John C. Morris, MD - US grants

The CERAD Clinical Task Force was established to develop a clinical assessment battery for the diagnosis and characterization of Alzheimer's disease (AD) and to standardize its administration and interpretation. In this revised application, the Task Force builds on the successful achievement of its original mission. Using unique resources developed through experience in standardizing criteria and assessment tools for probable AD across multiple centers, CERAD will continue to obtain follow- up studies of identically diagnosed and assessed subjects for longitudinal study until autopsy to determine clinical, neuropsychological, and neuropathologic findings. The data obtained will be used to examine already identified features of AD such as extrapyramidal dysfunction, and will permit examination of clinico-pathologic correlates of AD.

Cerebrovascular disease is a major cause of dementia and is potentially preventable. However, vascular dementia is poorly characterized and its true prevalence is unknown. Controversies in the understanding of vascular dementia relate to the mechanisms by which stroke affects cognition, the clinical features that distinguish vascular dementia from Alzheimer's disease, the role of cerebral white matter changes in presaging "brain t risk" for ischemic damage, and the size and location of cerebral infarcts necessary to produce cognitive impairment. Prospective studies of the clinical, neuropsychological, neuro-imaging, and neuropathological correlates of stroke and cognition are needed. This application addresses that need by longitudinally studying subjects at high risk for cerebral ischemic infarction on cognitive and behavioral measures. These measures have been validated in longitudinal studies of demented and nondemented elderly persons and will be obtained annually. They include clinical and psychometric methods that tap a wide range of cognitive abilities (verbal and nonverbal memory; intelligence; visuospatial and psychomotor abilities; language). An experimental neuropsychological battery will measure subtle deficits produced by unilateral hemispheric lesions. Cerebral hemodynamic studies at entry will evaluate increased regional oxygen extraction fraction as a potential marker for cerebral areas at risk for subsequent stroke. Magnetic resonance imaging at entry and 2 years will localize and semiquantitatively assess cerebral infarctions and white matter changes. In those patients who come to autopsy during the 5 year duration of the study, neuropathological examination will quantitate the number, location, and volume of cerebral infarctions and assess vascular pathology. These variables will be compared with those of identically assessed healthy controls and Alzheimer disease patients for descriptive features, slope of cognitive change, and correlates of impaired cognition. The application capitalizes on two currently funded projects at Washington University. The R01 "Role of cerebral hemodynamics in ischemic stroke" (NS 28947; RL Grubb, PI) will provide patients at high risk for cerebral infarction (carotid occlusion patients) after completion of their neurological and cerebral hemodynamic assessments. The control and Alzheimer patients will be recruited from the Alzheimer's Disease Research Center (ADRC) AG05681, L Berg, Pl), which also will support this application with resources from its Clinical, Psychometric, Neuropathology and Biostatistics Cores. The ADRC will be the performance site for the longitudinal cognitive and behavioral assessments, the focus of this application.

This Core recruits, enrolls and evaluates all subjects entered into the studies of the program project. It uses established clinical protocols at entry and at all assessments to obtain relevant clinical, neurological, and cognitive data to carefully characterize each subject, including for dementia diagnosis and staging. Core data are used by all Cores and projects to explore the correlates of very mild dementia of the Alzheimer type (DAT) in comparison with healthy brain aging. The Core recruits and maintains adequate samples to supply needed subjects for all projects and other cores. In addition to maintaining the longitudinal sample of subjects 65+years (required in all projects) the Core will recruit a sample of subjects at high risk for dementia (Adult Children Study) ages 45-74 to explore antecendents of Alzheimer disease in Project 2 (Novel Biomarkers to Predict Alzheimer's disease), Project 3 (Attention Profiles in Healthy Aging Early Stage DAT)and 4 (Predicting Cognitive Decline in Healthy Elders). For Project 1 (Dementia Assessment in the Community) a shortened dementia assessment is to be tested in the community and this Core will assess subjects using our established clinical protocols to validate the brief instrument. Through its successful voluntary autopsy program, it supplies Core C: Neuropathology with autopsy material and therefore the neuropatholgic diagnoses for the Projects. Core A: Clinical works closely with Core B: Psychometrics to integrate the clinical and psychometric assessments for all subjects and with CoreD: Biostatistics to ensure appropriate data management. The Core supports Core E: Administrative in promoting scientific interactions among all investigators to accomplish the aims of the program project as a whole.

DESCRIPTION (provided by applicant): This application is for the 5-year renewal of the program project, Healthy Aging and Senile Dementia (HASD), now in its 25th year. In this renewal, there is a continued focus on the clinical, psychometric, and neuropathologic correlates of dementia of the Alzheimer type (DAT) in comparison with healthy aging with a new thrust addressing preclinical Alzheimer's disease. Five interactive and supportive Cores are proposed: Core A: Administration provides administrative support to all components and assures progress in accomplishing program project goals. Core B: Clinical recruits, enrolls, psychometrically and clinically assesses subjects annually to supply all projects. Core C: Biostatistics oversees data management and provides statistical input to all Cores and projects. Core D: Neuropathology performs postmortem examinations for clinicopathological correlation for all studies and provides appropriate tissue and data to Projects as needed. Core E: Neuroimaging collects structural imaging data on our cohort to visualize change in anatomy associated with cognitive decline. Two new projects replace the current Projects 1 and 4, which have been completed. The new Project 1 (Preclinical AD predicts poststroke dementia JC Morris) examines the relationship between the presence of amyloid in the brain (as measured by PET PIB) at time of stroke to the later development of dementia. The new Project 4 (Sequence variation in genes for biomarker proteins and age at onset of Alzheimer's Disease AM Goate) uses CSF proteins as intermediate traits, or endophenotypes, to identify novel genetic risk factors for late onset DAT. Two current projects will continue in this application to extend their findings and explore new initiatives. Project 2 (Antecedent biomarkers of AD in CSF and plasma DM Holtzman) examines whether markers in the CSF and plasma proteome can be combined to develop a more accurate determination of dementia risk in cognitively normal elderly individuals. Project 3 (Markers for DAT: Control, Variability and Personality, D Balota) will develop cognitive markers as early indicators of DAT. Together, these projects and their supporting cores will focus on preclinical DAT in comparison with healthy brain aging and address the issue of detecting preclinical disease.

human therapy evaluation; psychotropic drugs; mental disorder chemotherapy; Alzheimer's disease; brain disorder chemotherapy; drug screening /evaluation; aging; drug administration rate /duration; pharmacokinetics; clinical research; human subject;

This Project will compare healthy aging and senile dementia of the Alzheimer type in a sample aged 80 and older with respect to longitudinal clinical and psychometric performance and neuropathologic data postmortem. Guidelines for the separation of Alzheimer and nonAlzheimer brains on the basis of quantitative neuropathologic markers in the very old will be developed. The extent of overlap in the brains of demented and nondemented very old persons will be examined. In the process we will extend our knowledge about clinical and psychometric performance in a nondemented sample of persons aged 80 and older. We will have studied approximately 400 very old subjects during life and expect to have at least 125 autopsies from this sample at the completion of this proposed Project. About one-third of the brains are expected to come from the nondemented and mildly/very mildly demented (SDAT) and two-thirds from the more severely demented very old subjects.

The Core serves the ADRC by: recruiting and enrolling research subjects; providing clinical, cognitive, and behavioral assessments at entry and annually thereafter for diagnosis, dementia staging, and monitoring of clinical course from entry until death; obtaining autopsy permission; and acquiring biological samples. A particular strength of this Core is its ability to identify the earlier symptomatic stages of Alzheimer's disease (AD) as distinguished from non-demented aging. The Core has notably improved its recruitment of minorities through the successful activities of its African-American Outreach Satellite. The Specific Aims of the Core are to: 1. Provide subjects, carefully characterized as to diagnosis and stage of dementia, to support the research studies of the ADRC and other investigators and particularly the current projects: Project 1: Identification of genes that modify age of onset of AD (A. Goate, PI); Project 2: ApoJ lipoproteins: Role in Abeta deposition (D. Holtzman, PI); Project 4: fMRI exploration of memory in aging and early-stage DAT (R. Buckner, PI). 2. Maintain the ADRC Subject Registry with individuals with dementia of the Alzheimer type (DAT) and related dementia and non-demented elderly controls by continuing longitudinal clinical psychometric, and behavioral assessments of subjects already enrolled; and recruiting new subjects able to participate in research protocols to replace those lost to dementia progression, death, or relocation far from St. Louis. 3. Obtain biologic samples from subjects for use by investigators within and outside the ADRC, including blood collection and postmortem tissue. 4. Support the African-American Training and Information Transfer) in clinical assessment, service delivery, and educational training activities. 5. Integrate data collection and entry procedures with Core A. Biostatistics, all other Cores and Projects, and the designated Alzheimer's Disease Data Coordinating Center.

