Overall Component Summary Centenarians delay age-related diseases and disabilities into their mid-nineties. Some remain cognitively intact despite extreme exposure to the strongest risk factor for cognitive impairment and AD, aging. The overall hypothesis of this study, titled “Resilience/Resistance to AD in Centenarians and Offspring” (RADCO), is: centenarian cognitive superagers and some of their offspring have protective factors that confer such resilience or in some cases, even resistance against cognitive decline and dementia. RADCO assembles an unprecedentedly large sample of prospectively studied centenarian cognitive superagers (n=495, essentially, centenarians with cognitive function that falls within the norms of septuagenarians) along with offspring (n=600) and offspring spouses (n=120), who, via RADCO cores, undergo careful, comprehensive and cutting edge neuropsychological, biomarker, neuroimaging and neuropathological phenotyping. These data are used by two projects with the overall scientific objective of gauging cognitive resilience in this sample, understanding the underlying protective biology and translating that into therapeutic targets. The Cognitive Resilience and Resistance Phenotypes Project (Project 1) gauges resilience by neuroimaging, plasma AD biomarkers risk and neuropathology and therefore generates a range of resilience endophenotypes. The Protective Factors and Mechanisms Project (Project 2) is the translation arm of RADCO; it discovers genes, candidate biological pathways and sets of mi-RNA regulators associated with the resilience endophenotypes characterized in Project 1. In-vitro models of AD incorporate cortical neurons, microglial cells and astrocytes created from centenarian cognitive superager induced pluripotent stem cell (iPSC) lines are used to test the candidate pathways for how they cause resilience against AD.

Centenarian cognitive superagers have exceptional cognitive function despite extreme exposure to the strongest risk factor for cognitive impairment and Alzheimer's disease, aging. The “Resilience/Resistance to AD in Centenarians and Offspring” (RADCO) Study gauges cognitive resilience among centenarian cognitive superagers and their offspring using cognitive testing, neuroimaging, blood biomarkers, and neuropathology and translational studies will identify protective factors and underlying mechanisms that confer resilience or in some cases, even resistance against cognitive decline and dementia.