Jeffrey L. Cummings, MD,University of Washington 1974 - US grants

The prevalence of Alzheimer's disease (AD) is rising at an alarming rate. California, with its large population and disproportionate number of elderly, is especially impacted by this disorder; there are an estimated 180,000 dementia patients, many of whom suffer from AD, in Los Angeles County alone. It is imperative that the scientific community respond to this public health challenge by developing improved means of treatment and management and generating strategies that will lead to cure and prevention of AD. Establishment of an Alzheimer's Disease Center (ADC) at UCLA will allow improved support of on-going AD-related projects, increased focusing of the considerable technological resources and faculty expertise on AD- related problems, and recruitment and support of new investigators with AD- related talents. We propose an ADC with five cores - Clinical, Neuroimaging, Neuropathology, Education/Information Transfer, and Administrative. A Data Management and Communications Unit will provide data management, data linking, image analysis capabilities, quality assurance, and statistical services as well as sophisticated electronic inter-site communication and information exchange. There will be three primary clinical sites - UCLA Medical Center, Harbor-UCLA Medical Center, and the West LA Veterans Affairs Medical Center (WLA VAMC). Patient access from Harbor-UCLA and WLA VAMC will maximize the ethnic and socioeconomic diversity of the ADC patient population. The unique strengths of the proposed ADC are: 1) presence of an extensive array of imaging techniques relevant to the study of AD, 2) availability of advanced neuropathological techniques that can routinely be applied to AD autopsies, 3) sophisticated data management techniques allowing linking of diverse types of information, 4) provision of access of an ethnically diverse population, 5) assessment of both the neuropsychiatric and the neuropsychological dimension of AD, 6) routine evaluation of the emotional state of caregivers of AD patients, and 7) extension of dementia research training to a variety of existing Fellowships and educational programs. Pilot studies will investigate a potential in vitro model of AD, study of the role of nerve growth factor in determining regional cellular vulnerability in AD, and determine the utility of magnetic resonance spectroscopy in the diagnosis and differential diagnosis of AD. An outstanding group of external and internal advisors have been assembled to guide the growth of the UCLA ADC.

The specific aims of the Los Angeles Area Alzheimer Outreach Program (LAAAOP) are to: 1) improve primary-care physician knowledge regarding the diagnosis and management of Alzheimer's disease (AD) by providing a comprehensive practice-integrated continuing medical education (CME) curriculum on AD and through periodic mailings of instructional materials; 2) improve the access of AD patients from minority populations to qualified physicians; and 3) enhance the participation of minority members in AD research projects of the Alzheimer's Disease Research Center (ADRC) Consortium of Los Angeles and Orange Counties and the UCLA Alzheimer's Disease Core Center (ADCC). The LAAAOP is a unique educational venture featuring the collaboration of two AD Centers and two chapters of the Alzheimer's Association (Los Angeles and Orange Counties). Physicians named through patient care networks as well as physicians identified through focused mailing lists will comprise the audience for educational outreach efforts. The practice-based curriculum involves reading a syllabus, learning to administer a neurobehavioral examination, submitting the evaluation of four dementia patients to an expert panel for review, and providing a report of the impact of the course on one's practice. Graduates of the course will be added to the Alzheimer's Association help line referral network and will receive 50 hours of CME credit. The course is available in English and Spanish. Educational mailings to physicians will be made every two months and will include an instructional module with questions that can be answered and returned for CME credit. Audiotaped versions of the modules will also be available. The Mini-Mental State Examination (MMSE) will be taught as a means of improving practice. Information will be obtained on the ethnicity, gender, age, type of practice, and use of the MMSE by the physicians on the mailing list. Monitoring the number of information requests, accuracy of CME responses, and alterations in the frequency of use of the MMSE will provide a quantitative means of assessing the impact of the module program. Los Angeles offers a unique opportunity to assess various methods of disseminating information to the physician community.

