The biological and clinical significance of amyloid ?-protein (A?) deposition in clinically normal older individuals remains to be elucidated. Consistent with prior autopsy studies, we and others have found that a substantial proportion (over 30%) of cognitively intact individuals over age 65 harbor significant amyloid pathology, detectable with PiB-PET imaging, in a similar pattern to that seen in Alzheimer's disease (AD). Our preliminary data indicate that the presence of amyloid is associated with subtle functional, structural and cognitive alterations, even among individuals who are considered clinically normal on screening tests. We seek to determine if asymptomatic older individuals with high amyloid burden are on a trajectory towards clinical AD, as this will open a critical time window for maximally effective therapeutic intervention. Furthermore, we believe that previous studies of "normal" cognitive aging have likely included many individuals in very early stages of prodromal AD, and that it is important to characterize age-related changes in cognition, brain structure and function in the absence of amyloid pathology. The Harvard Amyloid and Aging Brain PPG will study 300 clinically normal older individuals with a novel combination of molecular, functional, and structural imaging, plasma and CSF markers, and sensitive neuropsychological measures, to: 1) characterize brain and cognitive aging in the presence vs. absence of amyloid and 2) investigate the role of amyloid pathology in the transition from normal aging to prodromal AD. We propose four highly integrated projects, supported by four essential cores. Project 1 will examine executive function in aging, using sensitive imaging measures to assess the integrity of fronto-parietal networks and white matter tracts. Project 2 will investigate the impact of amyloid on memory networks, using functional MRI and challenging tests of episodic memory. Project 3 will characterize plasma and CSF markers of A? and tau, using novel assays to detect soluble A? oligomers and quantify their effects on synaptic structure and function with advanced electrophysiological and anatomical methods. Project 4 will investigate longitudinal accumulation of amyloid and its relationship to well-established imaging markers of AD, including FDG-PET and volumetric MRI, and to functional and cognitive decline. This PPG brings together an exceptional multidisciplinary team of clinical, statistical, cognitive neuroscience, imaging, and laboratory investigators dedicated to exploring the impact of amyloid on the aging brain.

Public Health Relevance

This Program Project will improve our understanding of the aging brain and determine the role of brain amyloid, one of the key brain lesions seen in Alzheimer's disease, in predicting cognitive decline among clinically normal older individuals. We hope to detect the earliest brain changes associated with Alzheimer's disease, even before there is significant cognitive impairment, as this is likely to be the point when treatment would likely be most effective in slowing cognitive decline and preventing dementia. REVIEW OF INDIVIDUAL COMPONENTS OF THE PROGRAM PROJECT CORE A: ADMINISTRATIVE CORE;Dr. Reisa Sperling, Core Leader (CL) DESCRIPTION (provided by applicant): The Administrative Core will provide the leadership, coordination, and administrative oversight to achieve the programmatic goals of the Harvard Amyloid and Aging Brain Program Project Grant (PPG). The Administrative Core will strive to ensure optimal integration among the four Cores and the four Research Projects of the PPG to achieve maximal scientific productivity. The Administrative Core consists of the Principal Investigator (Sperling), Co-investigator (Rentz) and Program Administrator (Houghton), and will work closely with the co-PIs of the PPG (Buckner and Johnson) to enhance the coordination among all components of the PPG. The Administrative Core will provide administrative and scientific oversight of the PPG (Aim 1), and will coordinate monthly meetings of the Executive Committee, and yearly meetings of the external Scientific Advisory Committee (to be named at the time of grant funding). The Administrative Core will facilitate the efficient communication and integration between all components of the PPG, provide oversight of timely data transfer from all Cores and Projects to Core D: Analytic Core to achieve maximal scientific productivity, and track all scientific publications (Aim 2). The Administrative Core will prepare NIH progress reports, interface with Core B: Clinical to prepare IRB documentation and annual continuing review, and with Core C: Imaging Core to prepare annual reports to the MGH Radioactive Drug Research Committee (Aim 3). The Administrative Core will oversee all aspects of the PPG finances to assure fiscal responsibility (Aim 4). The Administrative Core will prepare all budgets, and interface with the MGH Research Administration to monitor all financial and regulatory aspects of the PPG. The Administrative Core will also serve to facilitate coordination with the Massachusetts Alzheimer's Disease Research Center (MADRC), the Martinos Center for Biomedical Imaging at MGH, and other local resources available to the PPG at Harvard. The Administrative Core will oversee an outstanding multidisciplinary group of investigators with a strong record of collaboration and scientific productivity, and a common interest in elucidating the role of amyloid in the transition from normal aging to prodromal AD.

National Institute of Health (NIH)
Research Program Projects (P01)
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Special Emphasis Panel (ZAG1)
Program Officer
Hsiao, John
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Massachusetts General Hospital
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Ward, Andrew M; Mormino, Elizabeth C; Huijbers, Willem et al. (2015) Relationships between default-mode network connectivity, medial temporal lobe structure, and age-related memory deficits. Neurobiol Aging 36:265-72
Hong, Soyon; Ostaszewski, Beth L; Yang, Ting et al. (2014) Soluble A? oligomers are rapidly sequestered from brain ISF in vivo and bind GM1 ganglioside on cellular membranes. Neuron 82:308-19
Mormino, Elizabeth C (2014) The relevance of beta-amyloid on markers of Alzheimer's disease in clinically normal individuals and factors that influence these associations. Neuropsychol Rev 24:300-12
Sperling, Reisa; Mormino, Elizabeth; Johnson, Keith (2014) The evolution of preclinical Alzheimer's disease: implications for prevention trials. Neuron 84:608-22
Papp, Kathryn V; Amariglio, Rebecca E; Dekhtyar, Maria et al. (2014) Development of a psychometrically equivalent short form of the Face-Name Associative Memory Exam for use along the early Alzheimer's disease trajectory. Clin Neuropsychol 28:771-85
Schultz, Aaron P; Chhatwal, Jasmeer P; Huijbers, Willem et al. (2014) Template based rotation: a method for functional connectivity analysis with a priori templates. Neuroimage 102 Pt 2:620-36
Mormino, Elizabeth C; Betensky, Rebecca A; Hedden, Trey et al. (2014) Amyloid and APOE ?4 interact to influence short-term decline in preclinical Alzheimer disease. Neurology 82:1760-7
Huijbers, Willem; Mormino, Elizabeth C; Wigman, Sarah E et al. (2014) Amyloid deposition is linked to aberrant entorhinal activity among cognitively normal older adults. J Neurosci 34:5200-10
Mormino, Elizabeth C; Betensky, Rebecca A; Hedden, Trey et al. (2014) Synergistic effect of ?-amyloid and neurodegeneration on cognitive decline in clinically normal individuals. JAMA Neurol 71:1379-85
Muratore, Christina R; Rice, Heather C; Srikanth, Priya et al. (2014) The familial Alzheimer's disease APPV717I mutation alters APP processing and Tau expression in iPSC-derived neurons. Hum Mol Genet 23:3523-36

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