Cognitive health is central to successful aging, independence and well-being. The prevalence of dementia is increasing in the U.S. and there are no effective therapies to prevent cognitive decline or to treat Alzheimer's disease (AD) and related dementia. Neuroinflammation, including systemic immune cells, contributes to neurodegeneration in AD and age-related dementias. Convincing evidence from animal models of AD, large human genetic association studies of AD and dementia imaging markers, and small human case-control studies of AD, demonstrate a role for immune cells and processes in the disease. The complex relationships among the peripheral immune system, cardiovascular disease and its risk factors, and cognitive health are not yet understood. Understanding the biologic mechanisms connecting circulating immune cells and cognitive aging holds the potential to identify new blood based biomarkers and novel therapies for cognitive decline, dementia and AD. We propose a comprehensive investigation of the role of circulating immune cells across the spectrum of cognitive aging in the community-based Framingham Offspring cohort. The cohort is deeply phenotyped for cognitive outcomes, including longitudinal dementia surveillance and repeated neuro- psychological (NP) tests and brain MRI. We hypothesize that we will identify novel associations between immune cell phenotypes in the pro-inflammatory and regulatory pathways and incident adverse cognitive outcomes including development of clinical dementia, mild cognitive impairment (MCI), and measures of cognitive aging defined by NP testing and brain MRI scans. We will investigate whether vascular factors associated with immune cell phenotypes mediate the relationships, as vascular factors increase susceptibility to cognitive aging. We will test our hypotheses with the following Specific Aims: Aim 1: To profile circulating immune cell phenotypes in a dementia and stroke free community based sample of men and women across a wide age range (n=1000, mean age 63, range 40 to 88) and identify cross- sectional correlates of the immune cell phenotypes including age and sex. Aim 2: To identify circulating immune cell phenotypes in the pro-inflammatory and regulatory pathways that are risk factors for incident cognitive aging outcomes (dementia including AD and cognitive aging measures based on NP testing and MRI brain volumes). We will test whether associations differ by sex and genetic risk. Aim 3. To investigate whether the cognitive-outcome related immune cell phenotypes identified in Aim 2 are associated with vascular factors known to increase susceptibility to cognitive aging including incident cerebrovascular disease, cardiovascular disease and vascular risk factors. This work will uncover novel mechanistic insights into the relations between circulating immune cell phenotypes and the aging brain, identify new biomarkers for cognitive decline, and may reveal novel therapeutic targets to prevent and treat dementia consistent with NIAs strategic goals for aging research.

The prevalence of dementia in the population is increasing and there are currently no effective therapies or blood-based biomarkers to detect people at high risk. We plan to investigate the role of circulating immune cells as risk factors for dementia, Alzheimer's Disease and cognitive decline and to test whether associations differ in men and women and by genetic risk. This work will yield insights into the relationship between circulating immune cell types and brain aging, identify new biomarkers for cognitive decline, and may reveal novel therapeutic targets aimed at immune cell alterations to prevent and treat dementia.