The specific aims of the Los Angeles Area Alzheimer Outreach Program (LAAAOP) are to: 1) improve primary-care physician knowledge regarding the diagnosis and management of Alzheimer's disease (AD) by providing a comprehensive practice-integrated continuing medical education (CME) curriculum on AD and through periodic mailings of instructional materials; 2) improve the access of AD patients from minority populations to qualified physicians; and 3) enhance the participation of minority members in AD research projects of the Alzheimer's Disease Research Center (ADRC) Consortium of Los Angeles and Orange Counties and the UCLA Alzheimer's Disease Core Center (ADCC). The LAAAOP is a unique educational venture featuring the collaboration of two AD Centers and two chapters of the Alzheimer's Association (Los Angeles and Orange Counties). Physicians named through patient care networks as well as physicians identified through focused mailing lists will comprise the audience for educational outreach efforts. The practice-based curriculum involves reading a syllabus, learning to administer a neurobehavioral examination, submitting the evaluation of four dementia patients to an expert panel for review, and providing a report of the impact of the course on one's practice. Graduates of the course will be added to the Alzheimer's Association help line referral network and will receive 50 hours of CME credit. The course is available in English and Spanish. Educational mailings to physicians will be made every two months and will include an instructional module with questions that can be answered and returned for CME credit. Audiotaped versions of the modules will also be available. The Mini-Mental State Examination (MMSE) will be taught as a means of improving practice. Information will be obtained on the ethnicity, gender, age, type of practice, and use of the MMSE by the physicians on the mailing list. Monitoring the number of information requests, accuracy of CME responses, and alterations in the frequency of use of the MMSE will provide a quantitative means of assessing the impact of the module program. Los Angeles offers a unique opportunity to assess various methods of disseminating information to the physician community.

The Los Angeles Area Alzheimer's Outreach Program (LAAAOP) was funded by the National Institute on Aging in 1992 to provide education to community based physicians regarding the diagnosis and treatment of dementia. The program has been successful in disseminating educational information in the form of instructional modules sent to 10(x) physicians every two months, and in enrolling physicians in our comprehensive practice- integrated CME course. The program has focused on those physicians serving minority patients. The current specific aims of the LAAAOP are to I) expand upon our established physician outreach training program by enrolling nurse practitioners (NPs) and physician assistants (PAs) in our comprehensive practice integrated continuing medical education (CME) curriculum on AD; 2) to expand our educational outreach to NPs, PAs, and visiting home nurses (VHNs) via dissemination of periodic mailings of instructional materials on a variety of topics related to dementia; and 3) increase the ethnic diversity of patients referred to the research programs of the Alzheimer's Disease Research Center (ADRC) Consortium of Los Angeles and Orange Counties and the UCLA Alzheimer's Disease Core Center (ADCC). The LAAAOP represents a successful 3 year collaboration of two NIA funded Alzheimer's Disease Centers and the Los Angeles Chapter of the Alzheimer's Association. Primary care providers identified through focused mailing lists and patient care networks will comprise the audience for the educational outreach. The practice-integrated curriculum involves reading a syllabus, learning to administer a brief neuropsychological screening exam, submitting an evaluation of four patients to an expert panel for review and providing a report of the impact of the course on one's practice. Graduates of the course will be added to the Alzheimer's Association Helpline referral network, and will receive 30 hours of CME credit. The course is available in English and Spanish. Educational mailings to primary care providers will be made every two months and will include an instructional module with questions that can be answered for CME credit. Audiotaped versions of the modules will also be available. The Mini-Mental State Examination (MMSE) will be taught as a means of improving practice. Information will be obtained on the ethnicity, gender, age, type of practice, and use of the MMSE by primary care providers on the mailing list. Monitoring the number of information requests, accuracy of CME responses, and alterations in the frequency of use of the MMSE will provide a quantitative means of assessing the impact of the module program.

