Dopaminergic mechanisms of resilience to Alzheimer's disease neuropathology

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PROJECT SUMMARY While the development of Alzheimer’s disease (AD)-related β-amyloid (Aβ) and tau pathology is associated with declines in brain structure and cognitive function on a population level, there is considerable heterogeneity in these effects across individuals. Individual differences in the brain’s dopamine system represent a compelling moderator of Aβ and tau pathology’s effects on brain structure and function. Previous research has established that an “optimal” genetic polymorphism presumed to increase dopamine D2 receptor affinity (DRD2 C957T; rs6277) is associated with greater cortical thickness. While the mechanisms driving this effect are not known, dopamine can be neurotrophic and D2 receptors mediate a number of neuroprotective functions that may counteract AD processes including reduction of neuroinflammation. Relevant to the successful maintenance of cognitive function despite pathology, higher D2 receptor availability is associated with better executive function and memory. We propose the DRD2 T/T genotype supports resilience to AD- related tau and Aβ pathology. Analyses will focus on cognitively normal and mild cognitive impairment groups for which establishing the mechanisms of successful AD resilience are most relevant. We will use the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset to pursue the following Specific Aims. We will first establish a role of the DRD2 T/T genotype in conferring greater cortical thickness despite Aβ ([18F]Florbetapir/Florbetaben) and tau ([18F]Flortaucipir PET) pathology cross-sectionally (Aim 1). Next, we will investigate the role of DRD2 T/T genotype in cognitive reserve by probing genotype x pathology interactions in cross-sectional and longitudinal measures of executive function and memory using the Preclinical Alzheimer Cognition Composite. We will test the hypothesis that the T/T genotype is associated with better-than-expected cognition given tau and Aβ burden (Aim 2). Finally, we will track longitudinal clinical decline using the Clinical Dementia Scale – Sum of Boxes and longitudinal decline in cortical thickness to determine the extent to which the T/T genotype predicts slower clinical decline and brain maintenance (Aim 3). The successful completion of these aims will provide novel evidence that the dopamine system interacts with AD pathology to affect aging trajectories, and will support therapeutic targeting of the dopamine system for individuals predisposed to lower D2 affinity.