Protective factors and mechanisms

RADCO Project 2 Summary Much of cognitive impairment and dementia research has concentrated on disease mechanisms and targets for disrupting these. A compelling alternative approach is to delineate naturally occurring mechanisms of protection. Some centenarians remain cognitively intact despite an extreme exposure to the strongest risk factor for cognitive impairment and AD, aging. We hypothesize that these centenarians and some portion of their offspring have protective factors that lead to such resilience or in some cases, even resistance against cognitive decline and dementia. With the support of the Administrative, Phenotyping and Biosamples, and Neuroimaging Cores, and Project 1 (Resilience and Resistance Phenotypes), this 2nd project of the “Resistance/Resilience to AD in Centenarians and Offspring" (RADCO) study strives to discover factors and mechanisms protective against cognitive impairment, AD and other dementias. This project entails three related approaches: genetics (Aim 1), transcriptomic analyses (Aim 2), and 3D human neural-glial culture models of age-related brain pathology (Aim 3). Our goals are to 1) identify genetic variants and biological mechanisms of resilience/resistance in centenarian cognitive superagers, 2) predict mechanisms of cognitive resilience and validate candidate drugs that can enhance the resilience/resistance in human brain cells, and 3) establish induced pluripotent stem cells (iPSCs) and iPSC-derived 3D brain cell models of the centenarian superagers to test those mechanisms as well as discover and test others that could be exploitable for protective therapeutics.