AbstractINTRODUCTIONThere remains an urgent need to identify preclinical pathophysiological mechanisms of Alzheimer's disease (AD) development in high‐risk, racially diverse populations. We explored the relationship between cerebrospinal fluid (CSF) markers of vascular injury and neuroinflammation with AD biomarkers in middle‐aged Black/African American (B/AA) and non‐Hispanic White (NHW) participants.METHODSAdults (45–65 years) with a parental history of AD were enrolled (n = 82). CSF and blood biomarkers were collected at baseline and year 2.RESULTSCSF total tau (t‐tau), phosphorylated tau (p‐tau), and amyloid beta (Aβ)40 were elevated at year 2 compared to baseline. CSF soluble platelet‐derived growth factor receptor β (sPDGFRβ) levels, a marker of pericyte injury, correlated positively with t‐tau, p‐tau, Aβ40 markers of vascular injury, and cytokines at baseline and year 2. CSF sPDGFRβ and tau were significantly lower in B/AA than NHW.DISCUSSIONVascular dysfunction and neuroinflammation may precede cognitive decline and disease pathology in the very early preclinical stages of AD, and there are race‐related differences in these relationships.Highlights Cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarkers changed over 2 years in high‐risk middle‐aged adults. Markers of vascular dysfunction were associated with the CSF biomarkers amyloid beta and tau. AD biomarkers were lower in Black compared to non‐Hispanic White individuals. Markers of vascular dysfunction were lower among Black individuals.