The Washington University ADRC has been functioning since 1985. Emphasis on the work of the Center has focused on interdisciplinary longitudinal clinical analysis of dementia of the Alzheimer's type and the study of clinicopathologic correlates, with emphasis on distinguishing the earliest symptoms of AD. The ADRC performs and provides logistical and material support for research projects and this and many other institutes. It also provides for a range of informational and training activities aimed at both the professional and lay communities. To execute these activities the ADRC consists the ADRC consists of five Cores, Administrative, Clinical, Biostatistics, Neuropathology and Tissue Resource, and Training and Information Transfer (TITC). Two Satellites are supported by the Center. An African American Outreach Satellite of the Clinical Core designed to provide services to the African American Community in St. Louis and to increase the participation. of these subjects in the research activities of the Clinical Core. The Missouri/Iowa Satellite of TITC is designed to provide informational services to the rural populations of the states and the physicians and other health professionals that serve them Four research projects will be carried out using genetic, cell biological, biochemical, and neuroimaging, technologies to address fundamental mechanisms of the pathogenesis of Alzheimer's disease.

[unreadable] DESCRIPTION (provided by applicant): This proposal for an academic career leadership award for John C. Morris will establish the Center for Aging at Washington University. The Center will provide academic and administrative leadership to foster the development and implementation of activities that foster productive aging. Productive aging is closely allied with the concept of successful aging and broadly encompasses the goal of growing old with good health, vitality, and engagement. The University-wide Center will promote research, education, and service initiatives to enable older adults to remain healthy, active, independent, and contributing for as long as possible. The imperative for a Center for Aging is to meet the challenge of effectively integrating into society the growing and vigorous older adult segment of the population. Washington University is particularly well positioned to meet this challenge. There is a strong base of ongoing, high-quality research on aging, especially in three of the University's eight schools: Social Work, Arts and Sciences (Department of Psychology), and Medicine. The Center will enhance: ongoing research relevant to aging and enable new investigators to acquire research skills, mentoring, and experience; will generate new ideas and promote new lines of interdisciplinary and collaborative research, and it will serve as a local, regional, and national resource for aging research in general and productive aging in particular. The award will permit implementation and achievement of the inaugural specific aims of the Center: create a pilot project program to encourage innovative aging-related proposals by junior investigators and more senior investigators who are new to aging; attract junior faculty, postdoctoral fellows, and graduate and undergraduate students to the field of aging by means of awards for proposal development; and provide travel stipends to attend scientific conferences pertinent to aging, and other educational experiences. Dr. Morris is firmly committed to accomplishing these aims and, with this award and with outstanding institutional support, to establishing a preeminent Center for Aging at Washington University.

This project will address the need for a practical and valid assessment method which can be used by community physicians to enhance the recognition and diagnosis of dementia. The assessment method entitled the "Brief Instrument for Dementia Detection (BIDD)" to be used in this project will contain specific items identified from our current longitudinal research studies which are determined to best discriminate dementia from nondemented aging. These items will be combined into a brief clinical assessment tool for use by practicing physicians. The long-term objective is to validate that successful informant-based research clinical assessment procedures can be adapted to improve detection of dementia in the community. Currently, dementia is underdiagnosed in the community. Community physicians overwhelming request the availability of clear, time efficient assessment protocols to aid the recognition of dementia. Specifically: 1. This project will develop a sensitive, portable dementia assessment instrument from key items derived from a collateral source-based research dementia protocol. 2. Health care professionals will be trained about dementia, dementia therapy, and the administration and interpretation of the brief assessment tool called BIDD through the newly established Urban Partner's Program. 3. The BIDD will be refined and tested for cultural sensitivity in a pilot study using a population-based sample enrolled in the "Physical frailty in urban African Americans". 4. Evaluate the efficacy of the BIDD in detecting dementia in older adults (75 years old or older) by studying the change from baseline in the frequency of dementia diagnosis and treatment in St. Louis County Health Center patients and the increased request for dementia services from the Alzheimers Association. Also validity of the BIDD will studied by evaluating a randomly selected subset of Health Center patients and the population-based research subject sample with our research dementia assessment protocol to yield a "gold standard" diagnosis of dementia for comparison with the BIDD-derived diagnosis.

Core A: Administration will serve as the Coordinating Center for the entire DIAN project. As such, the specific aims of Core A: Administration are as follows: 1. Organize and coordinate activities and communication of the Cores, subcontractors and clinical performance sites toward achieving the stated goals of DIAN, to include administrative, and budgetary support and monitoring, and problem solving on a continuous basis. 2. With the Clinical Core and the Clinical Coordinating Center, delineate protocols;establish, coordinate and monitor participant recruitment and retention. 3. With the Clinical Core, the Clinical Coordinating Center, the Genetics Core and the Informatics Core, organize and monitor data and tissue collection, and storage. 4. With the Steering Committee and subcommittees, establish policies and procedures regarding: protection of research participants;resource (data, images and tissue) sharing, dissemination, an publications;and future expansion of DIAN to include other sites and languages. 5. Organize and support the DIAN Steering Committee and its subcommittees to include arranging meetings, communication and execution of their decisions. 6. Arrange for periodic external review and advice concerning DIAN goals and progress 7. Arrange for and finance genetic counseling and testing services when desired, and participant travel when necessary for participation.

This Core provides coordination and integration for all other cores, satellites and projects and acts to insure that the research and programmatic goals of the Center are met. The administrative leadership consists of the Program Director, two Associate Directors, and the Executive Director. They are assisted by the Executive Committee that includes these individuals, leaders of the Cores and Projects and other senior faculty. The Administration Core supports, monitors and coordinates the activities of all components of the ADRC. The specific aims of Core A: Administration are: 1. To establish and maintain administrative structure and governance, including budgetary oversight, future planning, and optimal resource utilization, to meet the overall goals of the Center. 2. To coordinate and integrate all ADRC activities and components (Cores, Satellites, Projects, Pilot projects) for research, training, information transfer, and resource sharing. 3. To promote scientific and educational interactions (including public relations) and collaborations on Alzheimer's disease (AD) and related conditions at all levels with other faculty at Washington University, other Alzheimer's Disease Centers, the National Alzheimer Coordinating Center (NACC), National Institute on Aging (NIA), and the Alzheimer's Association, locally and nationally. 4. To solicit, evaluate, select, and monitor Pilot Projects. 5. To provide for periodic external review of the ADRC. 6. To provide assurance of compliance with human subjects, animal welfare, scientific integrity, and the policy requirements of Washington University and the National Institutes of Health (NIH) regarding data sharing and public access to research findings.

Core B: Clinical recruits, assesses, and follows all participants in the ADRC Cohort. It uses well-established informant-based clinical and psychometric instruments (including the Uniform Data Set) at entry and annually thereafter to obtain clinical, cognitive, behavioral, and neurological data to carefully characterize each participant as to the presence or absence of dementia and, when present, its severity and etiology. The Core has successfully provided participants, tissue, and data to all requesting Cores and Projects since its inception in 1985 and will continue to do so in the next 5-year funding period. On a daily basis, the Core interacts directly or indirectly with every facet of the ADRC. The Core's Specific Aims in the proposed funding period are: 1. Maintain an active longitudinal Cohort of ~ 300 participants, cognitively normal and with DAT, of individuals 65 years or more by annually enrolling 30 new participants to replenish attritional loss and to serve Projects 1 and 3 of this competing renewal application. 2. Ensure that Cohort participants contribute to the imaging, biofluid, and DNA (Core F: Genetics) protocols of the ADRC and its affiliated grants and obtain autopsies in deceased participants for Core D: Neuropathology. 3. Support the Core's African American Outreach Satellite. 4. Coordinate with Core C: Data Management and Statistics to integrate data procedures and respond to data sharing initiatives. 5. Coordinate the Core A: Administration to maintain the ADRC's contributions to multicenter collaborative studies, including the National Alzheimer's Coordinating Center. 6. Interact cooperatively with Core E: Education and Information Transfer and its Rural Education and Outreach Satellite to further the educational, training, and outreach goals of the ADRC.

