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

Outline Case Presentations Concepts Discussion Adopted from Alberto Espay Discussion

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

Case 1

Case 1

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

Case 2

Case 2

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

Case 3

Case 3

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

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

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

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

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

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

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

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

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

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