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

Authors: CHEVLI, PARAG - Wake Forest School Of Medicine; SCHAICH, CHRISTOPHER - Wake Forest School Of Medicine; WOOD, ALEXIS - Children'S Nutrition Research Center (CNRC); THAZHATHWEETIL-KUNHA, LUQMAN - Wake Forest School Of Medicine; MEHTA, ANURAG - Virginia Commonwealth University; JAIN, VARDHMAAN - Emory University; CONNELLY, MARGERY - Non ARS Employee; CRAFT, SUZANNE - Wake Forest School Of Medicine; SHEMESH, ELAD - Non ARS Employee; LUCHSINGER, JOSE - Columbia University Medical Center; HAYDEN, KATHLEEN - Wake Forest School Of Medicine; SACHS, BONNIE - Wake Forest School Of Medicine; HUGHES, TIMOTHY - Wake Forest School Of Medicine; SHAPIRO, MICHAEL - Wake Forest School Of Medicine

Submitted to: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring (DADM)
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/22/2024
Publication Date: 11/23/2024
Citation: Chevli, P.A., Schaich, C.L., Wood, A.C., Thazhathweetil-Kunha, L.A., Mehta, A., Jain, V., Connelly, M., Craft, S., Shemesh, E., Luchsinger, J.A., Hayden, K.M., Sachs, B.C., Hughes, T.M., Shapiro, M.D. 2024. Association of circulating ketone bodies with cognitive performance and dementia in the Multi-Ethnic Study of Atherosclerosis (MESA). Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring (DADM). 16(4). Article e70039. https://doi.org/10.1002/dad2.70039.
DOI: https://doi.org/10.1002/dad2.70039

Interpretive Summary: This study explored the relationship between cognitive functioning and ketone bodies (KB), substances produced during fat metabolism. Ketone body levels and cognitive performance were each assessed several times over a decade, with higher levels of KB linked to poorer performance on cognitive tests, especially in areas like memory and spatial awareness, and to an increased risk of dementia. These findings suggest that elevated KB levels could be a useful indicator for predicting cognitive decline and the development of dementia, and highlights the potential role of nutrition and metabolism in brain health as we age.

Technical Abstract: Growing interest centers on the association between circulating ketone bodies (KB) and cognitive function, notably in aging and neurodegenerative diseases. 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). 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 [Beta:-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. In a diverse, cardiovascular disease-free population, elevated KB levels were associated with incident dementia and impaired cognitive performance in specific domains.