Arterial stiffness, a vascular aging biomarker, has emerged as an important risk factor for dementia, and is being cross-sectionally linked to brain MRI-measured neurodegeneration and PET-measured brain Aβ and Tau burden, imaging biomarkers of Alzheimer’s disease (AD) and AD related dementias (ADRD). However, mechanisms by which arterial stiffness may contribute to cognitive impairment and dementia are incompletely understood. Recently, several plasma biomarkers including phosphorylated tau (p-tau) has emerged as promising surrogates for Aβ/Tau PET burden and neurodegeneration. The goal of this application is to characterize AD pathology/neurodegeneration connecting arterial stiffness to cognitive impairment using plasma biomarkers, and identify the diverse and overlapping mechanisms underlying vascular and neuro-degeneration associated with cognitive impairment through the following aims: A1. To quantify plasma biomarkers of AD/neurodegeneration, and determine effects of baseline and progression of arterial stiffness on changes of the plasma biomarkers. A2. To examine effects of monocyte genomic features (DNA methylomics and transcriptomics) on vascular aging. A3. To examine effects of monocyte genomic features on changes of the plasma biomarkers of AD/ neurodegeneration. A4. To test effects of SIRT1 on vascular and neuro-degeneration and AD pathogenesis using in vitro and in vivo AD models. The proposed longitudinal study adding plasma biomarkers of neurodegeneration to the racially and ethnically diverse MESA cohort with multi-omics data, carotid vascular and other cardiometabolic measures, brain imaging, cognitive testing, and clinical MCI/ADRD data across the mid- to late-life transition period, coupled with in vitro and in vivo experimental studies, has the potential to elucidate the contributions of arterial stiffness to cognitive impairment and identify molecular and cellular mechanisms that can explain the common co-occurrence of vascular and early AD/neurodegenerative pathologies and could serve as targets for disease-modifying interventions.