Ca:Mg Ratio, APOE Cytosine Modifications, and Cognitive Function: Results from a Randomized Trial

Article type: Research Article

Authors: Zhu, Xiangzhu^a | Borenstein, Amy R.^{b; *} | Zheng, Yinan^c | Zhang, Wei^c | Seidner, Douglas L.^d | Ness, Reid^d | Murff, Harvey J.^e | Li, Bingshan^f | Shrubsole, Martha J.^a | Yu, Chang^g | Hou, Lifang^c | Dai, Qi^{a; *}

Affiliations: [a] Department of Medicine, Division of Epidemiology, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA | [b] Department of Family Medicine and Public Health, Division of Epidemiology, University of California-San Diego School of Medicine, La Jolla, CA, USA | [c] Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA | [d] Department of Medicine, Division of Gastroenterology, Vanderbilt School of Medicine, Nashville, TN, USA | [e] Division of Geriatric Medicine, General Internal Medicine and Public Health, Vanderbilt University School of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA | [f] Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA | [g] Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, TN, USA

Correspondence: [*] Correspondence to: Qi Dai, MD, PhD, Department of Medicine, Vanderbilt University Medical Center, 2525 West End Avenue, Suite 800, Nashville, TN 37203-1738, USA. Tel.: +1 615 936 0707; Fax: +1 615 343 5938; E-mail: [email protected]; Amy R. Borenstein, PhD, Department of Family Medicine and Public Health, University of California - San Diego, Medical Teaching Facility 162K, 9500 Gilman Drive, MC 0725, La Jolla, CA 92093, USA. Tel.: +1 858 534 9360; Fax: +1 858 534 4642; E-mail: [email protected].

Abstract: Background:Deterioration of ionized calcium (Ca2+) handling in neurons could lead to neurodegenerative disease. Magnesium (Mg) antagonizes Ca during many physiologic activities, including energy metabolism and catalyzation of demethylation from 5-methylcytosine(5-mC) to 5-hydroxymethylcytosine(5-hmC). Objective:To test the hypothesis that actively reducing the Ca:Mg intake ratio in the diet through Mg supplementation improves cognitive function, and to test whether this effect is partially mediated by modified cytosines in Apolipoprotein E (APOE). Methods:This study is nested within the Personalized Prevention of Colorectal Cancer Trial (PPCCT), a double-blind 2×2 factorial randomized controlled trial, which enrolled 250 participants from Vanderbilt University Medical Center. Target doses for both Mg and placebo arms were personalized. Results:Among those aged > 65 years old who consumed a high Ca:Mg ratio diet, we found that reducing the Ca:Mg ratio to around 2.3 by personalized Mg supplementation significantly improved cognitive function by 9.1% (p = 0.03). We also found that reducing the Ca:Mg ratio significantly reduced 5-mC at the cg13496662 and cg06750524 sites only among those aged > 65 years old (p values = 0.02 and 0.03, respectively). Furthermore, the beneficial effect of reducing the Ca:Mg ratio on cognitive function in those aged over 65 years was partially mediated by reductions in 5-mC levels (i.e., cg13496662 and cg06750524) in APOE (p for indirect effect = 0.05). Conclusion:Our findings suggest that, among those age 65 and over with a high dietary Ca:Mg ratio, optimal Mg status may improve cognitive function partially through modifications in APOE methylation. These findings, if confirmed, have significant implications for the prevention of cognitive aging and Alzheimer’s disease.Clinical Trial Registry number and website: #100106 https://clinicaltrials.gov/ct2/show/NCT03265483

Keywords: APOE methylation, calcium, cognitive function, magnesium, mediation analysis, ratio

DOI: 10.3233/JAD-191223

Journal: Journal of Alzheimer's Disease, vol. 75, no. 1, pp. 85-98, 2020