We hypothesize that Alzheimer's disease (AD) has a preclinical stage in which elevated levels of brain amyloid protein and accumulation of beta-amyloid deposits foreshadow the gradual onset of neuronal dysfunction, cell loss and dementia. While the exact role of amyloid in the initiation of brain damage is still unclear, it is clear that clarifying the exact timing of amyloid plaque deposition that precede AD would be extremely helpful in fully understanding the biological origins of AD and to assist in the design of appropriate interventions. This project will use a new method for the in vivo imaging of amyloid plaques in the human brain. Developed at the University of Pittsburgh, [11C]PIB has very high affinity for amyloid plaques with in vitro preparations and binds rapidly to amyloid plaques in a transgenic mouse model of amyloid deposits. We have implemented this method and demonstrated much greater cortical uptake in older participants diagnosed with DAT compared with nondemented control participants. In this project, 240 participants between the ages of 45 and 74 y will be recruited and undergo baseline imaging with PET and [11C]PIB for calculation of amyloid plaque binding. In each decade (45 - 54 y, 55 - 64 y, and 65 - 74 y) 40 participants with at least one biologic parent with DAT (age at onset, or AAO, <80y) and 40 participants whom neither parent has/had DAT (parents must be >70y) will be studied. In addition, we will re-image subjects with [11C]PIB after a three year interval to determine the longitudinal course of amyloid binding in these two cohorts. With this data we will achieve four specific aims: 1) In Years 01 - 03, we will measure and compare cortical [11C]PIB uptake in 120 ACS participants with a parent with DAT and in 120 participants without a parent with DAT. 2) We will correlate cortical [11C]PIB uptake with specific measures of cognitive performance, including presence and magnitude of learning effects, and with personality measures. 3) We will test for correlations between cortical [11C]PIB uptake and CSF biomarkers (Project 2), and between cortical [11C]PIB uptake and neuroanatomic biomarkers (Project 4). 4) In Years 04 and 05, we will repeat PET [11C]PIB imaging on participants enrolled in Years 01 and 02, respectively. By comparing the cortical [11C]PIB uptake at these two different time-points three years apart, we will be able to assess the ACS cohorts longitudinally to determine the natural history of [11C]PIB binding and its potential for preclinical detection of AD.

DESCRIPTION (provided by applicant): The overarching aim of this application is to greatly expand knowledge about preclinical AD and specifically to characterize the chronology of biomarker changes, determine their path biological signatures (if any), and identify cognitively normal persons who are at very high risk for developing symptomatic AD. Successful treatment strategies will require biomarkers that can identify individuals at high risk for AD and at the earliest clinical stages in order to target them for clinical trials, disease- modifying therapies nd to monitor therapy success. The overall Specific Aims in this renewal application are to: 1. Follow the current participants in ACS and add new enrollees to maintain the sample size at ~300. 2. Obtain longitudinal data from the ACS participants at 2 year intervals with the following measures: a. Clinical and cognitive assessments (Clinical Core) b. Amyloid imaging with PET PIB (Project 1) c. Assays of amyloid-beta (A¿), tau, phosphorylated tau181 (p- tau181), and novel analytes in CSF and blood (Project 2, supported by the Biomarker Core) d. Attentional control battery and task-related functional MRI (fMRI) (Project 3) e. Structural MRI, resting state functional connectivity MRI (fcMRI), diffusion tensor imaging (DTI), and cerebral blood flow using arterial spin labeling (ASL) (Project 4) 3. Analyze associations among rates of change of all disease markers from all Cores and Projects (Data Management and Biostatistics Core).

[unreadable] DESCRIPTION (provided by applicant): There is substantial evidence that Autosomal Dominant Alzheimer Disease (ADAD) is caused by over- production of A[unreadable]42 relative to A[unreadable]40, and shares a final common pathway with later onset Alzheimer Disease (AD). The pathophysiology of AD causing mutations can be directly measured in humans with CSF A[unreadable] metabolism studies. ADAD A[unreadable] metabolism results with other testing will allow for better understanding of the pathophysiology, A[unreadable] deposition (PET PIB), structural (MRI) and functional changes (clinical and neuropsychometrics) of the brain in ADAD. This information will likely lead to improved diagnostic testing and more precise pharmacodynamic testing of disease modifying treatments. Aims: 36 pre-symptomatic participants between the age of 21 and 74 will be recruited and undergo CSF A[unreadable] metabolism studies in addition to ACS PPG studies including PET/PIB (project 1), CSF biomarkers (project 2), attentional neuropsychometrics (project 3) and structural MRI (project 4). With these data we will achieve 3 specific aims. Aim 1: To determine A[unreadable]40, A[unreadable]42, and A[unreadable]Total production and clearance rates in ADAD mutation carriers versus controls. Direct measurement of the pathophysiological changes of A[unreadable] metabolism in humans in ADAD would provide a needed biological marker (biomarker) of a potential pathogenic cause of AD. A novel technique, developed at Washington University, allows for the direct measurement of production and clearance rates of A[unreadable] in humans(Bateman et al. 2006). Aim 2: To determine changes in absolute levels of A[unreadable] species in CSF and variability patterns in ADAD vs. controls. A[unreadable]42 is an important biomarker for AD and has been demonstrated to be sensitive and specific. A[unreadable] levels change significantly over hours in normal participants, but this normal pattern of variation may be disrupted in AD pathology. Aim 3: To determine changes in total levels biomarkers from initial CSF (A0, tau, and others), pathological deposition of A[unreadable] by PET PIB (pathology), structural changes on MRI (pathology), and neuropsychometric changes in ADAD versus controls. These ongoing studies of the ACS PPG will be performed with each participant, in addition to a clinical evaluation (CDR) to determine any clinically relevant cognitive changes. This study will measure cognitive, imaging, physiology, and bio-marker changes in people with a causative mutation that leads to Alzheimer disease. This information will provide important data to develop better tests for Alzheimer disease. It will also likely assist in developing new treatments for Alzheimer disease that may change the course of the disease. [unreadable] [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): Alzheimer's disease (AD) will become a public health crisis within the next 25 years if left unchecked. Despite the lack of proven treatments that delay the onset or prevent disease progression, several promising candidates are being developed. There is therefore an urgent need for antecedent biomarkers that will identify individuals with AD pathology but who are still cognitively normal ("preclinical AD"), a group in which targeted therapies would likely have the greatest clinical impact. Such biomarkers would also aid in assessing response to potential disease-modifying therapies in clinical trials and in practice. Our biomarkers program was developed and operates within the existing Alzheimer's Disease Research Center (ADRC) and two affiliated Program Project Grants ("The Adult Children Study" (ACS) and "Healthy Aging and Senile Dementia" (HASD)). While most of our scientific aims are being supported by these grants, our needs have grown well beyond the scope of the currently budgeted projects. As a supplement to the ACS, we propose to establish a Biomarkers Core that will provide the infrastructure for the standardized collection, storage, tracking and sharing of samples and the many biomarker data obtained from them. The specific aims of the Biomarkers Core are to: 1) establish a repository for fasted CSF and plasma samples for present and future AD biomarker studies; 2) obtain additional measures in CSF and/or plasma that are not currently obtained in the ACS or HASD that may help to define AD risk in middle-aged cohorts; 3) coordinate the distribution of CSF and plasma samples to qualified AD investigators; and 4) test and establish the measurement reliability of defined biomarkers and begin to explore possible biologic and methodologic sources of variability, important issues that have been inadequately addressed in the field to date. Data management and resource sharing functions will be implemented via a secure, web-based, relational database that is currently under final stages of development. A Biomarkers Core will facilitate research across the various projects of the ACS and HASD by greatly improving capacity and efficiency, as well as foster protocol standardization efforts and promote and facilitate collaborative research within the greater AD scientific community. Such collaborations are essential if the field is to move forward in discovering antecedent biomarkers, with the goal of bringing a truly useful biomarker(s) to the bedside. [unreadable] [unreadable] [unreadable]

Core A: Administration will serve as the Coordinating Center for the entire DIAN project. As such, the specific aims of Core A: Administration are as follows: 1. Organize and coordinate activities and communication of the Cores, subcontractors and clinical

Project 1 will test the hypothesis that poststroke dementia is a function of preclinical Alzheimer's disease (AD). The prediction from this hypothesis is that poststroke dementia will be disproportionately represented in stroke individuals with preclinical AD in comparison with stroke individuals without preclinical AD. The Specific Aims of the project are to: 1. Over 3.5 years, enroll a cohort of 240 older adults, age 65 years and older, hospitalized with acute ischemic stroke and obtain baseline demographic data, medical history, neurological status, neuropsychological evaluation, prestroke cognitive and functional status, and blood for Project 2 (plasma) and Project 4 (DMA). 2. In this hospitalized cohort, obtain magnetic resonance imaging (MRI) to characterize cerebral ischemic lesions and positron emission tomography (PET) with the [11C]benzothiazole amyloid tracer, Pittsburgh Compound B (PIB), to determine the presence or absence of preclinical AD (as defined by a positive PIB scan). 3. Every three months after discharge, maintain telephone contact with the patient and their families to monitor intercurrent events and maintain compliance. 4. One year poststroke, assess all patients with the Clinical Core clinical and neuropsychological batteries and derive a Clinical Dementia Rating (CDR) for correlation with baseline PIB status (CDR > 0.5 will be considered evidence for dementia). 5. Obtain MRI one year poststroke to evaluate potential new ischemic lesions;obtain blood for plasma biomarkers (Project 2);enroll patients into Project 3;and follow all patients annually with clinical and cognitive assessments and obtain voluntary consent for autopsy. This project directly addresses the overall aim of the program project grant, to characterize preclinical AD. It further addresses the unresolved issue of why dementia occurs in some, but not all, individuals with stroke. This project uses resources from all Cores. It also interacts with each of the individual projects

