Association of circulating ketone bodies with cognitive performance and dementia in the Multi-Ethnic Study of Atherosclerosis (MESA)

Introduction: Growing interest centers on the association between circulating ketone bodies (KB) and cognitive function, notably in aging and neurodegenerative diseases. Methods: Associations of plasma KB with incident dementia and cognitive performances were examined among Multi-Ethnic Study of Atherosclerosis (MESA) participants. KB were measured using plasma samples collected following an overnight fasting at Exam 1 (2000–02) and detailed cognitive testing at Exam 5 (2010–2012, N = 4392), Exam 6 (2016–2018, N = 1838), and in MESA-MIND (2019–2021, N = 2060). Results: Over 16.7 years, a doubling of total KB was associated with a greater risk of incident dementia (hazard ratio [HR]: 1.14 [1.04–1.29]). Higher total KB was associated with worse cognitive performance in the Digit Span test at exam 5 [β: −0.30 (−0.47, −0.14)]. We also found that a higher KB was associated with greater functional impairment and a higher Quick Dementia Rating Scale (QDRS) score. Discussion: In a diverse, cardiovascular disease-free population, elevated KB levels were associated with incident dementia and impaired cognitive performance in specific domains. Highlights: A study of ketone bodies (KB) and cognitive performance and incident dementia. Nuclear magnetic resonance (NMR) spectroscopy was used to measure plasma KB at baseline. Doubling of baseline total KB was associated with higher incident dementia. Higher KB was also associated with worse performance on a test of working memory.