Journal of Alzheimer’s Disease Reports 4 (2020) 399–404 399

DOI 10.3233/ADR-200220
IOS Press

Research Report

Association Between Serum Magnesium

Levels and Alzheimer’s Disease or Mixed
Dementia Patients: A Population-Based
Retrospective Controlled Study
Sara Ben Zakena , Zorian Radomyskyb and Gideon Korena,∗
a Adelson School of Medicine, Ariel University, Ariel, Israel
b Maccabi Health Services, Ariel, Israel

Accepted 16 August 2020

Abstract.
Background: High magnesium intake has been associated with a decreased risk of dementia. In contrast, other research has
found that both low and high serum magnesium levels were associated with an increased risk of Alzheimer’s disease and
mixed dementia. Hence, presently the role of magnesium levels in dementia is unclear.
Objective: To investigate a possible association between serum magnesium concentrations and dementia in a large population-
based sample.
Methods: Maccabi Healthcare Service in Israel provides healthcare to over 2 million citizens. Maccabi maintains a registry
with approximately 26,000 diagnosed dementia patients. We focused on patients of both sexes with Alzheimer’s disease or
mixed dementia aged 65 or older, excluding patients with clinical diagnoses that could affect serum magnesium level, or with
other causes of cognitive decline. Our control group consisted of patients of the same age and sex without dementia.
Results: No significant differences were found in mean, mode, and median magnesium levels between the dementia and
control groups. However, there were marginally but significantly more cases with low magnesium levels among dementia
patients than among controls: A total of 9.4% of tests done in patients with dementia and 7.81% done in non-dementia
subjects were hypomagnesemic (p < 0.00001).
Conclusion: Despite similar means and medians of serum magnesium in dementia and controls, the proportion of lower than
normal magnesium test results was slightly higher among dementia patients. It is possible that patients with dementia have
more episodes of hypomagnesemia than controls, despite similar overall mean levels of magnesium.

Keywords: Alzheimer’s disease, magnesium, mixed dementia, serum magnesium

INTRODUCTION RNA and DNA synthesis, and cell repair, as well as

for maintaining the antioxidant status of the cell. In
Magnesium is the fourth most abundant mineral in addition, it is an important cofactor for many bio-
the human body after calcium, potassium, and sodium logical processes and for the activation of a wide
[1]. It is essential for the stability of cell function, range of transporters and enzymes [1, 2]. Magnesium
∗ Correspondence to: Gideon Koren, MD, FRCPC, FACMT,
plays a critical role in nerve transmission, car-
diac excitability, maintaining normal heart rhythm,
Ariel University, Ariel 40700, Israel. Tel.: +972 587194777; E-
mail: gidiup [email protected]. neuromuscular conduction, muscular contraction,

ISSN 2542-4823/20/$35.00 © 2020 – IOS Press and the authors. All rights reserved
This article is published online with Open Access and distributed under the terms of the Creative Commons Attribution Non-Commercial License (CC BY-NC 4.0).
400 S.B. Zaken et al. / Association Between Serum Magnesium Levels and Alzheimer’s Disease or Mixed Dementia Patients