The Core supports the Adult Children Study Program Project Grant by recruiting, enrolling and longitudinally following adult children, age 45-74 years at entry, of parents with and without dementia of the Alzheimer type (DAT). ACS participants age 45-64 will have clinical and psychometric assessments at entry and every 2 years thereafter (annually for ACS participants >65y). The Core is essential in that it supplies carefully characterized participants to all relevant Cores and Projects. Core data are entered by Core personnel into the database maintained by the Data Management and Biostatistics Core (DMBC). The Clinical Core interacts directly or indirectly on a daily basis with virtually every facet of the ACS PPG. The functions of the Core are to: 1. Recruit, enroll, and maintain the ACS cohort to support the Projects in this application. In the first 2 years of the grant, the Core will enroll 60 ACS participants to compensate for attrition and to bring the total sample to ~300 participants equally distributed across 3 age ranges: 45-54 years, 55-64 years, and 65-74 years. The following 3 years the Clinical Core will recruit an estimated 5 participants annually to maintain the registry of ~300 active participants. 2. Comprehensively assess the ACS participants with well-established clinical and psychometric instruments at entry and every two years (annually for participants >65 years of age). 3. Obtain blood at the initial assessment from all participants for apolipoprotein E (apoE) genotyping and banking of extracted DNA and plasma (supported by the Genetics Core of the ADRC). 4. Coordinate the participation of ACS participants in the procedures of the Biomarker Core and all Projects: (Project 1 - The natural history of Ap accumulation in preclinical AD. Project 2 - CSF markers of antecedent AD; Project 3 - Behavioral and Neural Markers of Attentional Control; Antecedents of AD; Project 4 - Antecedent Neuroimaging Biomarkers.) 5. Integrate all core data with the DMBC, and interact cooperatively with all components of the PPG. 6. Encourage the retention of ACS participants by safeguarding their research data, monitoring the participants' burden as they complete the protocols of the Cores and Projects, annually sharing with them research results, and soliciting their input into the aims and operations of the ACS.

DESCRIPTION (provided by applicant): The Washington University Alzheimer's Disease Research Center (ADRC) initiates, fosters, and supports the performance of innovative, cutting-edge research on Alzheimer's disease (AD) and related topics with regard to the etiology, pathogenesis, diagnosis, treatment, and prevention of disease. We provide well-characterized research participants (persons with AD and age-matched controls), their clinical, psychometric, and imaging data, and their tissue (blood, DNA, CSF, autopsy material) to research projects. We also provide intellectual and financial support to scientists at Washington University, at other Alzheimer's Centers, and the research community nationally and internationally and engage in formal and informal collaborations, including multi-disciplinary/multi-Center studies and the initiatives sponsored by the National Institute on Aging, the National Alzheimer Coordinating Center, and the National Cell Repository for Alzheimer's Disease. Historically, our Center has focused on the earliest stages of dementia to identify the initial clinical and pathologic changes that distinguish AD from normal aging. Our approach is balanced between clinicopathologic and basic science domains with emphasis on interdisciplinary efforts. We will continue our training of students, fellows and junior faculty in clinical and basic science research skills. We will continue to engage in outreach activities to transfer information on AD to lay and professional audiences. We have a commitment to underserved populations that are the focus of our African American and Rural Satellites and will continue activities that promote the inclusion of these populations in research. This competing renewal application includes six cores: A: Administration, B: Clinical, C: Data Management and Statistics, D: Neuropathology, E: Education and F: Genetics. There are two satellites: African American (Core B: Clinical) and Rural (Core E: Education). The ADRC resources contained in these Cores and Satellites will promote and advance AD-related research as represented by the three projects in this application: Project 1. Novel protein biomarkers for Alzheimer's disease in cerebrospinal fluid; (Richard Perrin) 2. Changing tau protein levels and tau protein isoforms in mouse models of dementia; (Timothy Miller) 3. APOE metabolism in AD and controls; (Randall Bateman).

Project 1 aims to characterize the accumulation of fibrillar cerebral amyloid-beta (AP) over the age range from the time of onset of Ap deposits to the time when Ap levels approximate those of symptomatic Alzheimer's disease (AD). Project 1 proposes a longitudinal [^^C] PIB imaging study in the cohort of the Adult Children Study (ACS). PET PIB scans will be done on ail ACS participants every two years. The data to be obtained will greatly expand knowledge about preclinical AD and the clinical correlates of Ap accumulation. The long term objective of this effort is to obtain data that will facilitate and foster the design and conduct of clinical trials of anti-Ap therapies for the primary prevention of symptomatic AD. In particular, it aims to help determine the optimal time for intervention in such a trial. Specific Aims are: 1. Obtain longitudinal [C] PIB PET scans every 2 years in cognitively normal ACS participants to identify the conversion rate from no or minimal fibrillar Ajj deposition to appreciable AP accumulation, defined by mean cortical binding potential (MCBP) for PIB >0.18, and determine whether this rate is affected by age, APOE genotype, and parental history of AD. 2. Determine the rate and trajectory of change in Ap accumulation in ACS participants, both those with appreciable Ap deposits at their baseline [^^C] PIB PET scan and those lacking Ap deposits at baseline. 3. Examine associations and interactions of cognitive and brain reserve variables (e.g., normalized whole brain volume; regional atrophy; occupation; educational attainment) with longitudinal cognitive performance, obtained in the Clinical Core, in participants with and without Ap accumulation. 4. Correlate findings from Project 1 with appropriate data from Projects 2, 3, and 4 and utilize the Administration (e.g., budgetary oversight), Clinical (e.g., source of participants; longitudinal clinical and cognitive data), Biomarker (e.g., cerebrospinal fluid levels of AP42 in Project 1 participants imaged for Ap deposits), and Data Management and Biostatistics (e.g., data analyses) Cores of this program project grant.

Human CNS-Apolipoprotein E Isoform Production and Clearance A. Specific Aims: Alzheimer's disease (AD) is a common, devastating disease. 5 million Americans are suffering from AD, and it is currently estimated that by 2050 this number will triple. The only major and wellvalidated genetic risk factor for AD is one's Apolipoprotein E (ApoE) genotype. One ApoE4 allele increases the risk of developing AD by 3-fold, while two copies of ApoE4 increase this risk by 12-fold. A reduced risk for AD is associated with the ApoE2 allele. The metabolism and function of ApoE is partially understood in the periphery, however very little is known about ApoE in the central nervous system (CNS). Because ApoE plays such an important role in the CNS, and because its metabolism in the CNS is not well understood, we propose to determine the physiology and possible isoform pathophysiology as it relates to AD. Isoform dependent changes in ApoE metabolism and amount (and subsequently transport of AP) may underiie the increased risk of AD in humans. Hypothesis 1: ApoE4 amount is less in the brain and CSF vs. ApoE3. Hypothesis 2: ApoE4 clearance rate or turn-over rate if faster in the CNS compared to ApoE3. Specific Aim: Utilizing a recently developed mass spectrometry assay to measure ApoE isoforms independently, we will measure ApoE4 and ApoE3 in the human brain and CSF. In addition, the in vivo metabolism of human ApoE will be measured using stable isotope-labeling and mass spectrometry in 60 cognitively normal or dementia of the Alzheimer's type (DAT) participants with E2, E3 or E4 ApoE alleles. These participants will be recruited from the Washington University ADRC. B. Relevance to Alzheimer's Disease: ApoE is the strongest genetic risk factor for Alzheimer's disease, and is a potential target for disease-modifying therapies. Our data will provide an important link regarding how ApoE4 may be involved in the pathophysiology of Alzheimer's disease, and may lead to improved therapeutics, which target the major genetic risk factor of Alzheimer's disease, ApoE4.

