The Role of Dopamine in Cognitive Resilience to Alzheimer's Disease Pathology in Healthy Older Adults

PROJECT SUMMARY Alzheimer’s disease (AD) is characterized by β-amyloid and tau neuropathology, which are linked to disruptions in memory performance. Advances in human neuroimaging approaches that quantify pathology in vivo have revealed a promising target for AD therapeutics known as cognitive reserve, which is the capacity for some individuals to have better-than-expected cognition given their level of pathology. Our proposed research examines the role of brain dopamine in maintaining optimal cognitive function and youth-like patterns of brain activity despite pathology. Successful maintenance of dopamine function in aging may protect against pathology- related alterations in cognition as dopamine inputs directly into the hippocampus and supports optimal memory performance. The functional impact of hippocampal AD-related pathology can be assessed in humans using emerging fMRI analysis methods that measure local functional connectivity (i.e. regional homogeneity). This is a sensitive predictor of memory performance and pathology burden in rodent models and humans and is gaining traction as a functional neuroimaging biomarker. Local functional connectivity is also affected by neuromodulator systems like dopamine, which may support compensatory changes in aging and could have applications for AD. The extent to which AD-related pathology accumulation in aging interacts with dopamine neuromodulator functions to affect local functional connectivity and memory is not known. The proposed research will fill this gap by assessing, within an older adult sample, relationships among memory, positron emission tomography (PET) measured AD-related pathology (tau) and dopamine synthesis capacity, and local functional connectivity in AD-vulnerable regions. Connectivity will be measured with resting-state fMRI, and memory will be measured with standard neuropsychological assessment. The proposed research will examine interactions between dopamine synthesis capacity and tau pathology to test the hypothesis that elevated dopamine synthesis capacity counteracts effects of pathology on memory and local functional connectivity, thus representing a cognitive reserve mechanism. Aim 1 will establish age and tau pathology effects on local functional connectivity in AD-vulnerable regions. Aim 2 will investigate interactive effects of dopamine synthesis capacity and AD pathology on local functional connectivity and memory in older adults. This proposal uniquely integrates AD-relevant research and dopamine mechanisms in human subjects and may support AD treatment efforts. Completion of this research will achieve the applicant’s training goals including training in (1) multi-modal neuroimaging, (2) memory systems in aging, (3) statistics (4) scientific communication, and (5) mentorship. Brandeis University, Boston College, and Massachusetts General Hospital provide exceptional faculty and neuroimaging facilities. Dr. Anne Berry (sponsor) and Dr. Elizabeth Kensinger (co-sponsor) are experienced mentors and specialize in cognitive aging, fMRI, PET, and memory systems. The proposed project and training will successfully advance the applicant’s qualifications for successful pursuit of a career in aging and AD, dopamine, and memory systems.

PROJECT SUMMARY Alzheimer’s disease (AD) is characterized by β-amyloid and tau neuropathology, which are linked to disruptions in memory performance. Advances in human neuroimaging approaches that quantify pathology in vivo have revealed a promising target for AD therapeutics known as cognitive reserve, which is the capacity for some individuals to have better-than-expected cognition given their level of pathology. Our proposed research examines the role of brain dopamine in maintaining optimal cognitive function and youth-like patterns of brain activity despite pathology. Successful maintenance of dopamine function in aging may protect against pathology- related alterations in cognition as dopamine inputs directly into the hippocampus and supports optimal memory performance. The functional impact of hippocampal AD-related pathology can be assessed in humans using emerging fMRI analysis methods that measure local functional connectivity (i.e. regional homogeneity). This is a sensitive predictor of memory performance and pathology burden in rodent models and humans and is gaining traction as a functional neuroimaging biomarker. Local functional connectivity is also affected by neuromodulator systems like dopamine, which may support compensatory changes in aging and could have applications for AD. The extent to which AD-related pathology accumulation in aging interacts with dopamine neuromodulator functions to affect local functional connectivity and memory is not known. The proposed research will fill this gap by assessing, within an older adult sample, relationships among memory, positron emission tomography (PET) measured AD-related pathology (tau) and dopamine synthesis capacity, and local functional connectivity in AD-vulnerable regions. Connectivity will be measured with resting-state fMRI, and memory will be measured with standard neuropsychological assessment. The proposed research will examine interactions between dopamine synthesis capacity and tau pathology to test the hypothesis that elevated dopamine synthesis capacity counteracts effects of pathology on memory and local functional connectivity, thus representing a cognitive reserve mechanism. Aim 1 will establish age and tau pathology effects on local functional connectivity in AD-vulnerable regions. Aim 2 will investigate interactive effects of dopamine synthesis capacity and AD pathology on local functional connectivity and memory in older adults. This proposal uniquely integrates AD-relevant research and dopamine mechanisms in human subjects and may support AD treatment efforts. Completion of this research will achieve the applicant’s training goals including training in (1) multi-modal neuroimaging, (2) memory systems in aging, (3) statistics (4) scientific communication, and (5) mentorship. Brandeis University, Boston College, and Massachusetts General Hospital provide exceptional faculty and neuroimaging facilities. Dr. Anne Berry (sponsor) and Dr. Elizabeth Kensinger (co-sponsor) are experienced mentors and specialize in cognitive aging, fMRI, PET, and memory systems. The proposed project and training will successfully advance the applicant’s qualifications for successful pursuit of a career in aging and AD, dopamine, and memory systems.