PROJECT SUMMARY Alzheimer’s disease (AD) pathophysiology seldom occurs in isolation, and it is widely established from the neuropathology literature that the majority of individuals with dementia have multiple etiology dementia (MED). MED is common but undetected in extant major cohort studies and treatment trials for AD; many studies intentionally restrict clinical heterogeneity to an assumed single etiology by using narrowly defined clinical enrollment criteria. A major gap in our field is the lack of validated tools to detect MED in-vivo. The next era of large-scale imaging biomarker studies for AD and related disorders (ADRD) will require strategies commensurate with the known but largely unaddressed problem of etiologic heterogeneity. The Alzheimer’s Disease Research Centers (ADRCs) are uniquely positioned to meet this need. Collectively the 37 ADRCs follow ~14,000 active enrollees with high brain donor and autopsy rates (>60%). The ADRCs recruit across the clinical severity continuum and amply represent the several diseases comprising ADRD. Now, as a consortium, the centers will conduct a uniform imaging protocol capable of elucidating individualized etiological profiles including foundational PET imaging for AD proteinopathy (Amyloid and Tau), vascular burden with MRI and additional structural MRI and FDG PET for assessing the several patterns of morphologic and metabolic Neurodegeneration signatures of both AD and non-AD proteinopathies on deeply phenotyped patients. Design: This is a longitudinal imaging study at 2-year intervals that is superimposed on and fully integrated with the ongoing uniform cognitive and clinical data collection the 37 ADRCs already do. We will study 2,000 ethnoculturally diverse ADRC participants that are either clinically unimpaired (CU; N=800) or impaired (N=1,200) where AD is a considered, though need not be the primary suspected etiology. Aim 1 creates the ATN cohort through prospective imaging and plasma collection and establishes the foundational shared resource in conjunction with the National Alzheimer’s Coordinating Center (NACC) with linkage to the vast clinical, cognitive, and genetic datasets on these same participants. In Aim 2 we examine the temporal progression of the two most common etiologies—AD and vascular disease. We examine onset ages and duration of each and their joint effect on cognitive decline. Aim 3 focuses on other common proteinopathies. Classification and joint modelling methods will be applied to estimate etiologic composition and the effect of multi-proteinopathy on clinical and cognitive change. ATN imaging–a critical foundation for characterizing likely dementia etiologies—is needed on this expertly-diagnosed, uniformly evaluated MED ADRD cohort where neuropathology can inform clinicopathologic correlation, mechanistic underpinnings, and strategic diagnostic and therapeutic development. The consortium of ADRCs have the expertise and capacity to conduct this study and will work together to ensure its success and its impact on the field.

NARRATIVE Multiple etiologies variously contribute to the clinical syndrome of mild cognitive impairment and dementia presumed due to Alzheimer’s disease, but the many factors that give rise to symptoms are difficult to quantify at the level of the individual. A comprehensive panel of imaging and plasma biomarkers will improve the likelihood that etiologies beyond Alzheimer’s disease can be detected. Such individual-level characterization will greatly impact diagnostic accuracy, and prediction of symptom course and response to experimental therapies.