The Administration Core acts to ensure that the research and programmatic goals of the Adult Children Study program project grant (ACS PPG) are met. The administrative leadership consists of the Director (Morris) and the Executive Director (Buckles). They are assisted by the Executive Committee that includes these individuals, leaders of Cores and Projects, and other senior faculty. The Administration Core supports, monitors, and coordinates the activities of all components of the ACS PPG. It will annually convene an External Advisory Committee to review activities and progress. The specific aims are to: 1. Coordinate and integrate the Cores and Projects and provide administrative and budgetary support and oversight, ensuring appropriate utilization of funds 2. Monitor the effectiveness of the PPG toward achieving the stated goals 3. Arrange for periodic external review and advice concerning PPG goals and progress 4. Coordinate and oversee data integration with Washington University Center for Biomedical Informatics to develop, maintain, and monitor an integrated database

DESCRIPTION (provided by applicant): This proposal will pursue in cognitively normal individuals from the Adult Children Study (ACS; POI AG026276) detailed, quantitative cross-sectional and longitudinal measurements of regional brain circulation, oxygen consumption and glucose use (total as well as the fraction devoted to aerobic glycolysis (AG; glucose use outside of oxidative phosphorylation)), and compare for the first time these more comprehensive measurements of brain circulation and metabolism with state-of-the-art biomarkers and clinical assessments in the same individuals. This work is motivated by our observation that while AG represents about 15% of the total glucose metabolized by the normal adult human brain it is strikingly nonuniform in its distribution being highest the brain's default mode network (DMN). The DMN is noteworthy from a disease perspective in that it represents a primary site of beta-amyloid (A¿) plaque accumulation in Alzheimer's disease (AD). This apparent association between AG and AD prompted us to explore further this relationship in transgenic mice where we found that AG (but not total glucose consumption) and AP vary together not only regionally but with changes in synaptic activity. Furthermore, reducing synaptic activity chronically not only reduces AG and A¿ levels but also retards plaque deposition. Here we propose measuring for the first time AG in individuals in whom A¿ plaque distribution will be assessed with [11C]PIB PET imaging along with other state-of-the-art biomarkers and clinical assessments. The overarching aim of this application is to substantially enhance our knowledge of the pathophysiology of preclinical AD and specifically to more fully characterize AG as a biomarker of synaptic activity, a potential aggravating factor in the development of AD pathology. We will determine the chronology (cross-sectionally and longitudinally) of changes in AG and its relationship to clinical assessments and other biomarkers of AD. This project will not only provide novel and important information about development of preclinical AD and its transition to clinical stages, but also may provide a useful marker of the efficacy of anti-Abeta treatments especially those designed to modify synaptic function.

Core A: Administration oversees the entire DIAN project: coordinating activities of the other Cores and subcontractors, managing and supporting the DIAN Steering Committee, interacting with the NIA?s scientific and administrative liaisons, and managing financial affairs overall and with individual clinical sites. It is led by John C. Morris, with the assistance of Drs. David Holtzman, Alison Goate, Randall Bateman, Virginia Buckles, and Krista Moulder. DIAN was designed to establish an international, multisite collaborative study using comprehensive, intensive, uniform, standardized protocols in a rare group of participants at risk for autosomal dominant Alzheimer?s disease (ADAD). Its protocols harmonize imaging and biomarker procedures with the Alzheimer?s Disease Neuroimaging Initiative (ADNI) and clinical and psychometric procedures with the National Alzheimer?s Coordinating Center (NACC) to make future comparisons with sporadic AD possible. To this end Core A: Administration will pursue the following aims: 1. Organize and coordinate activities and communication of the Cores, subcontractors and clinical performance sites toward achieving the stated goals of DIAN, to include administrative and budgetary support and monitoring, and problem solving on a continuous basis. 2. Organize and support the DIAN Steering Committee and the Resource Allocation Review Committee to include arranging meetings, communication and execution of their decisions and recommendations to DIAN components. With Core B: Clinical, organize/coordinate clinical training of personnel at new DIAN sites or new personnel at established DIAN sites. 3. Following Steering Committee direction, and with all DIAN Cores and the Alzheimer?s Disease Coordinating Study (ADCS), maintain and update protocols; coordinate and monitor participant recruitment and retention; oversee and monitor data and tissue collection and storage. 4. With the Steering Committee, establish policies/procedures regarding: protection of research participants; resource (data, images, tissue) sharing and dissemination; publications; future expansion of DIAN to include other sites and languages (including the accompanying agreements); and potential new research directions. 5. Arrange for annual external review and advice concerning DIAN goals and progress 6. Generate payments to clinical performance sites for DIAN evaluations; arrange and finance genetic counseling/testing services when desired, translate protocol-consents-testing materials, and participant travel. 7. Ensure smooth transition of the leadership of DIAN from Dr. Morris, current Principal Investigator, to Dr. Bateman, Current Leader of the Clinical Core. Dr. Bateman will assume the position of Principal Investigator of DIAN during year 2 of the next budget period and will relinquish his role as Clinical Core Leader; Dr. Morris will become Associate Director of DIAN and Clinical Core Leader.

Project 1 Project Summary/Abstract The memory and thinking changes characteristic of Alzheimer disease (AD) are now known to be preceded by over a decade of brain amyloid deposition in cognitively normal older adults. The overarching goal of this renewal application is to characterize the indicators of the transition from cognitive normality to the earliest stages of symptomatic AD. However, the substantial heterogeneity in the cognitive abilities of older adults can blur this threshold. To address this concern, Project 1 proposes to identify the cognitive indicators (collected through Core B: Clinical) of the transition and to substantiate these cognitive markers with resting state functional connectivity MRI (rs-fcMRI; collected through Core E: Imaging). We hypothesize that the irreversible transition from cognitive normality to symptomatic AD can be detected by impairment in attentional control, impaired learning on cognitive measures and disruption in resting state networks (RSNs). To test this hypothesis, we propose the following Specific Aims: 1) To evaluate sensitive measures of cognitive performance as indicators of preclinical AD and as predictors of the development of symptomatic AD. 2) To evaluate alterations in RSNs using rs-fcMRI as indicators of preclinical AD and as predictors of the development of symptomatic AD. 3) To examine the relationship between the cognitive performance measures in SA1 with the RSN alterations in SA2, both cross-sectionally and longitudinally on the rate of change. 4) To relate the cognitive and rs-fcMRI findings in Project 1 with findings from all other Projects and Cores to develop a model that optimally characterizes the transition from cognitive normality to symptomatic AD. In particular, Project 1 findings will be examined in relation to the sleep variables and cerebrospinal fluid measures obtained in Project 2, genetic variants of AD progression in Project 3, volumetric and amyloid imaging data in Core E: Imaging, [and the molecular pathology of AD and markers of synaptic integrity and neuronal number (particularly in the relevant brain regions such as the dorsal anterior cingulate) obtained in Core D: Neuropathology]. .

Core B: Clinical Project Summary/Abstract Core B evaluates and follows all participants entered into the studies of the program project. It uses an established clinical and psychometric protocol at entry and annually thereafter to obtain clinical, neurological, and behavioral data to carefully characterize each participant in support of each of the 3 Projects of this Program Project Grant (PPG). Specific Aims of Core B are: 1. Maintain the current active cohort (n=225) of participants, carefully characterized as to the presence or absence of symptomatic AD, to support longitudinal studies of the clinical, cognitive, behavioral and biomedical correlates of symptomatic Alzheimer's disease (AD) in comparison with normal aging, and to mark the transition of cognitively normal participants with preclinical AD to cognitive impairment. 2. Annually enroll and assess 35 new participants (CDR 0=23; CDR 0.5/AD =12) each year who are age e 65 to replenish the Core's cohort to maintain a sufficient sample size (n~250) to support the aims of the PPG and to supply study participants and their data (and DNA to Project 3) to individual Projects: 3. Follow all participants with annual assessments and provide diagnostic and clinical and cognitive data to all Cores and Projects, working closely with Core C: Biostatistics and Core A: Administration to coordinate data acquisition and management to integrate the Core's activities with the scientific goals of the Program Project. In addition to HASD's traditional diagnostic methods, in this application HASD participants will (in accordance with the criteria established by the Alzheimer Disease Neuroimaging Initiative-2) also be classified as significant memory concern, early and late mild cognitive impairment (MCI). 4. Support Core D: Neuropathology through our voluntary autopsy consent program. 5. Support Core E: Imaging and all Projects by referring: a. all HASD participants for MRI and PET amyloid imaging session at baseline and every 3 years thereafter; b. provide Project 1 (Indicators of transition to symptomatic AD) clinical characterizations and data from cognitive measures of all participants; c. refer to Project 2 (Sleep: potential prognostic and theranostic marker for preclinical AD) all participants for sleep and cerebrospinal fluid studies; d. Collect blood from all newly enrolled Core participants for Project 3 (Identification of genetic variants associated with the progression of AD) for their GWAS and variant characterization.

