The Harvard Aging Brain Study (HABS) PPG was launched just over five years ago with the goal of elucidating the biological and clinical significance of amyloid ?-protein (A?) accumulation in clinically normal (CN) older humans. We have accomplished a great deal over the current funding cycle, including the successful recruitment of more than 300 older individuals (ages 60-90) who are diverse in ethnicity and socioeconomic status. We have published over 70 manuscripts, and contributed to international guidelines and prevention trial design. We have found consistent evidence that the nearly 1/3 of older CN with elevated A?, detectable on PiB-PET imaging, also demonstrate evidence of impaired synaptic function and neurodegeneration, as well as subtle but detectable changes in cognition. However, our findings thus far support the hypothesis that A? accumulation is necessary but not sufficient to predict imminent cognitive impairment. Thus it is imperative that we find additional markers to accurately predict cognitive decline along the Alzheimer's disease (AD) trajectory. Neuropathologic studies have long suggested that the other hallmark pathology of AD - neurofibrillary tangles (NFTs) and other tau aggregates (referred to as Tau) - correlate more strongly with synaptic and neuronal loss, and the cognitive symptoms of AD. Remarkable recent advances in PET imaging now allow us to image Tau pathology in vivo. Our preliminary Tau PET data using 18F-T807 suggest this new technology will prove extremely valuable in our quest to elucidate the link between A?, Tau, and cognitive decline. Our preliminary T807 data confirm previous autopsy reports that MTL Tau accumulation is very common after age 60, but it remains unknown how this pathology contributes to age-related memory change, with or without A?. Based on our preliminary work, we postulate that A? accelerates the spread of Tau both within and beyond the MTL, disrupting function and initiating neurodegeneration in distributed brain networks, resulting in cognitive decline. To investigate this further, we propose 4 integrated Projects, supported by 4 Cores. Project 1: Investigate the relationship of PET A? and Tau measures to glucose metabolism, synaptic dysfunction, and cortical thinning. Project 2: Investigate the neuropathologic correlates of T807, and neuronal, glial and synaptic alterations associated with Tau in brain specimens from cohorts similar to the HABS population. Project 3: Implement advanced MRI techniques to detect A?- and Tau-related alterations in intrinsic brain networks at the individual subject level. Project 4: Detect early alterations in cognitive function through novel iPad tests and task-fMRI, and investigate the interactions between A? and Tau in the prediction of longitudinal cognitive decline. This PPG renewal will leverage an outstanding group of multidisciplinary investigators, access to cutting-edge imaging and laboratory technology, and an extremely well-characterized cohort with longitudinal multi-modality imaging and sensitive cognitive assessments to determine the factors that best predict resilience vs. progression along the trajectory of preclinical AD.

Public Health Relevance

The Harvard Aging Brain Study Program Project Grant seeks to understand the earliest brain changes that will predict whether an older individual will develop memory loss and eventual cognitive decline associated with Alzheimer's disease or whether they will demonstrate resilient brain aging. Our study utilizes special imaging tests to detect evidence of the abnormal accumulation of proteins associated with Alzheimer's disease, such as amyloid plaques and tau tangles, in the brains of older people who do not yet show any symptoms of the disease. Our study has tremendous potential public health impact; if we can accurately identify people at high risk for cognitive decline, we can begin treatments aimed at these early brain changes and perhaps ultimately prevent Alzheimer's disease dementia.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program Projects (P01)
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Special Emphasis Panel (ZAG1)
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Hsiao, John
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Massachusetts General Hospital
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Schultz, Aaron P; Chhatwal, Jasmeer P; Hedden, Trey et al. (2017) Phases of Hyperconnectivity and Hypoconnectivity in the Default Mode and Salience Networks Track with Amyloid and Tau in Clinically Normal Individuals. J Neurosci 37:4323-4331
Buckley, R F; Sparks, K P; Papp, K V et al. (2017) Computerized Cognitive Testing for Use in Clinical Trials: A Comparison of the NIH Toolbox and Cogstate C3 Batteries. J Prev Alzheimers Dis 4:3-11
Buckley, Rachel F; Hanseeuw, Bernard; Schultz, Aaron P et al. (2017) Region-Specific Association of Subjective Cognitive Decline With Tauopathy Independent of Global ?-Amyloid Burden. JAMA Neurol 74:1455-1463
Buckley, Rachel F; Schultz, Aaron P; Hedden, Trey et al. (2017) Functional network integrity presages cognitive decline in preclinical Alzheimer disease. Neurology 89:29-37
Sepulcre, Jorge; Grothe, Michel J; Sabuncu, Mert et al. (2017) Hierarchical Organization of Tau and Amyloid Deposits in the Cerebral Cortex. JAMA Neurol 74:813-820
Marquié, Marta; Siao Tick Chong, Michael; Antón-Fernández, Alejandro et al. (2017) [F-18]-AV-1451 binding correlates with postmortem neurofibrillary tangle Braak staging. Acta Neuropathol 134:619-628
Wooten, Dustin W; Guehl, Nicolas J; Verwer, Eline E et al. (2017) Pharmacokinetic Evaluation of the Tau PET Radiotracer (18)F-T807 ((18)F-AV-1451) in Human Subjects. J Nucl Med 58:484-491
Hsu, David; Marshall, Gad A (2017) Primary and Secondary Prevention Trials in Alzheimer Disease: Looking Back, Moving Forward. Curr Alzheimer Res 14:426-440
Vannini, Patrizia; Hanseeuw, Bernard; Munro, Catherine E et al. (2017) Hippocampal hypometabolism in older adults with memory complaints and increased amyloid burden. Neurology 88:1759-1767
Hanseeuw, Bernard J; Betensky, Rebecca A; Schultz, Aaron P et al. (2017) Fluorodeoxyglucose metabolism associated with tau-amyloid interaction predicts memory decline. Ann Neurol 81:583-596

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