blood pressure, and glucose and insulin metabolism neurons, which results in activation of the calcium
[3]. related enzyme system and of free radicals, protein
Alzheimer’s disease is the most common form of destruction, lipid peroxidation, and neuron death with
dementia. While its etiology has not been identified, DNA destruction [8].
it is associated with environmental factors, nutrition, Increasing volume of research has explored the
and vitamins among other elements [4]. connection between magnesium and the role of
Differentiation of Alzheimer’s disease from other NMDA receptors in degenerative brain disorders.
common forms of dementia is important in order to NMDA receptors have a critical role in physiologi-
implement an appropriate treatment plan and provide cal and pathological processes of the central nervous
prognostic information for the patients [5]. Vascular system, including neuronal development, plastic-
dementia, caused by cerebrovascular disease, is the ity and neurodegeneration [5, 7]. These receptors
second most common cause of dementia. Cerebrovas- lead to channels which are permeable to calcium,
cular disease is a risk factor for Alzheimer’s disease, sodium and potassium ions and voltage-gated chan-
but can also coexist with Alzheimer’s disease, creat- nels blocked by magnesium ions. Transient glutamate
ing a form of “mixed” dementia. release from the presynaptic region occurs during
The role of magnesium in dementia and other normal learning and memory process. This release
degenerative disorders have been the focus of causes depolarization on the postsynaptic membrane,
increased attention in recent years [6]. There are two after which ionized magnesium Mg2+ leaves voltage-
main hypotheses for the role of magnesium in demen- gated channels on NMDARs, and Ca2+ influx inside
tia: the neuron occurs. Increase in Ca2+ levels inside the
neuron initiates a signal transmission process and
1) The direct effect of neuronal magnesium on reg-
this facilitates memory and learning. At the end of
ulation of the N-methyl-D-aspartate (NMDA)
stimulation, Mg2+ stops Ca2+ influx inside the neu-
receptors, which is an ionotropic glutamater-
ron by closing channels on the NMDA receptors
gic receptor. Magnesium is a soft-block of the
[5, 7].
receptor that is in place until depolarization,
There are several studies reporting favorable
which removes the block, in addition to clos-
effects of magnesium in the treatment of various
ing the calcium channel after neurotransmission
degenerative illnesses. Improvement in memory and
has occurred. It has been demonstrated that
other symptoms was reported with nutritional mag-
ionized magnesium leads to closure of cation
nesium support in patients with dementia [10, 11].
channels which have been opened by glutamate
Higher self-reported dietary intake of magnesium
on NMDA receptors [7].
was found to be associated with a decreased risk
2) The second hypothesis is related to oxidative
of dementia [11]. In this study, community-dwelling
stress. Magnesium deficiency has been found
Japanese individuals without dementia aged 60 and
to stimulate secretion of inflammatory media-
older were assessed. During a 17-year follow-up,
tors such as interleukins, tumor necrosis factors
303 participants experienced all-cause dementia. In
and nitric oxide. These mediators are thought to
multivariable-adjusted analysis, the hazards ratio
stimulate atherosclerosis and thereby increase
(HR) for the development of all-cause dementia was
the risk of dementia [7].
0.63 for the highest quartiles of magnesium intake,
Magnesium levels were found decreased in vari- compared with the corresponding lowest quartiles.
ous tissues of patients with Alzheimer’s disease in Similarly, the HR for the development of vascular
clinical, experimental, and autopsy studies (hypo- were 0.26 (95% CI = 0.11–0.61) for the highest quar-
magnesia) [8]. A reduction in the frequency of tiles of magnesium intake [11].
intracellular magnesium deposits in the neurons of In contrast, other research found that both low and
Alzheimer’s disease patients was observed when high serum magnesium levels were associated with
compared to normal controls. Decrease in Mg, K, and an increased risk of Alzheimer’s disease and mixed
glutamic acid have been shown in the hippocampal dementia [12]. These contrasting results render the
tissue of Alzheimer’s disease patients [9]. role of magnesium levels in dementia unclear. Large-
There is evidence that glutamate release and intake population based research is essential to try to better
are chronically disturbed in Alzheimer’s disease, and verify whether magnesium may contribute to the
glutamate levels are possibly increased in the synap- pathogenesis of dementia in general and Alzheimer’s
tic cleft, with resulting Ca2+ influx to postsynaptic disease in particular.
 S.B. Zaken et al. / Association Between Serum Magnesium Levels and Alzheimer’s Disease or Mixed Dementia Patients 401

The objective of the present study was to Table 1

investigate a possible association between serum Reference intervals of serum magnesium test
magnesium concentrations and dementia in a large Sex Normal range
population-based sample. Males 0.73–1.06 mmol/L (1.8–2.6 mg/dL)
Females 0.77–1.03 mmol/L (1.9–2.5 mg/dL)