Core A: Administration Project Summary/Abstract The Administration Core acts to ensure that the research and programmatic goals of the Healthy Aging and Senile Dementia program project grant (HASD PPG) are met. The administrative leadership consists of the Director (Morris) and the Executive Director (Moulder). They are assisted by the Executive Committee that includes these individuals, leaders of Cores and Projects, and other senior faculty. The Administration Core supports, monitors, and coordinates the activities of all components of the HASD PPG. It will annually convene an External Advisory Committee to review activities and progress. The specific aims are to: 1) Coordinate and integrate all Cores and Projects and monitor the effectiveness of the PPG toward achieving the stated goals. 2) Provide administrative and budgetary support and oversight to the Cores and Projects, ensuring appropriate utilization of the funds in all PPG activities. 3) Arrange for periodic external review and advice regarding PPG goals and programs. 4) Provide oversight and administrative support for data integration with Core C: Biostatistics to maintain and monitor an integrated database for the PPG 5) Coordinate the collaborations between Core E: Imaging and Avid/Lilly regarding amyloid imaging with [18F]florbetapir 6) Facilitate inclusion of HASD participants and data in other national AD initiatives, including the Alzheimer's Disease Neuroimaging Initiative (ADNI), the Alzheimer's Disease Genetics Consortium (ADGC), trials orchestrated by the Alzheimer's Disease Cooperative Study (ADCS), and as acceptable, the National Alzheimer Coordinating Center (NACC).

Core B: Clinical Summary/Abstract Core B: Clinical recruits, assesses, and follows all participants in the ADRC Cohort. It uses well- established informant-based clinical and psychometric instruments (including the Uniform Data Set) at entry and annually thereafter to obtain clinical, cognitive, behavioral, and neurological data to carefully characterize each participant as to the presence or absence of dementia and, when present, its severity and etiology. The Core has successfully provided participants, tissue, and data to all requesting Cores and Projects since its inception in 1985 and will continue to do so in the next 5-year funding period. The Core's Specific Aims in the proposed funding period are: 1. Maintain the current active cohort of participants (current N=306), carefully characterized as to the presence or absence of symptomatic AD, to support longitudinal studies of the clinical, cognitive, and biomedical correlates of symptomatic AD in comparison with normal aging and to mark the transition of participants with preclinical AD to cognitive impairment. 2. Annually enroll and assess 20 new participants age 65Y or older, 10 CDR 0 and 10 with symptomatic AD at the CDR 0.5/1 stage, to replenish attritional losses and increase the cohort size to ~350 to meet the needs of the Projects and to ensure that participant burden is appropriately distributed 3. Provide clinical and cognitive data to all Cores and Projects, work closely with Data Management and Statistics and Administration Cores to coordinate data acquisition and management, and integrate Core activities with the scientific goals of the ADRC. 4. Collect biospecimens from participants (blood, CSF) as appropriate. 5. Refer all Core participants to HASD's Imaging Core for structural MRI, rs-fcMRI, and PET amyloid imaging with florbetapir at baseline and every 3 years thereafter. These imaging studies are funded at no cost to the ADRC by an executed contract with Avid Radiopharmaceuticals, a wholly owned subsidiary of Eli Lilly Company. 6. Support the Neuropathology Core through our voluntary brain autopsy consent program and obtain information about cognitive status at time of death to support clinicopathological correlations. 7. Support all proposed Projects in this application with clinically well-characterized participants and/or their data and biospecimens as follows: 8. Support the ADRC's contributions to national and international collaborative studies, including the National Alzheimer Coordinating Center, the Alzheimer's Disease Cooperative Study, ADNI, NCRAD, the Genetics Consortium for Late Onset Alzheimer's Disease, and the Alzheimer's Disease Genetics Consortium.

Elucidation of the decades? long period of time during which Alzheimer disease (AD) pathologies begin to develop prior to the appearance of cognitive symptoms (i.e., ?preclinical? AD) has been largely driven by the study of disease biomarkers. Such biomarkers are now being used to more precisely define various stages within this preclinical period in order to better understand the pathologic processes taking place during this early stage and to better inform the design and interpretation of prevention trials aimed at identifying diseasemodifying therapies that have the best chance of preserving normal cognitive function. Data from ACS Project 2 contributed to the finding that preclinical AD (defined by CSF biomarkers) in older individuals (? 65 yrs) increases the risk for developing symptomatic AD in a stage-dependent manner. In addition, changes in amyloid-related markers (Aß42) over time were observed in early middle-aged participants (45-64 yrs), whereas changes in tau and ptau181 were observed in those in mid middle-age (55-64 yrs) and coincided with initial declines in cognition. As the current ACS cohort is aging, we are now poised to evaluate biomarker trajectories in individuals as they progress from being biomarker-negative to biomarker-positive (preclinical AD) to cognitively impaired (symptomatic AD). The proposed experiments are designed to evaluate the utility of CSF markers for identifying those individuals with preclinical AD who are in the transition period from cognitive normality to impairment. Novel markers of synaptic dysfunction will be evaluated in addition to the traditional markers of core AD pathologies. CSF tau and ptau181 will be compared with tau PET imaging to validate their utility as presumed markers of neurofibrillary tangles. Finally, in an exploratory aim, we will utilize the innovative method of Stable Isotope Labeling Kinetics (SILK) pioneered by Dr. Randall Bateman to evaluate the potential of a plasma (and CSF) Aß kinetic measure as an indicator of brain amyloid pathology. Aim 1. Continue to measure CSF concentrations of Aß40, Aß42, tau, ptau181, YKL-40, and VILIP-1, as well as novel markers of synaptic dysfunction, Neurogranin and SNAP-25. Aim 2. In longitudinal analyses, assess the annual rate of change in CSF biomarker concentrations as a function of AD risk (age, family history, APOE?4 status) and their relationships with baseline and future rates of change in other CSF markers. Aim 3. Correlate fluid biomarker measures (and rate of change over time) with clinical and psychometric performance (Clinical Core), novel tau imaging as assessed by T807 PET (Project 1), attentional control measures (Project 3), and structural neuroimaging (via MRI) and amyloid PET (via florbetapir) (Project 4). Aim 4. Evaluate the utility of Aß isotope kinetics (using stable isotope labeling kinetics methods [SILK]) in CSF and plasma as indicators of the presence/absence of brain amyloid.

The Adult Children Study (ACS) is an ongoing evaluation of middle to older adults at risk for development of Alzheimer disease (AD). In Project 4 of the ACS, we use a combination of advanced imaging techniques to explore the earliest signs of AD pathology. Using positron emission tomography (PET) we test for amyloid protein deposits in the brain, which can be present up to 20 years before dementia symptoms are present. We will do this using florbetapir F18, which is a test for amyloid which has approval by the Federal Food and Drug Administration (FDA). Using magnetic resonance imaging (MRI) we evaluate the functional changes in the brain associated with the transition from the asymptomatic (preclinical) stages of AD into the symptomatic stage of AD dementia. We also use MRI to evaluate the brain?s structure, looking at grey matter atrophy with volumetric MRI, and investigate the changes in white matter using a new technique, diffusion basis spectrum imaging (DBSI). In collaboration with Project 4, in Aim 1, we will generate unique brain maps for each imaging test, in each stage of AD, as people move from an asymptomatic state into AD dementia. In Aim 2, we will then examine these maps in relation to one another, to develop an integrated timeline for the imaging changes which occur during the transition from asymptomatic and symptomatic AD. We will then use these maps as a way to predict the stage of the disease in specific individuals ? in other words, to predict how long it would be before someone developed dementia. This mapping and predictive information is critical for the development of new drugs for AD and for the appropriate design of clinical trials in the future.

Project 1 explores the transition from asymptomatic, preclinical Alzheimer disease (AD) to symptomatic AD by incorporating the novel tau imaging tracer, T807 F18 (AV1451), into the biomarker-rich protocol of the Adult Children Study (ACS) to identify the temporal onset of neocortical involvement by tau and to quantify tau density and distribution. Project 1 findings will be correlated with other indicators of preclinical AD obtained in all Projects and relevant Cores of this application as described in the Specific Aims below. 1. Assess cerebral tau distribution and burden in the ACS, at baseline and longitudinally every three years thereafter, with T807 positron emission tomography (PET) imaging. a. Compare tau burden cross-sectionally in cognitively normal participants and those with symptomatic AD. b. Correlate cerebrospinal fluid (CSF) tau and p-tau181 (Biomarker Core, Project 2) with T807 to test the hypothesis: tauopathy-related neural injury predicts the transition from preclinical to symptomatic AD. c. Similarly, correlate the spatial distribution of tauopathy to test the hypothesis: the spread of tauopathy from the transentorhinal region to the neocortex predicts the transition from preclinical to symptomatic AD. 2. Correlate cross-sectional and longitudinal T807 imaging: a. With amyloid PET imaging (Project 4) to test the hypothesis that cerebral amyloidosis and tauopathy each are necessary to predict the transition to symptomatic AD. b. With CSF concentrations of tau, p-tau181, VILIP-1, SNAP-25, and Neurogranin (Biomarker Core, Project 2), as markers of synaptic and neural injury, and with CSF A?42 and YKL-40. c. With imaging measures of hippocampal atrophy, reduced cortical thickness, and disrupted resting state networks (Project 4) as markers of neural injury 3. Identify inflection points (changepoints) on composite measures of episodic memory (Clinical Core), attentional control (Project 3), and global cognitive performance (Clinical Core) that indicate the cognitive decline heralding the onset of symptomatic AD.