Specific Aims 1. To determine the value of structural and functional neuroimaging for the diagnosis of Alzheimer's disease (AD) and other non-AD dementias. 2. To correlate the clinical, imaging and neuropathologic diagnosis in AD patients

Although neurochemical deficits in Alzheimer's disease (AD) are varied and complex, the earliest, most marked, and consistent neurochemical changes result from the degeneration of the basal forebrain cholinergic neurons which project to the hippocampus and cortex. Degeneration of these asceding pathways results in deficits in presynaptic cholinergic markers in cortex and hippocampus.

This application proposes the establishment of an Alzheimer's Disease Research Center (ADRC) at UCLA. The theme of the ADRC is "understanding the mechanisms and optimizing the treatment of Alzheimer's disease". An ADRC would add a basic science dimension to established activities of the current UCLA Alzheimer's Disease Core Center (ADCC), use tissues and antibodies from the ADCC Neuropathology Core, and facilitate an invigorating interchange between clinical scientists and the growing cadre of basic scientists at UCLA. The ADCC has accomplished its original goals and established a flow of well characterized patients that are being followed longitudinally (Clinical Core); accessioned 148 brains into the ADCC brain bank (Neuropathology Core); created an imaging archive with sophisticated image analysis techniques available to investigators (Imaging Subcore of Imaging and Genetics Core); developed mechanisms for routine genotyping and established a DNA bank for genetic investigations (Genetics Subcore of Imaging and Genetics Core); and engaged ore than 3600 clinicians in education programs (Education/Information Transfer Core). The ADCC database contains information on 1261 patients and control, in the past year we have achieved an annualized follow-up rate of 90%. In the past five years, we have awarded funding for 12 Pilot Projects; these projects have contributed to 10 funded grants and 22 publications. The ADCC has three clinical sites, each serving a different ethnic population: UCLA (primarily majority culture patients), Martin Luther King Medical Center/Drew Medical School (primarily an African-American population), and Olive View Medical Center (an Hispanic population). UCLA investigators using data from the Cores have advanced understanding of frontotemporal dementias, dementia with Lewy bodies, behavioral aspects of AD, the role of vascular disease in AD and vascular dementia, and the role of imaging and genetics in the diagnosis and characterization of AD. ADCC investigators published 375 articles and 338 abstracts on dementia-related topics between 1993 and 1997. Three basic science projects are being proposed: 1) apolipoprotein influences on amyloid deposition (Greg Cole, Ph.D.), 2) amyloid deposition, toxicity, and inflammation in an amyloid infusion model of AD (Sally Frautschy Ph.D.) and intracellular amyloid signaling (Istvan Mody, Ph.D.). The activities of the Cores will be continued an expanded in the ADRC and the Project Leaders will be integrated into all aspects of the ADRC.

The purpose of this study is to determine the effectiveness and safety of melatonin administration in decreasing nosturnal activity and improving sleep in patients with AD and frequent nosturnal awakening.

The primary objective of the metrifonate investigational trial is to evalutate the tolerability and efficacy of metrifonate when used to treat patients with mild to moderately severe dementia of the Alzheimer's type over a 12 week period. This study is designed to measure the effect of metrifonate on these patterns.

