Discrimination, Inflammation, and Alzheimer's Disease Risk: A Study of Middle‐Aged Adults with a Family History of AD

Abstract Background Discrimination is a psychosocial stressor linked to poor cardiovascular and metabolic health. Chronic exposure can drive inflammation, immune activation, and vascular dysfunction, both of which are known Alzheimer's disease (AD) risk factors. Few studies have examined how types of discrimination relate to inflammation, vascular dysfunction, and neurodegeneration. We explored how situational and lifetime discrimination relates to biological mechanisms contributing to AD risk. Method Cognitively unimpaired middle‐aged adults with a parental history of AD were enrolled in this study (PI Wharton). We measured AD, vascular and inflammatory biomarkers in brain via cerebrospinal‐fluid (Aβ40; ICAM, sPDGFRß; TGFα, MCP‐1, MDC, IL‐9, MMP‐1). Blood samples were taken to assess cortisol, inflammation markers (IL‐9, IFNγ), and vascular function (ACE‐2). Discrimination was evaluated using a battery of validated measures including Everyday Discrimination, Chronic Work Discrimination and Harassment, Heightened Vigilance, Major Experiences of Discrimination, and Coping with Discrimination. Result Participants were 59±7 years, 70% women, college‐educated (90%), and 30% were Black Americans. Everyday discrimination was positively associated with brain [TGFα ( p = .043), MCP‐1 ( p = .010), ICAM (r=.488, p = .011)] and peripheral [IFNγ ( p = .031) and IL‐9 ( p = .014)] inflammation, and was negatively associated with sPDGFRß ( p = .015). Higher work discrimination was correlated to central MMP1 ( p = .019), peripheral cortisol ( p = .027), and ACE2 ( p = .011). Major discrimination correlated with brain [MDC ( p = .044), TGFα ( p = .002), MCP‐1 (r=.498, p = .010), MMP9 ( p = .005), ICAM (r=.547, p = .004)] and peripheral [IFNγ ( p = .014) and IL‐9 ( p = .007)]. Heightened vigilance was associated with central TGFα (r=.616, p = .001), Aβ40 ( p = .002), IL‐9 (r=.440, p = .046), ICAM ( p <.001), and peripheral IL‐9 ( p = .044). Coping was positively linked to Aβ40 ( p = .021). Conclusion Chronic, everyday, and major discrimination correlated with higher inflammation and immune activation, both of which are risk factors for AD. Heightened vigilance (i.e. actively avoiding potential discrimination) was associated with higher inflammatory markers and Aβ 40 , while higher coping strategies correlated to increased AD biomarkers. Further research on the impact of direct (AD biomarkers) and indirect (AD risk factors) effects via discrimination is crucial, as is the need for supportive research environments and personnel to ensure participants feel comfortable sharing such experiences.