The Data Management and Biostatistics Core (DMBC) will serve as a resource and collaborator for all Projects and Cores related to this Program Project. The Core will consult on the design of all Projects and in the application of appropriate statistical and methodological techniques, and lead and collaborate in data analysis and report preparation for all Cores and Projects, especially in the analysis of associations among longitudinal growth/decline patterns of all disease markers across the individual Projects. The significance of the DMBC is to enhance and support the research objectives of the Adult Children Study (ACS) by providing timely data management and appropriate analytic expertise to all the Cores and Projects.

Data from fluid biomarker studies have been critical for defining Alzheimer disease (AD) as a continuum, with pathology developing decades prior to the onset of cognitive symptoms which eventually progress to dementia at the end stage of the disease. This concept is impacting disease nomenclature, diagnostic criteria, prognostic potential, and clinical trial design. Revisions in diagnostic criteria to incorporate biomarker results have recently been proposed in order to increase the confidence of AD as the underlying etiology of a clinical impairment and to permit a diagnosis of AD across the disease continuum, eventually perhaps in the asymptomatic period. Individuals in this ?preclinical? stage are receiving intense focus as a targeted population for secondary prevention trials aimed at identifying disease-modifying therapies that have the best chance of preserving normal cognitive function. The ACS Biomarker Core (Core C) implements well-established and efficient workflows and standard operating procedures for the standardized collection, storage, tracking and sharing of fasted CSF and plasma samples and associated data. Data from samples obtained to date have identified biomarker abnormalities that characterize preclinical AD and have shed preliminary light on the rates of change of these biomarkers in relation to their clinical consequences (i.e., progression from cognitive normality to abnormality). Having already obtained CSF and plasma samples (>600 each) from 337 unique ACS participants (longitudinal samples from 187) who are largely middle-aged, through continued collection of samples (and providing them to Project 2 and other qualified investigators), we will be able to assess whether the biomarker changes initially observed during middle-age are predictive of greater rates of change at older ages and ultimately cognitive decline and progression to dementia. Furthermore, as one of the leading groups in fluid biomarker discovery and world-wide standardization efforts, we will continue to participate in ongoing and future collaborative (and internal) projects involving the performance of current and future biomarker candidates and their assays. Aim 1. Continue to maintain and grow a biorepository of fasted CSF and plasma for present and future studies of aging and AD. Aim 2. Coordinate the distribution of CSF and plasma samples to qualified investigators. Aim 3. Participate in studies regarding fluid biomarker assay development/validation and protocol quality control and standardization efforts.

Core B: Clinical supports the Adult Children Study Program Project Grant by recruiting, enrolling and longitudinally following adult children, age 45-74 years at entry, of parents with and without symptomatic Alzheimer disease. ACS participants age 45-64y will have clinical and psychometric assessments at entry and every 3 years thereafter (annually for ACS participants ?65y). The Core is essential in that it supplies carefully characterized participants to all relevant Cores and Projects. The Clinical Core interacts directly or indirectly on a daily basis with virtually every facet of the ACS PPG. The functions of the Core are to: 1. Recruit, enroll, and maintain the ACS cohort at ~300 active participants to support the Projects in this application. Twenty-five new participants <65y will be enrolled each year to replenish the younger groups due to aging into the ?65y group. 2. Comprehensively assess the ACS participants with well-established clinical and psychometric instruments at entry and every three years (annually for participants ?65 years of age). 3. Obtain blood at the initial assessment from all participants for apolipoprotein E (APOE) genotyping and banking of extracted DNA and plasma (supported by the Knight ADRC Genetics Core). 4. Coordinate the participation of ACS participants in the procedures of the Biomarker Core and all Projects: Project 1 ? Preclinical Predictors of Progression from Cognitive Normality to Impairment Project 2 ? CSF Biomarkers of AD Progression Project 3 ? Attentional Control, Sleep, and Memory Consolidation: The Role of AD Biomarkers Project 4 ? Dynamic Ordering of Imaging Biomarkers in Preclinical AD 5. Integrate all Core data with the DMBC, and interact cooperatively with all components of the PPG. 6. Encourage the retention of ACS participants by safeguarding their research data, monitoring the participants? burden as they complete the protocols of the Cores and Projects, annually sharing with them research results, and soliciting their input into the aims and operations of the ACS.

? DESCRIPTION (provided by applicant): In the current budget period, the Adult Children Study (ACS) transitioned from cross-sectional to longitudinal analyses, many of which are ongoing. With this application, the ACS now incorporates new biomarkers to address the overarching hypothesis that disrupted neural integrity is the proximate cause of the transition from preclinica to symptomatic Alzheimer disease (AD). Two corollary hypotheses will be addressed: 1) cerebral amyloidosis and tauopathy individually are necessary but insufficient to cause the transition from cognitive normality to impairment; and 2) the spread of tauopathy from the medial temporal lobe to the neocortex is the tau imaging correlate of the transition from preclinical to symptomatic AD. Predicting individual-level development of symptomatic AD will be enormously important for the field and may accelerate secondary prevention trials of anti-AD therapies by permitting the enrollment of only cognitively normal individuals who have near certainty of progressing to symptomatic AD. The ACS investigators and its cohort are uniquely qualified to accomplish the following Specific Aims: 1. Recruit, enroll, and maintain the ACS cohort (N?300) 2. At entry and every 3 years thereafter comprehensively assess all participants with: 1) well-established clinical and cognitive instruments (annually for participants >65 years); 2) blood for genotyping for apolipoprotein E and other susceptibility genetic variants; 3) PET scans with amyloid and tau tracers (florbetapir and T807); 4) lumbar puncture (LP) for the collection of CSF; 5) an attentional battery; and 6) structural and functional MRI. 3. In ACS participants who transition from cognitive normality to impairment, correlate phenoconversion with: a. The regional distribution and density of tau retention (Project 1) b. CSF markers of neural (tau, p-tau181) and synaptic (SNAP-25, neurogranin) injury (Project 2) c. Longitudinal rates of change on measures of global cognition and episodic memory (Clinical Core, Project 1) and attentional control (Project 3), cross sectional event-related fMRI as a function of AD markers, and the relation among A?42, sleep, and memory consolidation mechanisms (Project 3) d. The regional distribution and density of amyloid retention, and changes in brain structure and function (hippocampal volume, cortical thickness, functional connectivity) (Project 4) e. CSF concentrations of A?42, and also novel analytes (YKL-40, VILIP 1) (Project 2) 4. Analyze associations among rates of change of all AD markers from all Cores and Projects (Data Management and Biostatistics Core).

This Adult Children Study (ACS) Program Project Grant (PPG) renewal application represents the logical evolution of our longstanding research interests in the interrelationships and predictive value of clinical, cognitive, imaging, and fluid biomarker correlates of Alzheimer disease (AD) by now exploring the transition from cognitive normality to symptomatic AD. The Administration Core acts to ensure that the research and programmatic goals of the ACS PPG are met. The administrative leadership consists of the Director (Morris) and the Executive Director (Moulder). The Administration Core supports, monitors, and coordinates the activities of all components of the ACS PPG. It will annually convene an External Advisory Committee to review activities and progress. The specific aims are to: 1. Coordinate and integrate the Cores and Projects and provide administrative and budgetary support and oversight, ensuring appropriate utilization of funds. 2. Monitor the effectiveness of the ACS PPG toward achieving its stated goals. 3. Arrange for periodic external review and advice concerning ACS PPG goals and progress. 4. Coordinate and oversee data integration with Core D: Data Management and Biostatistics and the Washington University Center for Biomedical Informatics to maintain and monitor an integrated database. 5. Facilitate the Preclinical AD Consortium efforts to harmonize data among key studies of preclinical AD.