DESCRIPTION (provided by applicant) Dementia is becoming increasingly common in underdeveloped societies. Methods for detecting, diagnosing, and treating dementia appropriate for application in developing economies is critically important to avoid the emergence of health disparities in care of dementia patients. The Dementia and Disability in Thai Elderly Project (DDP) unites the expertise of the UCLA Alzheimer's Disease Center and the Neurodegenerative Disease and Behavioral Neurology Section of the Division of Neurology of Mahidol University to respond to a newly instituted public health mandate (the Rehabilitation and Disabled Persons Act, BE2534) requiring that each university or medical center take responsibility for the care of patients in their assigned catchment areas in Bangkok. This research will be done primarily in Thailand at Mahidol University in collaboration with Vorapun Senanarong, M.D. as an extension of NIH grant #P50 AG16570. The methodology proposed in the DDP has been accepted by the individual responsible for the Mahidol catchment area, Professor Udom Kachitorn, as the means of detecting and characterizing dementia and disability in Thai elderly. Two thousand-six hundred fifty Thai elderly live in the catchment area and will be screened over a 6-month period in temples, schools, and elderly clubs. We anticipate the identification of 130 individuals with dementia and 450 individuals with cognitive impairment with no dementia (CIND). These patients will be assessed to determine the cause of the dementia and cognitive impairment. These patients plus 100 non-demented, non-disabled controls will be reassessed 1 year later. We hypothesize that the Thai Activities of Daily Living scale will detect disability in 40% of Thai elderly; dementia will be present in 5% of Thai elderly; Alzheimer's disease will account for 60% of the dementia detected in Thai elderly; CIND will be present in 17% of Thai elderly, the 1-year incidence of dementia will be present in those with CIND at baseline; patients with dementia at baseline will exhibit a cognitive decline of 4 Thai Mental Status Examination points per year; and disability will be highly correlated with cognitive deterioration. The phases of the study (training, screening, assessment, and follow-up) will be completed over a 3-year period. Our program is ambitious and substantial cost sharing will be undertaken by Mahidol University. The outcomes of this study are critically important for public health planning of the needs of disabled and cognitively impaired urban Thai elderly. The DDP will serve as a model for the implementation for disability and dementia screening in other catchment areas of Bangkok. The major foreign collaborators and the principal investigator of the UCLA Alzheimer's Disease Center have successfully collaborated on several past projects and have published several manuscripts together.

simvastatin; neuropathology; amyloidosis; antihypercholesterolemic agent; brain disorder chemotherapy; drug screening /evaluation; human therapy evaluation; Alzheimer's disease; cognition; amyloid proteins; cholesterol; patient oriented research; human subject; clinical research;

human therapy evaluation; male; drug screening /evaluation; hormone therapy; brain disorder chemotherapy; testosterone; human old age (65+); Alzheimer's disease; patient oriented research; human subject; clinical research;

DESCRIPTION (provided by applicant): The theme of the UCLA Alzheimer's Disease Research Center (ADRC) is "understanding the mechanisms and optimizing the treatment of Alzheimer's disease." In this competitive renewal proposal, we describe the six Cores of the Center and the three Projects that will achieve our specific aims of developing an interdisciplinary research environment devoted to advancing the neuroscience of AD; enhancing research through Cores that support multiple Projects and investigators; creating an informatics infrastructure with a new Data Management and Statistics Core (DMSC); establishing Projects that address key areas of AD research; providing an environment that stimulates trainees and junior faculty; collaborating with other agencies involved in AD-related research; insuring that advances and understanding of treating of AD are exported to the community through the Education/Information Transfer Core (E/ITC); and extending research opportunities to women and minorities. The five Cores include Clinical, DMSC, Neuropathology and Molecular Genetics (NPMG), E/ITC, and Imaging. The three Projects will address dynamic changes in imaging as a biological marker for AD (Project 1), antioxidants in transgenic mouse models of AD (Project 2), and use of a tau transgenic Drosophila model as a bioassay for tau active compounds (Project 3). This proposal is responsive to the Request for Applications in emphasizing recruitment and characterization of patients with mild cognitive impairment (MCI), cognitive impairment not demented (CIND), and non-AD dementias including frontotemporal dementia (FTD) and dementia with Lewy bodies (DLB). The ADRC has been productive in its past funded period. ADRC-related faculty have published 17 books and 362 papers relevant to AD. 598 patients were assessed in the period between 1999-2002. 36% of patients are members of ethnic minorities. Over 157 Projects have been supported by UCLA Cores, 188 trainees and faculty have been included in rater training sessions, and 3,144 professionals have been included in educational events. 397 minority members have been included in research Projects.

