Peripheral immunity and the aging brain: Studying the relationship of platelet and neutrophil activity with markers of vascular contributions to cognitive decline and dementia

Abstract The underlying biological causes of Alzheimer’s disease (AD) and AD-related dementias (AD/ADRD) remain unclear. Although a vascular component in AD has been discussed since the 1960s, its importance has increased with advancements in biomarkers and imaging techniques, and the current interest in disease heterogeneity. A significant limitation in defining the vascular component of AD is the frequent coexistence of cerebrovascular disease. Recent studies indicate that vascular dysfunction and neuroinflammation may synergistically contribute to AD progression, yet the precise mechanisms remain unclear. Our preliminary data indicate that circulating markers of vascular and immune dysfunction, such as platelet aggregation and neutrophil levels, are associated with dementia risk and increased AD biomarkers in cognitively unimpaired people and in people with high risk of cardiovascular disease events. To further understand this relationship, multidisciplinary studies integrating biofluid data with advanced imaging techniques are needed. This proposal will examine the association between markers of vascular and immune dysfunction (platelet, neutrophil activity, and proteomic data) with MRI measures of cerebrovascular burden in two cohorts: the Framingham Heart Study, and the ARISE-DP cohort, which includes a diverse population with a high prevalence of cardiovascular risk factors (Aim 1); Study the relationship between these markers and PET measures of amyloid and tau pathology, exploring potential interactions between cerebrovascular burden and amyloid positivity (Aim 2); and to determine whether baseline vascular and inflammatory markers associate with cognitive decline and AD biomarker progression (p-tau181 and 217). By integrating biofluid biomarkers with imaging data, this study aims to identify novel biological mediators and therapeutic targets in AD/ADRD, ultimately increasing our understanding of how vascular and immune dysfunction contribute to disease progression