1. The document discusses recommendations from a workgroup on defining the preclinical stages of Alzheimer's disease. 2. The workgroup proposes operational research criteria for the preclinical stage to provide a framework for studies investigating whether biomarkers can predict cognitive decline. 3. The criteria stage preclinical AD based on biomarkers of amyloid and neurodegeneration, though individual prognosis remains unclear as not all with pathology develop dementia.

1. Toward defining the preclinical stages of Alzheimer’s disease Recommendations from the NIA/Alzheimer’s Association Preclinical Workgroup Reisa Sperling, M.D. Center for Alzheimer’s Research and Treatment Brigham and Women’s Hospital Massachusetts General Hospital Harvard Medical School

2. Disclosures/Funding Consultant to : Janssen, Elan, Pfizer/Wyeth, Bristol-Myers-Squibb, Link, Bayer, Eisai, Roche, Avid (unpaid) Clinical Trial Site Investigator: Bristol-Myers-Squibb, Janssen, Elan, Pfizer/Wyeth, Avid Research funding from: National Institute on Aging: P01AG036694; P50AG005134 R01AG027435; K24AG035007 Alzheimer’s Association American Federation of Aging Research American Health Assistance Foundation

3. Preclinical Workgroup Reisa Sperling , Brigham and Women’s Hospital (Chair) Paul Aisen , University of California, San Diego Laurel Beckett , University of California, Davis David Bennett, Rush University Medical Center Suzanne Craft, VA Puget Sound Health Care System Anne Fagan , Washington University Takeshi Iwatsubo, University of Tokyo Cliff Jack , Mayo Clinic Jeffrey Kaye, Oregon Health Science University Thomas Montine , University of Washington Denise Park , University of Texas, Dallas Eric Reiman , Banner Alzheimer’s Institute Chris Rowe, University of Melbourne Eric Siemers , Eli Lilly and Company Yaakov Stern , Columbia University Kristine Yaffe , University of California, San Francisco Maria Carrillo, Bill Thies , Alzheimer’s Association Tony Phelps , Mollie Wagster, Marcelle Morrison-Bogorad, NIA

7. Years Cognitive function Aging MCI AD Dementia The continuum of Alzheimer’s disease } Preclinical Asymptomatic Early symptomatic Sperling et al Alzheimer & Dementia 2011 NIA-AA Preclinical Workgroup

10. Brain and cognitive reserve ? Environmental factors Hypothetical model of AD pathophysiological cascade ? Sperling et al Alzheimer & Dementia 2011 NIA-AA Preclinical Workgroup Cerebrovascular risk factors Other age-related brain diseases Age Genetics Amyloid-  Accumulation Synaptic Dysfunction Glial Activation Tangle Formation Neuronal Death Cognitive Decline

11. Amyloid-  accumulation  (CSF/PET) Synaptic dysfunction (FDG-PET/fMRI) Tau-mediated neuronal injury (CSF) Brain structure (volumetric MRI) Cognition Clinical function Clinical Disease Stage Normal Abnormal MCI Preclinical Dementia Figure adapted from Jack et al. 2010 Sperling et al Alzheimer & Dementia 2011

15. Staging Framework for Preclinical AD

18. Thank you Workgroup Alzheimer Association Cliff Jack Maria Carillo Paul Aisen Bill Thies David Bennett Anne Fagan Yaakov Stern NIA Eric Siemers Tony Phelps Tom Montine Molly Wagster Suzanne Craft Marcelle Morrison-Denise Park Bogorad Laurel Beckett Cerise Elliot Kristine Yaffe Neil Buckholtz Jeffrey Kaye Chris Rowe Takeshi Iwatsubo