chemoprevention; tocopherols; human therapy evaluation; cognition disorders; pathologic process; piperidine; vitamin therapy; medical complication; Alzheimer's disease; longitudinal human study; drug screening /evaluation; clinical trials; drug administration rate /duration; patient oriented research; human subject; clinical research;

comorbidity; human therapy evaluation; antipsychotic agents; psychosis; anxiety; Parkinson's disease; piperidine; combination chemotherapy; Alzheimer's disease; dementia; brain disorder chemotherapy; drug screening /evaluation; Lewy body; neural degeneration; patient oriented research; clinical research; human subject;

neuroanatomy; nervous system disorder diagnosis; Alzheimer's disease; biomedical resource; clinical research;

brain morphology; cognition disorders; hippocampus; biomedical resource; clinical research;

experimental designs; data collection methodology /evaluation; disease /disorder prevention /control; diagnosis design /evaluation; questionnaires; brain disorder diagnosis; Alzheimer's disease; memory disorders; cognition disorders; aging; clinical research; human subject;

Alzheimer; Alzheimer disease; Alzheimer sclerosis; Alzheimer syndrome; Alzheimer's; Alzheimer's Disease; Alzheimers Dementia; Alzheimers disease; Amentia; Archives; CRISP; California; Care Givers; Caregivers; Clinical Research; Clinical Study; Code; Coding System; Computer Retrieval of Information on Scientific Projects Database; Data; Data Banks; Data Bases; Data Set; Databank, Electronic; Databanks; Database, Electronic; Databases; Dataset; Dementia; Dementia, Alzheimer Type; Dementia, Primary Senile Degenerative; Dementia, Senile; Disease; Disorder; Ethics Committees, Research; Funding; Grant; IRBs; Individual; Institution; Institutional Review Boards; Investigators; Memory; Memory Loss; NIH; National Institutes of Health; National Institutes of Health (U.S.); Primary Senile Degenerative Dementia; Process; Protocol; Protocols documentation; Research; Research Ethics Committees; Research Personnel; Research Resources; Researchers; Resources; Site; Source; United States National Institutes of Health; clinical data repository; clinical data warehouse; data repository; dementia of the Alzheimer type; disease/disorder; primary degenerative dementia; relational database; senile dementia of the Alzheimer type; volunteer

PROJECT SUMMARY/ABSTRACT The Administrative Core (AC) of the proposed COBRE Center for Neurodegeneration and Translational Neuroscience (CNTN) will advance the goals of the CNTN to establish a multidisciplinary sustainable research environment, advance junior investigators by preparing them for independent research careers, and improve understanding of Alzheimer's disease and Parkinson's disease. The CNTN is based on a coalition between the Cleveland Clinic Lou Ruvo Center for Brain Health (LRCBH) in Las Vegas, NV and the University of Nevada Las Vegas (UNLV). Both institutions are making substantial commitments to this enterprise including recruiting an imaging specialist to the LRCBH and establishing an Institute for Quantitative Health Sciences at UNLV, which will make statistical expertise available to the CNTN. The AC provides the vision and leadership, oversees daily activities, insures the interaction of cores and projects, facilitates the development of junior faculty, follows expenditures and budgetary commitments, organizes the meetings of the Internal and External Advisory Committees as well as the Steering Committee, documents that all reporting requirements are met, and follows the summative and formative assessments to insure that the goals of the CNTN and the junior investigators are being achieved. The CNTN will be led by Dr. Jeffrey Cummings, an experienced investigator with over 20 years of continuous P50 funding while at UCLA, prior to becoming director of the LRCBH and the proposed CNTN. The AC will oversee the cores (total 3) and projects (total 3) of the CNTN and will facilitate the formative and summative assessments that provide the metrics of the center and the junior investigators. The AC has a well-planned mentoring program for all junior investigators including a local scientific mentor and a specialist scientific mentor. The AC will provide an annual research training course taught by faculty members of the LRCBH and UNLV, and will inaugurate outreach activities to inform the academic community of the availability of CNTN resources. The AC will plan the transition of the CNTN to independent and sustainable funding through Phase II COBRE to other grant mechanisms.