METHODS
Briefly, the magnesium reagent utilizes a direct
This was a retrospective population-based con- method in which magnesium ions form a col-
trolled study of magnesium serum concentrations, ored complex with xylidyl blue in a strongly basic
comparing dementia patients with non-dementia con- solution. The color produced is measured bichro-
trols. The study was approved by Assuta Hospital matically at 520/800 nm and is proportional to the
Research Ethics Committee in Tel Aviv. magnesium concentration in the sample. Calcium
interference is eliminated by glycoletherdiamine-
Settings N,N,N‘,N‘-tetraacetic acid (GEDTA) [15–17].
Magnesium normal range of serum concentrations
Maccabi Healthcare Service is Israel’s second may vary with age, sex, sample type, nutrition, and
largest health insurance organization, providing geographical location. The laboratory verified the
healthcare to over 2 million citizens [13, 14]. Maccabi transferability of the expected values to its own popu-
has a central computerized database which contains lation, and if necessary determines its own reference
demographic and medical data, including diagnoses, interval according to good laboratory practice. Mag-
drug purchases (all prescriptions and part of OTC nesium reference intervals at Maccabi’s Mega Lab
drugs), laboratory data, hospitalizations, and physi- have been stable since 2004, as shown in Table 1
cian visits. [17].
Maccabi maintains a registry of dementia patients, Magnesium levels below 1.8 mg/dL in men and
diagnosed by a geriatrician, a psychiatrist, or a neu- 1.9 mg/dL in women were defined as hypomagne-
rologist. Our study focused on patients of both sexes semia, whereas levels above 2.6 mg/dL in men or
with Alzheimer’s disease or mixed dementia aged 2.5 mg/dL in women were defined as hypermagne-
65 or older. We identified all cases of dementia semia (Table 1).
(ICD-9 code 294.20). Alzheimer’s disease (ICD-9
code 331.0) is the most common form of dementia.
Analysis
Vascular dementia (ICD-9 code 290.42), caused by
cerebrovascular disease, is the second most common From the electronic charts we extracted all results
cause of dementia. of serum magnesium levels of the study and control
The dementia registry contains medical informa- groups between January 2001 and December 2019. In
tion of 25,800 patients. We excluded 23,039 patients patients with more than one level of magnesium, we
with either clinical diagnoses that could affect serum calculated the mean, maximum, and minimum levels
magnesium level [1]: use of diuretics, laxatives, over this time period. The two groups were compared
Crohn’s disease, or with other causes of cognitive using Student’s t-test for normally distributed con-
decline, such as alcohol abuse history, hypo and tinuous variables, Mann Whitney U tests for non-
hyperthyroidism, hepatic and heart failure, patients normally distributed values (medians), and by Chi
on dialysis or with significant decline in renal func- square for dichotomous variables.
tion, patients with Parkinson’s disease, brain injury,
hypoglycemia and other rare types of dementia. RESULTS
Our control group consisted of patients of the
same age (±1 year), same sex, with the same inclu- General characteristics of participants in both test
sion criteria but without dementia (42,698 patients). and control groups are described in Table 2.
The groups included similar proportions of sexes No significant differences were found in mean,
(Table 2). mode, and median magnesium levels between the
Serum magnesium was measured in Maccabi dementia and control groups. However, there were
Healthcare Service Mega Lab by a photometric a slight by statistically significant more cases with
color on Olympus AU5800 Beckman Coulter ana- low magnesium levels among dementia patients than
lyzer (Beckman Coulter, Inc., Brea, CA, USA). among controls.
402 S.B. Zaken et al. / Association Between Serum Magnesium Levels and Alzheimer’s Disease or Mixed Dementia Patients

Table 2
Magnesium kevels in the study and control groups
Parameter Dementia* Controls Significance
Number of participants 2,761 42,698
M/F 988/1773 (35.8/64.2%) 16,160/26,538 (37.8/62.2%) N.S.
Mean Age (before matching) 78.88 72.05 p < 0.01
Mean Mg (mg/dL) 2.064 ± 0.18 2.065 ± 0.18 N.S.
Mode Mg (mg/dL) 2 2 N.S.
Median Mg (mg/dL) 2.1 2.1 N.S.
Minimal Mg result (mg/dL) 0.9 0.3 N.S.
Maximal Mg result (mg/dL) 2.9 3.6 N.S.
*Alzheimer 43%, vascular dementia 47%, mixed dementia 10%. No differences have been detected between the mean,
mode and median serum Mg concentrations in dementia cases versus controls.

Table 3
Proportions of serum magnesium tests below and above the normal ranges among males,
females, and all patients
Number of of Mg results Males Females
control test control test
Normal range 37,874 2,483 64,496 4,527
Hypomagnesemia 1478 107 7,869 629
3.75%*** 4.12%*** 10.84%* 12.14%*
Hypermagnesemia 46 1 203 21
0.11% 0.038% 0.027%** 0.4%**
Total 39,398 2,591 72,568 5,177
Female hypomagnesemia: *p = 0.0035; Male hypomagnesemia: ***p = 0.089 (N.S); Female hyper-
magnesemia: **p = 0.04; Male hypermagnesemia: p = 0.3 (N.S); Total hypomagnesemia (males
and females): ***p < 0.00001; There was a marginal, but significantly higher proportion of cases of
hypomagnesemia among patients with dementia (9.4%) as compared to controls (7.81%). The total
numbers differ from Table 2 because here all samples were counted whereas in Table 2 the mean
levels of more than one sample are presented.

