1. Systems Based Approach to Disease Modifying Therapies for Alzheimer’s Disease
Aaron Ritter MD
Cleveland Clinic Lou Ruvo Center for Brain Health
September 2018

2. Outline Case Presentations Concepts Discussion
Adopted from Alberto Espay
Discussion

3. Case 1
Case 1
63 yr old male with 2-3 years of getting lost, difficulty at work, forced early retirement from Parks Service
Frequently misplacing items
Behavioral change: paranoid (Isis/Russia)
No family history
College educated/physically fit

4. Case 1

5. Case 1

6. Case 2 68 yr old short term memory loss
Memory has worsened with unexpected death of son
No medical history
No family history
HS educated, cognitively active (computer/ipad) but not physically active

7. Case 2

8. Case 2

9. Case 3
Case 3
68 yr old male 3 year history of new onset severe depression and anxiety, multiple psychiatric hospitalizations for anxiety (no VH) and delusions. Diagnosed with psychotic depression
No family history
HS education
Physically healthy

10. Case 3

11. Case 3

12. Cases
Blue line= Patient 1 (63 yr old Park Ranger with high tau)=improved over 2 years
Orange line=Patient 2 (68 yr old patient with depression following death of son)=improved over 2 years
Grey line= Patient 3 (68 yr old with psychosis)=rapid decline

13. Current Concept Current conception : Alzheimer’s disease
A single (but complicated) entity with stages or levels
Viewing AD as a single disorder has been useful for the development of symptomatic treatments

14. Current Concept
My clinical experience: Alzheimer’s disease is not a single disorder but a variety of different disease subtypes sharing common endpoint of neurodegeneration and cognitive dysfunction
clinical, epidemiological, and genetic subtypes
Success in disease modifying therapies will require a shift from reductionist clinically based definition of AD to a Systems Based disease subtyping
Wilkosz 2009
201 patients for 13.5 years

15. Reductionism Complex system is nothing but a sum of its parts
Individual constituents are reduced to a common denominator
Biology: Central Dogma
debunked
Medicine: Osler’s interpretations
Disease=organ system correlated with pathology
Variations=physiological noise

16. Reductionist Approach to AD
Main pathological processes in AD=amyloid and tau
Result from combined effect of many small but quantifiable genetic risk factors and certain environmental insults
Converging into a recognizable pattern of abnormal aging
Disease modifying clinical trials have focused on understanding the elementary disease mechanisms common to all individuals with AD
What happens if not all participants share the same pathogenesis
Non-responders are not accounted for in clinical trials

17. Systems Based Approaches
Approaches complex biological systems under the assumption that the networks that form the whole of living organisms are more than the sum of their parts
Welcomes noise or diversity in systems
Focus on network schemes and the complex interactions between genetics, proteomics, metabolomics, epigenomics
Definition of AD phenotypes would require three pathophysiological tiers: clinical, pathological, genetic-molecular for each patient
Therapies targeted at each tier

18. Oncology Example
Problem is cell proliferation rather than degeneration
Most of 20th century
Viewed as a single heterogeneous disease
1980s=systems biology approach
Breast cancer now 9 histological types, combined with variable molecular markers (estrogen receptor, HER2, etc)
Prescribed drug cocktail is targeted to specific clinical (stage), histology and molecular marker

19. How to get to a systems based approach
Biomarker development
Biomarker-driven phenotypes
Non-hypotheses driven
Both disease and non-affected individuals

20. Implications for Clinical Trials
1) Candidate agents should require the identification of similar pathogenic mechanisms in the targeted AD cluster from which those ascertained in animal models from which those therapies emerged 2) Single mechanism trials only appropriate for targeting robust and widespread pathogenic abnormalities 3) Biological samples from clinical trials analyzed in responders 4) New diagnostic criteria are needed that incorporate clinical as well as biomarker subtypes 5) Ageing needs to be considered carefully when performing phenotypic clustering

21. Conclusion
AD is a disorder composed of many related diseases with different phenotypes, responses to treatment and survival
Likely due to different genetic, epigenetic, biological, and molecular contributions
Greater diagnostic sophistication is needed to improve the success of disease modifying therapies as the MOA of each agent will only benefit a subset of patients
Contributions from each pathogenic mechanisms are likely to vary between patients and this variation will need to be incorporated from the outset in the design of future trials