? DESCRIPTION (provided by applicant): The COBRE Center for Neurodegeneration and Translational Neuroscience (CNTN) is proposed by a coalition of Cleveland Clinic Lou Ruvo Center for Brain Health (LRCBH) in Las Vegas, NV and the University of Nevada Las Vegas (UNLV) to: 1) establish an independent and sustainable infrastructure for translational research that will create a rich and unique scientific environment; 2) provide a transformative research training experience for 3 junior investigators/Project Leaders working in the area of neurodegenerative disorders (NDD); and 3) advance understanding of Alzheimer's disease (AD) and Parkinson's disease (PD), the two most common NDD. The CNTN will consist of 3 cores and 3 projects plus internal and external advisory committees. The Administrative Core will lead the vision, administrative oversight, budgetary and reporting aspects of the center, and will support the formative and summative assessment processes. The Data Management and Statistics Core will provide the technical hardware and software for data management for all aspects of the CNTN as well as providing expert statistical input on project design, analysis and interpretation. The Clinical and Translational Research Core will establish a well-characterized cohort of healthy controls (HC) and patients with AD or PD for Projects 1 and 2 as well as other junior investigators attracted to the CNTN. Project 1 will investigate the resting state default mode network with functional Magnetic Resonance Imaging (fMRI) in patients with mild cognitive impairment (MCI), mild-moderate AD, and HC. Project 1 will also use a novel positron emission tomography ligand to investigate microglial activity in AD, PD, and HC. Project 2 will use fMRI and diffusion tensor imaging to study the biological underpinnings of cognitive impairment in PD. Project 3 investigates the role of GABA receptors in the control of microglial activity in animal models of AD. A multifaceted mentoring program provides both local scientific mentors and specialist scientific mentors to all junior investigators. COBRE funds complemented by institutional commitment from LRCBH will be used to hire an imaging expert who will serve as mentor for Projects 1 and 2 as well as strengthening the research environment.

? DESCRIPTION (provided by applicant): Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease characterized by a distinct deposition of an abnormal form of the tau protein in a pattern that is unique from other diseases, including Alzheimer's disease (AD). CTE has been found most often in professional contact sport athletes (e.g., boxing, football) who have been subjected to repetitive blows to the head resulting in concussive and subconcussive trauma. Neuropathologically-confirmed CTE has been reported in individuals as young as 17 and in athletes who only played sports through high school or college. It also has been found in non-athletes who experienced repetitive head impacts, including epileptics, victims of physical abuse, and military service members. In contrast to what may be inferred by the extensive media attention on CTE, the science of CTE remains in its infancy; critical questions remain, such as whether or not it is a common disease. Although the neuropathological features of CTE have become further clarified in recent years, the clinical presentation of CTE is still not well characterized, even though there have been case reports in the literature of dementia pugilistica in boxers since the early 1900's. Clinical diagnostic criteria have only recently been published and lack validation. Neuroimaging and fluid biomarkers developed for the diagnosis of other neurodegenerative diseases have only been used in preliminary studies. There is thus an urgent need to develop accurate methods for detecting and diagnosing CTE during life so that effective interventions for prevention and treatment can be developed. Moreover, though a history of repetitive head impacts is a necessary risk factor for CTE, it alone is not sufficient. There is a need to understand what specific aspects of the head impact exposure places an individual at increased risk for CTE and to examine potential genetic modifiers of that risk. To address these needs, we propose a multidisciplinary, multicenter, longitudinal study of former athletes with high exposure to repetitive head impacts (120 former NFL players with and without symptoms) or medium exposure to repetitive head impact (60 former college football players with and without symptoms) and a control group of 60 asymptomatic same-age men without any history of repetitive head impact exposure or traumatic brain injury. The aims of our proposal are: (1) to collect and analyze neuroimaging and fluid biomarkers for the detection of CTE during life, including the use of a novel PET tracer to measure the amount of abnormal brain tau; (2) to characterize the clinical presentation of CTE; (3) to examine the progression of CTE over a three year period; (4) to refine and validate diagnostic criteria for the clinical diagnosisof CTE; (5) to investigate genetic and head impact exposure risk factors for CTE; and (6) to share project data with researchers across the country and abroad in order to expedite growth in our understanding and treatment of this disease.

