Resilience and Resistance Phenotypes

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Project 1 Summary Cognitively intact centenarians as extreme outliers are likely to be an informative cohort for discovering behavioral, environmental, and/or biological mechanisms of resistance and resilience to AD and related dementias. Aims 1-3 of this RADCO Project 1 titled, The Cognitive Resilience and Resistance Phenotypes Project, are 3 different approaches to gauging cognitive resilience amongst a sample of almost 500 centenarian cognitive super agers, 600 offspring with and without cognitive impairment, and 120 spouse controls without parental longevity. With no cognitive impairment, particularly at their extreme age, centenarian cognitive superagers are by definition, cognitively resilient. In the absence of neuropathologic changes associated with AD, they would be resistant to AD. Project 1 proposes the following 3 specific aims: Specific Aim 1. Cognitive Function-Neuroimaging Correlation. Gauge cognitive resilience in centenarian cognitive superagers, assessing discordance between cognitive function measures and structural and functional MRI correlates of cognitive impairment and AD. Specific Aim 2: Cognitive Function–Biomarker Risk of AD Correlation. Gauge cognitive resilience in the RADCO sample by assessing discordance between cognitive function measures and longitudinally assayed biomarker indices of AD, neurodegeneration and neuroinflammation. Specific Aim 3: Cognitive Function-Neuropathology Correlation. Gauge cognitive and brain resilience and resistance to AD and other neuropathologies in brain donors by assessing discordance between cognitive function measures and neuropathological measures. The conduct of these aims will differentiate participants according to resilience endophenotypes. These endophenotypes along with associated biosample resources including plasma and brain tissues will be passed on for use by Project 2 investigators for the discovery of protective factors and mechanisms associated with resilience.