In general women tended to have on average 85% significantly more cases with low magnesium lev-
more magnesium tests done than men, probably due els among dementia patients than among controls
to higher prevalence and recognition of osteoporo- with 9.4% of tests done in patients with dementia
sis. Approximately 12% of tests done in women with and 7.81 done in non-dementia subjects were hypo-
dementia and 10% done by healthy women were magnesemic (p < 0.00001). Hypermagnesemia was
lower than normal range, hence hypomagnesemic negligible in both genders and both dementia and
(p = 0.0035). In men the difference was not signifi- control groups.
cant, probably due to the substantially smaller sample There are studies establishing hypomagnesia
(p = 0.08). When combining men and women, the within Alzheimer’s disease and dementia using ion-
difference was highly significant (9.4% versus 7.81 ized Mg, cerebrospinal fluid, hair, plasma, and red
%) when comparing the dementia group to the con- blood cell Mg samples [18, 19].
trol group (p < 0.00001) (Table 3). Hypermagnesemia Higher self-reported dietary intake of magnesium
was negligible in both genders and both dementia was found to be associated with a decreased risk of
and control groups. In a trend analysis, time did not dementia [11]. Kieboom et al. found that both low and
impact magnesium serum levels for both groups sep- high serum magnesium levels were associated with
arately between 2001 and 2019. an increased risk of Alzheimer’s disease and mixed
dementia [2].
The question leading to this research was whether
DISCUSSION dementia is associated with lower serum concentra-
tions of Mg, as has been suggested in some studies.
In the present study we could not detect sig- We have utilized a large population-based database to
nificant differences in mean, mode, and median address this question. A registry of dementia patients,
magnesium levels between the dementia and con- with over 25,000 cases, has allowed us to match indi-
trol groups. However, there were marginally but viduals without dementia based on variables that may
 S.B. Zaken et al. / Association Between Serum Magnesium Levels and Alzheimer’s Disease or Mixed Dementia Patients 403

affect magnesium levels, such as use of diuretics, confirmed by a geriatrician, neurologist or psychia-
laxative, and diseases such as Crohn’s. It was also trist. The large cohort has also allowed us to exclude
hoped that it will have statistical power to discern subjects that have known confounders of either low
small effects of magnesium on dementia. magnesium levels, or effects on cognition.
Overall, our results indicate that dementia patients Potential weaknesses of the present study need to
did not exhibit lower means, medians, or modes of be acknowledged. Availability of magnesium serum
serum magnesium levels, and thus not being able to concentrations did not include all patients, and the
support the hypothesis that hypomagnesemia has a number of samples was not standardized. Clearly
major role in the pathogenesis of dementia. women had significantly more measurements, most
These results are consistent with the findings of our probably due to much larger numbers of investiga-
recent study in which we analyzed in a treat-control tions into osteoporosis, which is much more prevalent
context how the switch to desalinated drinking water among females. Another potential weakness is in the
affected serum magnesium concentrations and the retrospective nature of the study; therefore collection
prevalence of dementia [20]. of magnesium serum samples was not standardized
We selected two cities which differed in terms of and could have been impacted by unknown con-
their access to underground aquifers but were other- founders. Using serum Mg has inherent limitations
wise similar. One city has no underground water and and although total serum magnesium concentration is
uses over 90% desalinated water whereas the other the most commonly used test, this laboratory marker
relies almost entirely on its own aquifers. Using med- has limited clinical benefit as it does not accurately
ical records for all subjects insured by the Maccabi reflect intracellular or total body magnesium status
Health Services, we examined mean serum concen- [4, 21].
trations of Mg in the period prior to desalination We also do not have records whether the dementia
(2001-2006) and post desalination (2007-2018). group were taking magnesium supplements or had a
Serum magnesium levels were significantly lower diet high in magnesium, which could normalize their
following the switch to desalinated water yet the serum values. Further comparison of the dementia
prevalence of dementia was similar in the two cities. group to the controls in rates of other conditions (e.g.,
While this ecological study could not rule out some diabetes) or use of medications (e.g., proton pump
effect of hypomagnesemia on dementia morbidity, it inhibitors, diuretics) is not likely to shed light on the
suggested, similar to the present study, that the effect findings of this study.
if exists, is relatively small. The question whether magnesium supplements can
In the present study, despite similar means and prevent or reduce the progress or severity of dementia
medians of serum magnesium in dementia and con- requires more studies employing different method-
trols (Table 2), the proportion of lower than normal ologies.
magnesium test results was marginally but signifi-
cantly higher among dementia patients (p < 0.00001)
CONFLICT OF INTEREST
(Table 3). It is possible that patients with demen-
tia exhibit more episodes of hypomagnesemia than
The authors have no conflict of interest to report.
controls, despite similar overall mean levels of mag-
nesium. It could be hypothesized that there was an
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