Identification of plasma lipoprotein proteins and lipids as biomarkers of innate-immunity and vascular contributions to Alzheimer's disease and Alzheimer's disease-related dementias in older adults

项目总结。目前迫切需要充分了解阿尔茨海默病（AD）的复杂性。

Project Summary. Critical needs exist to fully understand the complexity of Alzheimer’s disease (AD) pathophysiology and more accurately characterize AD using biomarkers beyond amyloid, tau, and neuronal injury (AT[N]). Vascular pathology substantially increases the risk of AD and AD-related dementias (ADRDs) and coexists with AD pathology (brain amyloid deposition) in the majority of AD/ADRD cases. Neuroinflammation underlies the development of both vascular and AD pathologies and is modulated by peripheral factors that exacerbate or attenuate cognitive decline. Evidence suggests that plasma lipoproteins influence the development of brain amyloid deposition and cerebral small vessel diseases and underlying neuroinflammation, neurodegeneration, and AD/ADRD sequelae (cognitive decline and incident dementia). The objective of this proposal is to identify protein and lipid cargo of plasma lipoproteins that are associated with AD pathology, vascular pathology, neuroinflammation, neurodegeneration, cognitive decline, and incident dementia in older adults. The central hypotheses are that plasma lipoproteins influence brain amyloid deposition, vascular pathology, and neuroinflammation, and alter neurodegeneration and trajectories of cognitive decline and incident dementia. This proposed study will employ already-collected plasma samples and outcome data from the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS). We identified 743 eligible ARIC-NCS participants without dementia (mean age: 76.4 years) who had blood collected at baseline and had baseline plasma measures of brain amyloid deposition (Ab 42/40 ratio, p-tau 181), neuroinflammation (GFAP), and neurodegeneration (NfL) available. These participants also had central arterial stiffness and cognitive function and status evaluated at baseline, concurrent with the baseline blood collection that we will use for our plasma lipoprotein fractionation, and had cognitive function and status evaluated twice more over a mean follow-up period of 6.5 years. We will randomly select 346 participants and fractionate their plasma samples, measure proteins and lipids in 1384 fractionated plasma lipoproteins (346 of each fraction [VLDL, IDL, LDL, HDL]) using MS-based proteomics and lipidomics, respectively, and identify proteins, lipids, or their interactions in plasma lipoproteins in relation to AD/ADRD-related outcomes. The specific aims are: 1) Determine proteins or lipids in fractionated plasma lipoproteins as biomarkers indicative of AD pathology and vascular pathology; 2) Establish proteins or lipids in fractionated plasma lipoproteins as biomarkers suggestive of neuroinflammation and neurodegeneration; and 3) Identify proteins or lipids in fractionated plasma lipoproteins as biomarkers predictive of cognitive decline and incident dementia. Our proposal will broaden our perspective and understanding of peripheral factors in the development of AD/ADRD pathophysiology and will identify potentially useful plasma lipoprotein–based therapeutic strategies and biomarkers beyond the current AT[N] paradigm for treating or preventing AD/ADRDs.