1. Population-based Neuropathology: classification of disease biomarker discovery tool Thomas J. Montine, MD, PhD Alvord Professor and Chair Department of Pathology University of Washington Disclosures: Consultant to: Eisai, Amgen, BMS No off-label medications No medical devices

2. Risk Genetics Previous life events Likelihood of initiation or progression disease in the future. Actual Clinical Data degree & character of functional impairment Normal Mild Impairment Dementia or Parkinsonian Laboratory Data disease type & burden None++++++ Chronic Disease Model No Disease LatencyProdrome Full Expression “ Laboratory data” can be neuropath, lab med, and neuroimaging “Clinical data” can be signs, symptoms, and neuropsych findings Neuropathology of Dementia Classification of Disease Neuropathology of Dementia Classification of Disease Risk of disease vs. Actual disease Extent vs. Causes of functional impairment Risk of disease vs. Actual disease Extent vs. Causes of functional impairment

3. AD Proteinopathy Mito Stress Glial activation Etc. Proteinopathy Mito Stress Glial activation Etc. Aging, Genetics, Environment PRODROMEPRODROMEPRODROMEPRODROME VBI LBD DEDEMEMENTIANTIADEDEMEMENTIANTIA LATENT DISEASE Injury & Response to Injury Injury & Response to Injury Repair & Functional Compensa- tion Repair & Functional Compensa- tion Chronic disease model of dementia AD ≈45% VBI ≈33% LBD ≈10% COGNITIVELY NORMAL Neuropathology of Dementia Classification of Disease Neuropathology of Dementia Classification of Disease

4. Dementia stage Neuropathology of Dementia Classification of Disease Neuropathology of Dementia Classification of Disease

5. AD Proteinopathy Mito Stress Glial activation Etc. Proteinopathy Mito Stress Glial activation Etc. Aging, Genetics, Environment PRODROMEPRODROMEPRODROMEPRODROME VBI LBD DEDEMEMENTIANTIADEDEMEMENTIANTIA LATENT DISEASE Injury & Response to Injury Injury & Response to Injury Repair & Functional Compensa- tion Repair & Functional Compensa- tion Chronic disease model of dementia AD ≈45% VBI ≈33% LBD ≈10% Neuropathology of Dementia COGNITIVELY NORMAL

6. AD Proteinopathy Mito Stress Glial activation Etc. Proteinopathy Mito Stress Glial activation Etc. Aging, Genetics, Environment PRODROMEPRODROMEPRODROMEPRODROME VBI LBD DEDEMEMENTIANTIADEDEMEMENTIANTIA LATENT DISEASE Injury & Response to Injury Injury & Response to Injury Repair & Functional Compensa- tion Repair & Functional Compensa- tion Chronic disease model of dementia AD ≈45% VBI ≈33% LBD ≈10% Neuropathology of Dementia COGNITIVELY NORMAL ACT HAAS Nun Study OBAS

7. AD Proteinopathy Mito Stress Glial activation Etc. Proteinopathy Mito Stress Glial activation Etc. Aging, Genetics, Environment PRODROMEPRODROMEPRODROMEPRODROME VBI LBD DEDEMEMENTIANTIADEDEMEMENTIANTIA LATENT DISEASE Injury & Response to Injury Injury & Response to Injury Repair & Functional Compensa- tion Repair & Functional Compensa- tion Summary AD ≈45% VBI ≈33% LBD ≈10% COGNITIVELY NORMAL Neuropathology of Dementia Classification of Disease Neuropathology of Dementia Classification of Disease 3 chronic diseases account for vast majority of dementia Idiosyncratic convergence at all stages of impairment Progressive aggregate disease vs. functional impairment Apparent resilience and hightened vulnerability 3 chronic diseases account for vast majority of dementia Idiosyncratic convergence at all stages of impairment Progressive aggregate disease vs. functional impairment Apparent resilience and hightened vulnerability

8. 2012 NIA-AA revised Guidelines for Neuropath Evaluation Neuropathology of Dementia Classification of Disease Neuropathology of Dementia Classification of Disease

10. Isssue19972012 Clinical Dx of dementia required for NP Dx of AD YesNo NP assessment based onBraak for NFTs & CERAD for Neuritic plaques These plus Thal phase for A  regional accumulation NP assessment of commonly co-morbid diseases Little guidanceExplicit Minimum regions to sample and stains to be used SilentExplicit Reporting and CPCSilentGuidelines 2012 NIA-AA revised Guidelines for Neuropath Evaluation Neuropathology of Dementia Classification of Disease Neuropathology of Dementia Classification of Disease

11. LP within 3 wk of cognitive testing Clinical Lab evidence for AD is rare in cognitively normal volunteers younger than 50 yr-old ≈ 20% of cognitively normal volunteers > 50 yr- old have laboratory evidence of AD Have poorer cognitive function at baseline Have much greater risk of converting to MCI or AD in next 3 to 4 years Clinical Lab evidence for AD is rare in cognitively normal volunteers younger than 50 yr-old ≈ 20% of cognitively normal volunteers > 50 yr- old have laboratory evidence of AD Have poorer cognitive function at baseline Have much greater risk of converting to MCI or AD in next 3 to 4 years CSF tau and A  42 Volunteers for lumbar puncture: OHSU, UCSD, & UW ADC Spectrum of Normal Cognition to Dementia CSF tau and A  42 Volunteers for lumbar puncture: OHSU, UCSD, & UW ADC Spectrum of Normal Cognition to Dementia Neuropathology of Dementia Biomarkers Neuropathology of Dementia Biomarkers

12. Neuropathology of Dementia Discovery Tool Neuropathology of Dementia Discovery Tool Histelide Molecular-specific regional quantification IHC Histelide Molecular-specific regional quantification IHC

13. Neuropathology of Dementia Discovery Tool Neuropathology of Dementia Discovery Tool Histelide Molecular-specific regional quantification IHC Histelide Molecular-specific regional quantification IHC

14. Neuropathology of Dementia Discovery Tool Neuropathology of Dementia Discovery Tool Histelide Molecular-specific regional quantification IHC Histelide Molecular-specific regional quantification IHC

15. Neuropathology of Dementia Discovery Tool Neuropathology of Dementia Discovery Tool Histelide Molecular-specific regional quantification IHC Histelide Molecular-specific regional quantification IHC