Global Alzheimer's Platform Trial-Ready Cohort for Preclinical/Prodromal Alzheimer's Disease (GAP TRC-PAD) Academic PIs: Paul Aisen, Reisa Sperling, Jeff Cummings SUMMARY Based on growing recognition that the long pre-dementia stages of Alzheimer's disease (AD) represent the optimal time for interventions aimed at modifying the neurobiology of the disease, most recent drug development programs enroll participants at the preclinical/asymptomatic and prodromal/mild cognitive impairment stages. However, the timeframe, complexity and expense of the recruitment process and site activation for these secondary prevention trials are extremely challenging, and indeed site start-up and trial enrollment, in general, represent the greatest bottleneck for drug development for AD. Thus, there is growing consensus in our field that we must fundamentally overhaul the current clinical trial recruitment and assessment process for these early intervention trials. The overarching goal of this proposal is to accelerate current and future secondary prevention trial enrollment through an innovative, highly efficient approach to identify, evaluate, and enroll appropriate preclinical and prodromal trial candidates, supported by a new site network with enhanced capacities for more efficient and effective conduct of AD clinical trials. It is our view that this can be accomplished only through a public-private partnership, the GAP Partnership, between this project and the GAP Foundation. Beginning in early 2014, the Global Alzheimer Platform (GAP) brought together academic, industry, advocacy and other Alzheimer's leaders to identify the necessary components to build large ?trial-ready cohorts? (TRC) for preclinical/prodromal AD (PAD) trials (TRC-PAD) and to support a network (GAP-Net) of pre-qualified ?trial-ready sites? with specific expertise in and uniform processes for the clinical and biomarker assessments required for prevention trials. The specific goal of the current project is to build a large TRC-PAD (n=2000; 1000 preclinical/1000 prodromal AD), to facilitate enrollment into ongoing PAD trials using the GAP-Net framework. This application describes a process of connecting existing ?feeder? registries and studies to a GAP Registry to capture demographic, genetic and longitudinal clinical and cognitive information on older, non-demented individuals interested in trials. The Registry data generates risk scores for AD pathology (initially elevated amyloid in brain, but with methods adaptable to tau pathology and other biomarkers), that allows efficient selection of candidates for in-person biomarker (initially amyloid PET scans) and clinical assessment. The results of these assessments, in turn, allow an adaptive statistical algorithm to improve the selection process moving forward. Individuals with PET scans showing amyloid accumulation in brain (or alternative biomarker confirmation) are invited to join the GAP Cohort, with semi-annual in-person follow-up within the GAP-Net network of pre-qualified clinical sites, from which they can be invited to enroll in early stage trials. Overall, the process will dramatically shorten the timeline for preclinical/prodromal trials, and will address a series of scientific hypotheses to guide further development in the field.

