TY - JOUR
T1 - Ca:Mg Ratio, APOE Cytosine Modifications, and Cognitive Function
T2 - Results from a Randomized Trial
AU - Zhu, Xiangzhu
AU - Borenstein, Amy R.
AU - Zheng, Yinan
AU - Zhang, Wei
AU - Seidner, Douglas L.
AU - Ness, Reid
AU - Murff, Harvey J.
AU - Li, Bingshan
AU - Shrubsole, Martha J.
AU - Yu, Chang
AU - Hou, Lifang
AU - Dai, Qi
N1 - Funding Information:
This study was supported by R01 CA149633 (to Qi Dai -Chang Yu) and R01 CA202936 (to Qi Dai - Lifang Hou) from the National Cancer Institute, Department of Health and Human Services as well as the Ingram Cancer Center Endowment Fund. Data collection, sample storage and processing for this study were partially conducted by the Survey and Biospecimen Shared Resource, which is supported in part by P30CA68485. Clinical visits to the Vanderbilt Clinical Research Center were supported in part by the Vanderbilt CTSA grant UL1 RR024975 from NCRR/NIH. The parent study data were stored in Research Electronic Data Capture (REDCap) and data analyses (VR12960) were supported in part by the Vanderbilt Institute for Clinical and Translational Research (UL1TR000445).
Funding Information:
This study was supported by R01 CA149633 (to Qi Dai & Chang Yu) and R01 CA202936 (to Qi Dai & Lifang Hou) from the National Cancer Institute, Department of Health and Human Services as well as the Ingram Cancer Center Endowment Fund. Data collection, sample storage and processing for this study were partially conducted by the Survey and Biospecimen Shared Resource, which is supported in part by P30CA68485. Clinical visits to the Vanderbilt Clinical Research Center were supported in part by the Vanderbilt CTSA grant UL1 RR024975 from NCRR/NIH. The parent study data were stored in Research Electronic Data Capture (REDCap) and data analyses (VR12960) were supported in part by the Vanderbilt Institute for Clinical and Translational Research (UL1TR000445).
Publisher Copyright:
© 2020 - IOS Press and the authors. All rights reserved.
PY - 2020
Y1 - 2020
N2 - 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
AB - 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
KW - APOE methylation
KW - calcium
KW - cognitive function
KW - magnesium
KW - mediation analysis
KW - ratio
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UR - http://www.scopus.com/inward/citedby.url?scp=85084721916&partnerID=8YFLogxK
U2 - 10.3233/JAD-jad191223
DO - 10.3233/JAD-jad191223
M3 - Article
C2 - 32280092
AN - SCOPUS:85084721916
VL - 75
SP - 85
EP - 98
JO - Journal of Alzheimer's Disease
JF - Journal of Alzheimer's Disease
SN - 1387-2877
IS - 1
ER -
