ABSTRACT (Project 2) Immune and inflammatory system functions are important to respond to infection, however, emerging evidence suggests that alterations in these systems accompany normative aging and neurodegenerative disease changes (like Alzheimer's disease, AD). Less deeply understood is the constitutive impact of these systems on organs and cells throughout the life span. In the proposed work we will explore the potential impact of immune and inflammatory processes on the brain and the influence of these processes on resistance and resilience to age-related cognitive changes that contribute to SuperAging. The basis for this approach is the well documented immune and inflammatory system changes noted in normative aging, the pro-inflammatory microglial changes associated with aging and AD, and the emergence of well-validated genetic risk factors for AD that have demonstrated the importance of immune and inflammatory system genes in risk for the disease. These findings suggest the immune and inflammatory system may play both a role in acute responses to infection as well as exert a long-term impact on brain health, age-related cognitive changes, and/or resilience to brain-related diseases. Project 2 of the SuperAging Consortium will explore this question through the study of unique individuals within the general population who exhibit the phenotype of cognitive SuperAging – a trait defined as a two- decade, or greater, superiority of memory capacity when compared to age-matched peers. We propose that immune and inflammatory system function is related to the cognitive resilience seen in SuperAging individuals – in the opposing way that it is related to risk for AD. We hypothesize that SuperAgers (SA) will demonstrate a shift toward neuroprotection and lower pro-inflammatory profiles compared to Control and AD participants and that these differences will clarify mechanisms of resilience to age-related phenomena. These hypotheses will be pursued through three aims. In Aim 1 we will profile the individual transcriptomes of microglia and other cells in brain tissue from SAs, Controls, and AD participants. In Aim 2 we will examine three different measures of the adaptive immune and inflammatory systems – cytokine levels, T- and B-cell receptor repertoires, and antibody profiles – in peripheral samples from SAs, Controls, and AD participants. Lastly, in Aim 3, we will investigate the DNA sequence variations in ~500 different immune and inflammatory system genes in SAs and Controls. This study design will allow us to unravel the link between potentially modifiable immune and inflammatory processes and resistance to age-related decline of cognitive capacity.