1. Alzheimer's Disease – Current Status; Future Perspectives
Nicola Oliver
AMUS Meeting, 6th March 2013

2. How does Life Guide approach this problem?
Overview
Dementia – what is it?
Alzheimer’s Disease
Current Status
History
Neuropathology
Risk factors
Life expectancy
Current treatments
Prevention
Future Perspectives
Aging society
Future prevalence
Advances in diagnostics
Pharma developments
Challenges
How does Life Guide approach this problem?

3. Dementia Not a single disease
Affects memory, attention, language, and problem solving
Alzheimer's disease, vascular dementia, fronto- temporal dementia, semantic dementia and dementia with Lewy bodies
reduces the ability to learn, reason, retain or recall past experience
also loss of patterns of thoughts, feelings and activities
symptoms must be present for at least six months to support a diagnosis
Test
Sensitivity
Specificity
MMSE
71%-92%
56%-96%
3MS
83%-93.5%
85%-90%
AMTS
73%-100%
71%-100%
Non-specific syndrome

4. Auguste Deter – Alois Alzheimer's patient in
History
First officially identified in 1901 by German psychiatrist Dr Alois Alzheimer
It is an incurable, degenerative and terminal disease
Characterised by protein tangles in the brain which lead to cell degeneration and death
Age is the greatest risk factor with incident risk doubling every 5 years after the age of 65
In general, a diagnosis of Alzheimer’s disease halves life-expectancy
Auguste Deter – Alois Alzheimer's patient in
1902. Hers was the first described case of what became known as Alzheimer's disease

5. Neuro-pathology of Alzheimer's Disease

6. Magnetic Resonance Imaging (MRI) in Alzheimer’s disease
Normal older individual
(age = 77)
Patient with mild AD dementia
(age = 77)
AMUS 6TH mARCH 2013

7. Cardiovascular Disease, Head Injury, Diabetes & Down Syndrome
Risk Factors
Cardiovascular Disease, Head Injury, Diabetes & Down Syndrome
Familial/Genetic
APOE ε4, PSEN1 & 2
Increasing Age

8. Alzheimer’s Disease Trajectory
Normal Aging
Cognitive
function
Asymptomatic
Early symptomatic
MCI
(prodromal)
Preclinical
Clinical Dementia
Mild
Moderate
Severe
Age
AMUS 6TH mARCH 2013

9. Baltimore Longitudinal Study of Aging BALSA
Men
Women
Age (yrs)
Cases of Alzheimer's Disease
BLSA
US Life Tables 60
9.3
28.5
20.0
10.6
32.5
24.1 65
7.8
23.5
16.1
8.9
27.5
19.8 70
6.5
18.7
12.5
7.5
22.6
15.6 75
5.5
14.1
9.4 63
17.7
11.9 80
4.6
10.3
6.7
5.2
13.2
8.6 85
3.8
7.3
4.7
4.4
5.9 90
3.2
5.1
3.3
3.7
6.4
4.1 95
2.7
3.6
3.1
4.3
2.8
Source: Brookmeyer R et al (2002) Survival following a diagnosis of Alzheimer Disease Archives of Neurology 59:

10. Current Treatment Approaches for AD
1993
1997
2000
2001
2003
tacrine
(Cognex®)
donepezil (Aricept®)
rivastigmine
(Exelon®)
galantamine
(Razadyne®)
memantine
(Namenda®)
AMUS 6TH mARCH 2013

11. Modifiable Risk Factors
Population Prevalence
Relative Risk (95% CI)
PAR (confidence range)
Number of cases attributable (thousands; confidence range)
Worldwide
Diabetes Mellitus
6.4%
1.39 ( )
2.4% ( )
826 ( )
Midlife Hypertension
8.9%
1.61 ( )
5.1% ( )
1746 ( )
Midlife Obesity
3.4%
1.60 ( )
2.0% ( )
678 ( )
Depression
13.2%
1.90 ( )
10.6% ( )
3600 ( )
Physical Inactivity
17.7%
1.82 ( )
12.7% ( )
4297 ( )
Smoking
27.4%
1.59 ( )
13.9% ( )
4718 ( )
Low Education
40.0%
1.59 ( )
19.1% ( )
6473 ( )
Combined (maximum)
50.7%
17,187,028 *
USA
8.7%
3.3% ( )
174 (77-288)
14.3%
161 ( )
8.0% ( )
425 ( )
13.1%
7.3% ( )
386 ( )
19.2%
14.7% ( )
781 ( )
32.5%
21.0% ( )
1115 ( )
20.6%
10.8% ( )
574 ( )
13.3%
159 ( )
7.3% ( )
386 ( )
54.1%
2,866,951*
Source: Barnes D and Yaffe K (2011) The projected effect of risk factor reduction on Alzheimer’s disease prevalence
Lancet Neurology 10:

12. Potential number of AD cases that could be prevented through risk factor reduction
Source: Barnes D and Yaffe K (2011) The projected effect of risk factor reduction on Alzheimer’s disease prevalence
Lancet Neurology 10:

14. Future Perspectives

15. Changes in Population by Age-group

16. Future Prevalence – by age group - UK
Source: Alzheimer’s Society (2007) Dementia UK – The full report. A report to the Alzheimer’s Society on the prevalence and economic cost of dementia in the UK produced by King’s College London and the London School of economics Abbo Litho. London

17. Future Prevalence – by gender - UK
Source; Alzheimer’s Society (2007) Dementia UK – The full report. A report to the Alzheimer’s Society on the prevalence and economic cost of dementia in the UK produced by King’s College London and the London School of economics Abbo Litho. London

18. Pharmaceutical Developments
every anti-Abeta drug which has reached late stage development has failed in clinical studies
Both Bapineuzumab and Solanezumab failed to meet primary endpoints, though Solanezumab may be effective in mild AD
DIAN have selected 2 investigational monoclonal antibodies for clinical trials in pre-clinical AD (Gantenerumab and Solanezumab) in a randomized controlled trial
This trial will include 160 mutation carriers in their 30's, 40's or 50's who range from 15 years before to 10 years after the expected onset of symptoms
To commence early 2013

19. Advances in early diagnosis
Biomarkers
Identification of tau and amyloid in blood, urine and CSF
Biomarker signatures in CSF in particular correlate with the course of AD
Brain Imaging
MRI for functional and structural assessments
Contrast PET imaging using F-18 or PiB to identify amyloid deposition
FDA approval of Florbetapir

20. Florbetapir-PET Imaging
Low amyloid on PET and autopsy
Source: Clark et al (2011) use of Florbetapir-PET for Imaging β-Amyloid Pathology
JAMA 305(3):
Intermediate amyloid on PET and autopsy
High amyloid on PET and autopsy
AMUS 6TH mARCH 2013

21. Colombian Cohort

22. Challenges Ahead
Large and lengthy trials – need patients and families willing to volunteer
“Surrogate markers” of disease modifying effects may shorten duration of trial (Neuroimaging, CSF)
Trials in mild-moderate AD dementia are failing
Nine phase III trial failures over the past decade
Are we targeting the wrong mechanism of action or is it too late in the disease course?
Disease modifying therapies may work best prior to dementia (and stage of irreversible brain cell loss)
MCI/prodromal or even preclinical stage
Delaying dementia by 5 years would reduce projected Medicare costs by nearly 50%
AMUS 6TH mARCH 2013 30 22

23. Thank you

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