Metabolites Associated with Early Cognitive Changes Implicated in Alzheimer’s Disease

Article type: Research Article

Authors: Darst, Burcu F.^{a; 1; *} | Huo, Zhiguang^b | Jonaitis, Erin M.^c | Koscik, Rebecca L.^c | Clark, Lindsay R.^{c; d; e} | Lu, Qiongshi^f | Kremen, William S.^g | Franz, Carol E.^g | Rana, Brinda^g | Lyons, Michael J.^h | Hogan, Kirk J.^{c; i} | Zhao, Jinying^j | Johnson, Sterling C.^{c; d; e} | Engelman, Corinne D.^{a; c; e}

Affiliations: [a] Department of Population Health Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA | [b] Department of Biostatistics, University of Florida, Gainesville, FL, USA | [c] Wisconsin Alzheimer’s Institute, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA | [d] Geriatric Research Education and Clinical Center, Wm. S. Middleton Memorial VA Hospital, Madison, WI, USA | [e] Alzheimer’s Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA | [f] Department of Biostatistics & Medical Informatics, University of Wisconsin, Madison, WI, USA | [g] University of California, San Diego, La Jolla, CA, USA | [h] Department of Psychological & Brain Sciences, Boston University, Boston, MA, USA | [i] Department of Anesthesiology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA | [j] Department of Epidemiology, University of Florida, Gainesville, FL, USA

Correspondence: [*] Correspondence to: Burcu F. Darst, 1450 Biggy Street, 1517-F, Los Angeles, CA 90033, USA. Tel.: +1 323 442 0078; E-mail: bdarst@usc.edu.

Note: [1] Present address: Center for∥Genetic Epidemiology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

Abstract: Background:Understanding metabolic mechanisms associated with cognitive changes preceding an Alzheimer’s disease (AD) diagnosis could advance our understanding of AD progression and inform preventive methods. Objective:We investigated the metabolomics of the early changes in executive function and delayed recall, the earliest aspects of cognitive function to change in the course of AD development, in order to better understand mechanisms that could contribute to early stages and progression of this disease. Methods:This investigation used longitudinal plasma samples from the Wisconsin Registry for Alzheimer’s Prevention (WRAP), a cohort of participants who were dementia free at enrollment and enriched with a parental history of AD. Metabolomic profiles were quantified for 2,324 fasting plasma samples among 1,200 participants, each with up to three study visits, which occurred every two years. Metabolites were individually tested for association with executive function and delayed recall trajectories across age. Results:Of 1,097 metabolites tested, levels of seven were associated with executive function trajectories, including an amino acid cysteine S-sulfate and three fatty acids, including erucate (22 : 1n9), while none were associated with delayed recall trajectories. Replication was attempted for four of these metabolites that were present in the Vietnam Era Twin Study of Aging (VETSA). Although none reached statistical significance, three of these associations showed consistent effectdirections. Conclusion:Our results suggest potential metabolomic mechanisms that could contribute to the earliest signs of cognitive decline. In particular, fatty acids may be associated with cognition in a manner that is more complex than previously suspected.

Keywords: Alzheimer’s disease, amino acids, cognition, executive function, fatty acids, longitudinal analysis, metabolomics

DOI: 10.3233/JAD-200176

Journal: Journal of Alzheimer's Disease, vol. 79, no. 3, pp. 1041-1054, 2021