Project Summary Based on growing recognition that the long pre-dementia stages of Alzheimer's disease (AD) represent the optimal time for interventions aimed at modifying the neurobiology of the disease, most recent drug development programs enroll participants at the preclinical/asymptomatic and prodromal/mild cognitive impairment stages. However, the timeframe, complexity and expense of the recruitment process and site activation for these secondary prevention trials are extremely challenging, and indeed site start-up and trial enrollment, in general, represent the greatest bottleneck for drug development for AD. Thus, there is growing consensus in our field that we must fundamentally overhaul the current clinical trial recruitment and assessment process for these early intervention trials. The overarching goal of this proposal is to accelerate current and future secondary prevention trial enrollment through an innovative, highly efficient approach to identify, evaluate, and enroll appropriate preclinical and prodromal trial candidates, supported by a new site network with enhanced capacities for more efficient and effective conduct of AD clinical trials. The specific goal of the current project is to build a large trial- ready cohort (TRC) for preclinical/prodromal AD (PAD) trials (TRC-PAD). TRC-PAD (n=2000; 1000 preclinical/1000 prodromal AD) will facilitate enrollment into ongoing PAD trials using the ACTC framework. This application describes a process of connecting existing ?feeder? registries and studies to a web based Registry to capture demographic, genetic and longitudinal clinical and cognitive information on older, non-demented individuals interested in trials. The Registry data generates risk scores for AD pathology (initially elevated amyloid in brain, but with methods adaptable to tau pathology and other biomarkers), that allows efficient selection of candidates for in-person biomarker (initially amyloid PET scans) and clinical assessment. The results of these assessments, in turn, allow an adaptive statistical algorithm to improve the selection process moving forward. Individuals with PET scans showing amyloid accumulation in brain (or alternative biomarker confirmation) are invited to join with semi-annual in-person follow-up within the network of pre-qualified clinical sites, from which they can be invited to enroll in early stage trials. Overall, the process will dramatically shorten the timeline for preclinical/prodromal trials, and will address a series of scientific hypotheses to guide further development in the field.

Abstract The National Institute on Aging Alzheimer's Disease and Related Dementias Research Implementation Milestones articulate the goals of the Institute for advancing Alzheimer's disease (AD) research. The Leadership Award for AD and Related Disorders requires that the applicant address objectives of the Milestones and provide mentorship to new and early stage investigators. The research proposed must be groundbreaking and paradigm changing. Among the eight focus areas within the Implementation Milestones' framework are Trial Innovation and Translation and Clinical Research ? Pharmacological. The Alzheimer's Clinical Trial InnOvationN (ACTION) Initiative proposed here embraces both the research and mentoring aspects of the Leadership Award. The ACTION Initiative will include development of a Clinical Trials Observatory (CTO) and an embedded mentorship program. The CTO builds on the principal investigator's prior analyses of clinicaltrials.gov. This federal registry contains all trials conducted in the US and many trials conducted ex-US. It includes Phase 1, 2 and 3 clinical trials of preclinical, prodromal, and AD dementia trials. The PI has conducted and published research on the trial design, biomarker, and clinical outcomes data from the registry. In 2016, Congress passed a law requiring that trial outcomes be posted on the site within 1 year of completion of the trial. The PI proposes to build a multi-disciplinary team of engineers, computer scientists, statisticians, and bioinformatic experts to interrogate the range of data now available using artificial intelligence techniques including machine learning and deep learning. An external advisory committee will ensure quality and dissemination. The Alzheimer's Association will collaborate on results dissemination. An accessible web portal for the database will make reviewed data readily available for analyses and prediction/modeling of planned clinical trials. The growing database of real-world AD trial data will allow increasingly precise prediction of trial outcomes based on complex relationships among baseline features, trajectories of decline, drug mechanisms, and clinical and biomarker characteristics across all stages of AD. The data will be used by the PI, mentees, academic trial leaders, and industry trial sponsors. Three initial mentees are identified from neuropsychology, psychiatry, and engineering; more will be added with growth of the program. The ACTION Initiative has the potential to transform clinical trial planning and outcomes, leading to substantial impact on the Implementation Milestones of the NIA and accelerating development of new therapies for patients with AD and those at risk. Mentees will power the future of AD drug development and clinical trial planning.