-finding difficulty, trouble organizing tasks at home and work. May be lost away from home. Depression common (2-4 years)
Moderate AD- Decline in personal hygiene and dress, unable to perform routine tasks around the house. May wander from home. Agitation and sleep problems common. Cannot be left alone (2-10 years)
Severe AD- Requires assistance in all ADL (bathing, dressing, feeding and toileting) Falls, infection, malnutrition common. Total care (1-3 years)

9. Biomarkers in AD

10. Cost Dementia vs National Economies
Disease burden
AD is the 6th cause of death in the US.
Average survival after diagnosis is 4 to 8 years
Impact on family and caregivers
Alzheimer’s Association
World Alzheimer’s Report 2010
Cost Dementia vs National Economies
$ Billions

11. Treatment options No Disease Modifying Therapies
Cholinesterase inhibitors
Donepezil
Galantamine
Rivastigmine
Tacrine
NMDA receptor antagonist
Memantine
Caprylidene

12. Disease modification
Figure quoted from: Hampel H et al. (2010)

13. Perspectives: Drugs in Development
Amyloid
Neurofibrillary tangles (NFTs)
Inflammation
Energy
Folding and removal
Roberson and Mucke Science 314: 781 (2006)

14. Competitive landscape
Name
Indication
MoA
Phase
Estimated launch
Bapineuzumab*
Mild to moderate AD
Humanised monoclonal antibody to beta-amyloid
Phase III
Q in US
Q in Japan
Q in 5EU
Gammagard*
Passive immunisation against beta-amyloid
2015
LY (solanezumab)*
Passive immunisation against soluble beta-amyloid
Q in US and 5EU
ELND005 (scyllo-inositol)
Beta-amyloid aggregation inhibitor
Phase II
Q3 2014
Methylthioniniu m
Chloride
Tau aggregation inhibitor
Q in US and Europe
Davunetide
AD, mild cognitive impairment, frontotemporal dementia and cognitive impairment in schizophrenia
Tau hyperphosphorylation
inhibitor
Not known
Tideglusib AD
GSK-3 beta inhibitor
Phase II
Not known SB
Mild to moderate AD
5-HT6 receptor antagonist
Q (US, 5EU)

15. Unmet medical needs Disease modifying therapies
Prevention of symptom development
Therapies for behavioral problems
Effective management of sleep
Read slide
Plassman et al. Ann Int Med, :427-34 15

16. Conclusions
Alzheimer’s disease is the most common cause of dementia with major costs for individuals, families and society.
No current therapies prevent development of symptoms or modify disease progression.
The aging of the population will lead to a dramatic increase in the number of individuals with Alzheimer’s disease.