Roche satellite symposium/educational session CTAD Asia - China Conference Transforming AD in China: From Diagnosis to Treatment Sunday 2 September 2018 Location: Shanghai, China NP/AZD/1807/0003
Complex problem, complete solution: Why we need to tackle AD from all angles Jeffrey Cummings, MD, ScD Cleveland Clinic Lou Ruvo Center for Brain Health NP/AZD/1807/0003a
Disclosures Dr. Cummings has provided consultation to Acadia, Actinogen, Avanir, BiOasis, Biogen, Bracket, Eisai, Lilly, Lundbeck, MedAvante, Merck, Otsuka, Resverlogix, Roche, and Samus pharmaceutical and assessment companies Dr. Cummings has stock options in BiOasis, Prana, ADAMAS, MedAvante, and QR Pharma Dr. Cummings owns the copyright of the Neuropsychiatric Inventory This presentation will include reference to unapproved medications and diagnostics
Intercepting AD: Complex Problem, Complete Solutions Levels of complexity in AD Biological complexity and biomarkers: Professor Eric Reiman Applying biomarkers in China: Professor Jing Yuan Clinical complexity and neuropsychological assessment: Professor Andreas Monsch Clinical assessment in China: Professor Huali Wang Therapeutic complexity: Dr Rachelle Doody
Levels of Complexity in Alzheimer s Disease Genetics Intracellular Pathways Cell Changes (Aβ, tau, inflammation) Circuit Changes Clinical Manifestations
Genetic Complexity: Map of relationships of Alzheimer-specific genes Hu Y-S, et al. Alz Res Ther 2017; 9:29.
Levels of Complexity in Alzheimer s Disease Genetics Intracellular Pathways Cell Changes (Aβ, tau, inflammation) Circuit Changes Clinical Manifestations
Biological Complexity: Cell signaling Mizuno S, et al. BMC Systems Biology 2012; 6:52.
Levels of Complexity in Alzheimer s Disease Genetics Intracellular Pathways Cell Changes (Aβ, tau, inflammation) Circuit Changes Clinical Manifestations
Brain Circuit Complexity: Neurodegenerative Disorders Target Anatomically Dissociable Circuits Seeley W, et al. Neuron 2009; 62:42 52.
Levels of Complexity in Alzheimer s Disease Genetics Intracellular Pathways Fluid biomarkers, tau and Aβ PET, MRI, FDG Cell Changes (Aβ, tau, inflammation) MRI, FDG, EEG, MEG Circuit Changes Clinical Manifestations
Population Complexity: Phases of AD Normal Preclinical Prodromal Dementia
Levels of Complexity in Alzheimer s Disease Genetics Intracellular Pathways Fluid biomarkers, tau and Aβ PET, MRI, FDG Cell Changes (Aβ, tau, inflammation) MRI, FDG, EEG, MEG Circuit Changes Clinical Manifestations
Clinical Complexity Recognition of presenting symptoms Clinical assessment Engaging the family Neuropsychological assessment Laboratory assessment Imaging assessment Standard of care Referral for trials
Levels of Complexity in Alzheimer s Disease Genetics Intracellular Pathways Cell Changes (Aβ, tau, inflammation) Circuit Changes Clinical Manifestations
Treatment Complexity What targets? Amyloid (which form?) Tau (which form?) Inflammation What agents? Monoclonal antibodies Small molecules Which population? Preclinical AD Prodromal AD AD dementia Which clinical outcomes?
Levels of Complexity in Alzheimer s Disease Intervention Genetics Intervention Intracellular Pathways Outcomes Cell Changes (Aβ, tau, inflammation) Circuit Changes Clinical Manifestations
Alzheimer s Disease: Complex Problem, Complete Solutions Complexity is the rule Many levels of complexity: genetic, omic, pathway, circuit, clinical, population, trial Interventions must anticipate complexity We are making progress
Emerging roles of biomarkers in AD Eric M. Reiman, MD Banner Alzheimer s Institute Banner Research University of Arizona Arizona State University Translational Genomics Research Institute Arizona Alzheimer s Consortium NP/AZD/1807/0003b
Disclosures Scientific Advisor Roche (expenses only) Alkahest, Alzheon, Aural Analytics, Denali, Green Valley, United Neuroscience Industry-Supported Grants & Contracts Genentech/Roche, Novartis/Amgen & Avid/Eli Lilly NIH & State Grants, Philanthropic & Foundation Support Patent for the accelerated evaluation of preclinical AD treatments
AD Biomarkers Brain Imaging biomarkers e.g., amyloid, tau & FDG PET; volumetric MRI; others CSF biomarkers e.g., CSF Aβ 42, Aβ 40, total & phospho-tau; others in development Emerging blood tests e.g., plasma Aβ 42 /Aβ 40, NfL; others in development Genetic risk factors e.g., PSEN1, PSEN2 & APP mutations, Trisomy 21, APOE4, & polygenic risk scores Others in development
Biomarker Roles In observational studies the detection, tracking, staging & study of AD evaluating risk modifiers In therapeutic trials participant selection target engagement & dose selection treatment monitoring (e.g., for ARIA) treatment prediction treatment evaluation accelerated evaluation of prevention therapies In the clinical setting diagnosis prognosis management screening
Amyloid PET X X Fleisher et al, Lancet Neurol, 2010
Tau PET Scholl et al, Neuron 2016
FDG PET & Volumetric MRI: Brain Imaging Biomarkers of Neurodegeneration Reiman & Langbaum, in Imaging in the Aging Brain, 2009
CSF Ab42/Tau Ratios Predict Progression to Subsequent AD Stages Hansson et al, Lancet Neurol 2006
Reconceptualization of AD Sperling et al, Alzheimers Dementia 2011; Jack et al, Alzheimer s Dementia 2018 (from Langbaum et al, Nature Neurol Rev 2013)
Proposed Sequence of AD Biomarker Changes Jack et al, Lancet Neurol 2010; Jack et al, Alzheimer s Dementia 2018
Fleisher et al, Lancet Neurol 2012
Fleisher et al, Lancet Neurol 2012
Fibrillar Ab PET in the Clinical Setting Appropriate Use Criteria: Persons who have subjective & objective evidence of cognitive impairment, and have possible AD due to an atypical or etiologically mixed presentation, and in whom a positive or negative scan would increase diagnostic certainty and alter management Appropriate Situations Persons with unexplained MCI Persons with an atypical or etiologically mixed presentation Persons with a progressive dementia & an unusually early age (<65) at onset Future Considerations If an anti-ab treatment works & is approved for use in mild-to-moderate AD dementia, MCI &/or unimpaired persons with biomarker evidence of Ab plaques Johnson et al, Alzheimers Dementia 2013; Rabinovici et al, Alzheimers Dement 2016; Mallik et al, Semin Nucl Med 2017
Looking into the Future Continued biomarker development More sensitive, precise & scalable CSF biomarkers & blood tests Clarifying their value in therapeutic trials & the clinical setting Helping to find & support the approval, affordability & availability of preclinical AD treatments as quickly as possible