Project Summary/Abstract Although 16% of the United States population self-identifies as African American (AA), AAs comprise fewer than 6% of research volunteers in studies of Alzheimer disease and related dementias (ADRD). The under-representation by AAs and members of other minorities in research programs that focus on ADRD seriously comprises the ability to fully understand the inherent heterogeneity of these disorders. Moreover, this under-representation obviates the opportunity to assess whether or not diagnostic algorithms and therapeutic and prevention strategies developed from studies of overwhelmingly non-Hispanic white cohorts are equally relevant for diverse populations. The network of Alzheimer Disuse Centers (ADCs), funded by the National Institute on Aging (NIA), has yet to systematically address how to successfully recruit and retain research volunteers from under-represented groups in studies of ADRD. This Project proposes that all 31 ADCs participate in a Workshop that is dedicated to developing, and then testing, effective strategies to improve the recruitment, retention, and participation of AAs in ADRD research. The Workshop will be held in October, 2018, at Washington University School of Medicine and hosted by the School's Knight Alzheimer Disease Research Center (ADRC), one of the 31 ADCs. [Note: The Workshop specifically addresses AA participation as AAs are twice as likely to develop Alzheimer disease dementia as non-Hispanic whites, but the strategies that are developed in this Workshop are expected also to be relevant for other under-represented groups.] The Workshop is designed to encourage the participation of all ADCs and also other stakeholders in ADRD research, including the Alzheimer's Association (both the national office and the Greater Missouri Chapter in St. Louis), the national organization AfricanAmericansAgainstAlzheimersDisease, and the NIA. Community engagement will be integral to the Workshop deliberations and output, and St. Louis community groups (including the African American Advisory Board of the Knight ADRC, the St. Louis Chapter of Links, Inc., and the St. Louis Clergy Coalition) and officials from relevant Washington University programs (including the Office of Diversity and Inclusion, the Center for Community Health Partnerships and Research, and the Health Communication Research Laboratory) will be active participants. The scientific program of the Workshop will feature ten national leaders in minority recruitment; 6 of the speakers are women and 5 are AA. The ?best practices? developed and evaluated by the Workshop will be disseminated to the ADC network and the scientific community at large to enable improved AA participation in ADRC research.

Core B: Clinical PROJECT SUMMARY The Dominantly Inherited Alzheimer Network (DIAN), Core B: Clinical is responsible for the protocol implementation of all clinical operations for the research studies, including participant recruitment, retention, and protection, performing clinical evaluations including CDR and psychometric testing, completing imaging, blood and CSF collections, and offering genetic counseling and testing. The study of longitudinal progression of dominantly inherited Alzheimer disease will likely lead to a better understanding of the causes of Alzheimer disease. DIAN studies inform about potential methods of detecting AD and the sequence of events at the earliest stages of the illness, even before clinical symptoms have begun. The DIAN-Observational study will continue to support and enable preventative treatments to be tested. The Clinical Core will obtain highly sensitive clinical evaluations to determine the earliest symptoms and progression rates. A remote assessment platform will be added to aid in the study of lifestyle factors as contributors to disease heterogeneity. The longitudinal study of cognitive and clinical measures will be analyzed by estimated years to symptomatic onset and followed longitudinally to estimate progression and rates of change. The data generated from these studies will be used by DIAN investigators to advance the understanding of the causes of Alzheimer disease, methods of early detection, and support ongoing and future preventative treatments.

Core A: Administration Project Summary The Administration Core acts to ensure that the research and programmatic goals of the Healthy Aging and Senile Dementia Program Project grant (HASD PPG) are met. The administrative leadership consists of the Director (Morris), Associate Director (Holtzman), and Executive Director (Moulder). They are assisted by the Leadership Committee that includes these individuals, leaders of Cores and Projects, and other senior faculty. The Administration Core supports, monitors, and coordinates the activities of all components of the HASD PPG. It will annually convene an External Advisory Committee to review activities and progress. The specific aims are to: 1) Coordinate and integrate all Cores and Projects and monitor the effectiveness of the PPG toward achieving the stated goals. 2) Provide administrative and budgetary support and oversight to the Cores and Projects, ensuring appropriate utilization of the funds in all PPG activities. 3) Arrange for periodic external review and advice regarding PPG goals and programs. 4) Provide oversight and administrative support for data integration with Core C: Biostatistics to maintain and monitor an integrated database for the PPG. 5) Facilitate inclusion of HASD participants and data in other local (AD research at Washington University) and national AD initiatives, including the Alzheimer's Disease Neuroimaging Initiative (ADNI), the Alzheimer's Disease Genetics Consortium (ADGC), the National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site (NIAGADS), trials orchestrated by the Alzheimer's Therapeutic Research Institute (ATRI) and the new Alzheimer Clinical Trials Consortium (ACTC), and the National Alzheimer Coordinating Center (NACC).

Project 1 Project Summary Almost all studies of Alzheimer disease (AD) investigating ?molecular biomarkers? that reflect the brain lesions of the disorder are conducted in research volunteers who overwhelmingly are of the non-Hispanic white race. Project 1 of the Healthy Aging and Senile Dementia (HASD) Program Project Grant will use the molecular biomarkers of AD to predict which cognitively normal older adults will develop its symptoms (i.e., dementia). However, Project 1 also will examine potential racial differences in these molecular biomarkers between African Americans and non-Hispanic whites. To accomplish its Aims, Project 1 will interact closely with other components of HASD to innovatively increase the number of African American research volunteers who participate in molecular biomarker procedures, including positron emission tomography (PET) imaging studies and lumbar puncture to obtain cerebrospinal fluid (CSF) for analysis. The Specific Aims of Project 1 are to: 1. Compare molecular biomarkers of AD (i.e., amyloid PET, tau PET, and CSF measures of amyloid- beta42 and tau) at baseline and longitudinally in African Americans and non-Hispanic whites. 2. Compare in African Americans and non-Hispanic whites the rates of conversion from cognitively normal to symptomatic AD. 3. Correlate the results from Specific Aims 1 and 2 with other variables obtained in HASD: clinical information (including the presence of comorbid disorders, such as cerebrovascular disease, and socioeconomic status), cognitive measures, indicators of sleep disruption, genetic variants for risk and protection, imaging measures (including magnetic resonance imaging and PET studies of the brain), and CSF analytes. 4. Increase the number of brain autopsies in African Americans to compare the neuropathological features of AD, including the presence of comorbid diseases, with non-Hispanic whites.

Overall: Project Summary/Abstract ?Antecedent Biomarkers for Alzheimer Disease: The Adult Children Study? (ACS) will determine when during the lifespan molecular markers of Alzheimer disease (AD) appear in the brain of cognitively normal, largely middle-age individuals and also will characterize the course of preclinical AD. With maturation of the original ACS cohort, we now will identify the factors that mediate the transition from preclinical AD to symptomatic AD (the latter term in this application is used to encompass both mild cognitive impairment due to AD and AD dementia). This renewal application examines the hypothesis that disrupted neural integrity predicts the transition from preclinical to symptomatic AD and thus proposes four Cores (Administration, Clinical, Fluid Biomarker, and Data Management and Biostatistics) to support four Projects: Project 1 (JC Morris and T Benzinger, Co-Project Leaders), ?Tau burden and spatial spread in preclinical Alzheimer disease?; Project 2 (AM Fagan, PL), ?Plasma and cerebrospinal fluid (CSF) biomarkers that predict risk for symptomatic Alzheimer disease?; Project 3 (B Ances, PL), ?Alzheimer disease progression, host gut microbiome, and enteric dysfunction?; and Project 4 (D Head, PL), ?Mechanisms and moderators of the effects of physical activity in preclinical AD?. Although these Cores and Projects each address unique Specific Aims, they will generate a wealth of cross-sectional and longitudinal data from ACS participants to permit a cohesive and comprehensive examination of the overarching Aims of this renewal application. Hence, the ACS as a whole is far greater than the sum of its Cores and Projects.

Project 1: Project Summary/Abstract The Adult Children Study (ACS) is an ongoing evaluation of middle to older adults at risk for development of Alzheimer disease (AD). In Project 1 of the ACS, we use a combination of advanced imaging techniques to explore the earliest signs of AD pathology. Using positron emission tomography (PET) we test for amyloid and tau protein deposits in the brain, using Pittsburgh Compound B C11 (PiB) and Flortaucipir F18 (FTP) and we examine brain structural networks, pathology and physiology using magnetic resonance imaging (MRI). While amyloid deposits can be present up to 20 years before dementia symptoms, tau deposits are closely linked with cognitive decline. We will evaluate the structural and functional changes in the brain associated with the transition from the asymptomatic (preclinical) phase of AD into the symptomatic stages of AD dementia. We will generate unique brain maps for each imaging modality and we will then examine these maps in relation to one another, to develop an integrated understanding of the imaging changes which occur during the transition from asymptomatic and symptomatic AD. We will combine this information with information about lifestyle, exercise, diet, inflammation, and blood and cerebrospinal fluid (CSF) tests obtained in the other ACS Cores and Projects in order to better understand what factors lead to AD dementia.