Longitudinal Associations of Plasma TMAO and Related Metabolites with Cognitive Impairment and Dementia in Older Adults: The Cardiovascular Health Study

Article type: Research Article

Authors: de Oliveira Otto, Marcia C.^{a; *} | Li, Xinmin S.^{f; g} | Wang, Zeneng^{f; g} | Siscovick, David S.^b | Newman, Anne B.^c | Lai, Heidi Tsz Mung^{d; j} | Nemet, Ina^{f; g} | Lee, Yujin^{d; k} | Wang, Meng^d | Fretts, Amanda^e | Lemaitre, Rozenn N.^e | Tang, W.H. Wilson^{f; g; h} | Lopez, Oscarⁱ | Hazen, Stanley L.^{f; g; h} | Mozaffarian, Dariush^d

Affiliations: [a] Division of Epidemiology, Human Genetics and Environmental Science, The University of Texas Health Science Center at Houston School of Public Health, Houston, TX, USA | [b] New York Academy of Medicine, New York, NY, USA | [c] Department of Epidemiology, University of Pittsburg, Pittsburg, PA, USA | [d] Friedman School of Nutrition Science and Policy. Tufts University, Boston, MA, USA | [e] Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA | [f] Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland, OH, USA | [g] Center for Microbiome and Human Health, Lerner Research Institute, Cleveland, OH, USA | [h] Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH, USA | [i] Department of Neurology, University of Pittsburg School of Medicine Pittsburg, PA, USA | [j] Department of Primary Care and Public Health, Imperial College London, London, UK | [k] Department of Food and Nutrition, Myongji University, Korea

Correspondence: [*] Correspondence to: Marcia C de Oliveira Otto, PhD, 1200 Pressler Street, Suite E-619, Houston, TX 77030-3900, USA. Tel.: +1 713 500 9248; Fax: +1 713 500 9264; E-mail:marcia.c.otto@uth.tmc.edu.

Abstract: Background:Animal studies suggest that gut microbiome metabolites such as trimethylamine N-oxide (TMAO) may influence cognitive function and dementia risk. However potential health effects of TMAO and related metabolites remain unclear. Objective:We examined prospective associations of TMAO, γ-butyrobetaine, crotonobetaine, carnitine, choline, and betaine with risk of cognitive impairment and dementia among older adults aged 65 years and older in the Cardiovascular Health Study (CHS). Methods:TMAO and metabolites were measured in stored plasma specimens collected at baseline. Incident cognitive impairment was assessed using the 100-point Modified Mini-Mental State Examination administered serially up to 7 times. Clinical dementia was identified using neuropsychological tests adjudicated by CHS Cognition Study investigators, and by ICD-9 codes from linked Medicare data. Associations of each metabolite with cognitive outcomes were assessed using Cox proportional hazards models. Results:Over a median of 13 years of follow-up, 529 cases of cognitive impairment, and 522 of dementia were identified. After multivariable adjustment for relevant risk factors, no associations were seen with TMAO, carnitine, choline, or betaine. In contrast, higher crotonobetaine was associated with 20–32% higher risk of cognitive impairment and dementia per interquintile range (IQR), while γ-butyrobetaine was associated with ∼25% lower risk of the same cognitive outcomes per IQR.∥ Conclusion:These findings suggest that γ-butyrobetaine, crotonobetaine, two gut microbe and host metabolites, are associated with risk of cognitive impairment and dementia. Our results indicate a need for mechanistic studies evaluating potential effects of these metabolites, and their interconversion on brain health, especially later in life.

Keywords: Aging, cognition, dementia, diet, gut metabolites

DOI: 10.3233/JAD-220477

Journal: Journal of Alzheimer's Disease, vol. 89, no. 4, pp. 1439-1452, 2022