Magnesium Research (1990) 3, 3, 217-218
Letter to the Editor
Magnesium depletion and pathogenesis of Alzheimer's
disease
Jean Durlach
SDRM, Hôpital Saint-Vincent-de-Paul, 74-82 Avenue
Denfert-Rochereau F-75674, Paris Cedex 14, France
Summary: Mg depletion,
particularly in the hippocampus, appears to represent an
important pathogenic factor in Alzheimer's disease. It is
associated with high aluminium incorporation into brain neurones.
This type of Mg deficit cannot respond to mere Mg
supplementation, but requires correction of the dysregulation
inducing this Mg depletion. Further research should seek to
control the alterations of albumin, which may induce this brain
Mg depletion.
Key words: Alzheimer's disease,
aluminium, hippocampus, magnesium, Mg depletion.
Among the recent studies concerning the difficult problem of
the pathogenesis of Alzheimer's disease numerous studies have
revealed the increased presence of aluminium (Al) in brain tissue
obtained from autopsies of Alzheimer disease patients. However,
while Perl et al. stressed the significance of their
findings concerning Al in hippocampal tissue, they ignored
practically any discussion of their findings concerning magnesium
(Mg)1,2. Glick3 subjects the Mg data of
Perl and colleagues to a statistical analysis which shows a
significant decrease in the frequency of intracellular Mg
deposits in neurones of Alzheimer disease patients as compared
with control patients. These data agree with more recent
observations by Korf et al. who report decreases in Mg,
K, and glutamic acid in hippocampal atissue of Alzheimer
patients4 while the Mg content of the whole brain
remains normal5. Mg has been shown in vitro
to gate cation channels opened by glutamate, and particularly
those on the N-methyl-D-asparte (NMDA) receptors6.
Glutamate binding to NMDA receptors was reduced by 75-80% in the
hippocampus of Alzheimer disease brains7. The
hypothesis of a link between this loss of glutamatergic
transmission and Mg depletion in the hippocampus in Alzheimer's
disease has been proposed. Glick3 goes further and
suggests that Alzheimer's disease involves a defective transport
process characterized by both an abnormally low Mg incorporation
and an abnormally high Al incorporation into brain neurones. The
origin of this disturbance rests on an alteration of serum
albumin, forming a species which has a greater affinity for Al
than for Mg, in contrast to the normal protein which binds Mg
better than Al. The altered albumin crosses the blood-brain
barrier more efficiently than the normal protein and competes
with it in binding to brain neurones. Binding of the altered
albumin to the target neurones would both impede Mg uptake and
facilitate Al uptake.
Deloncle et al.8, after in vitro
studies, suggest that in brain neurones, L-glutamic acid may
produce much more stable chelate formation as an Al complex than
as an Mg complex. Al complex is unable to detoxify ammonia and
produces L-glutamine. The result at the cellular level is an
accumulation of ammonia, responsible for neuronal death.
Strangely, after promoting this interesting hypothesis, Glick
proposes "a prophylactic and palliative approach towards
Alzheimer's disease involving dietary supplementation of Mg" and
rigorous control of Al intake". This therapeutic suggestion of Mg
supplementation does not take into account the basic distinction
between two types of Mg deficit: Mg deficiency and Mg
depletion9. Mg deficiency is a type of Mg deficit due
to insufficient Mg intake, ie routine experimental Mg deficiency
It responds to simple Mg supplementation. Mg depletion is due to
a dysregulation in the mechanisms which control or disturb Mg
metabolism. This type of Mg deficit responds to the correction of
the pathogenic dysregulation.
The brilliant hypothesis of Glick should stimulate further
therapeutic research on the control of albumin alteration
considered as the basic disturbance in the Mg depletion found in
Alzheimer's disease. Other studies agree on the presence of Mg
depletion rather than of Mg deficiency in Alzheimer's disease.
First the nervous consequences of Mg deficiency are usually
merely diffuse nervous hyperexcitability and not dementia
accompanied by reduced Mg concentration in the hippocampus
10,11. Secondly, in patients affected by Alzheimer's
disease, plasma, red blood cell, and lymphocyte Mg concentrations
are not significantly different from those of healthy old people.
The only marker of Mg dysregulation is a significant increase in
Mg/K ratio measured in granulocytes12.
In summary, Mg depletion appears to be an important pathogenic
factor in Alzheimer's disease. Further research should seek to
control the alterations of albumin which may constitute the
origin of this hippocampal Mg depletion.
References
1. Perl, D.P. & Broady, A.R. (1980): Alzheimer's disease:
X ray spectrometric evidence of aluminum accumulation in neuro
fibrillary tangle-bearing neurons. Science
208, 297-299.
2. Perl, D.P. & Broady, A.R. (1980): Detection of aluminum
by SEM-X ray spectrometry within neurofibrillary tangle-bearing
neurons of Alzheimer's disease. Neurotoxicology
1 (special issue 4), 133-137.
3. Glick, J.L. (1990): Dementias: the role of magnesium
deficiency and an hypothesis concerning the pathogenesis of
Alzheimer's disease. Med. Hypotheses
31, 211-225.
4. Korf, J., Gramsbergen, J.-B.P., Prenen, G.H.M. & Go,
K.G. (1986): Cation shifts and excitotoxins in Alzheimer and
Huntington disease and experimental brain damage. Proc. Brain
Res. 70, 213-226.
5. Hershey, C.O., Hershey, L.A., Wongmongkolrit, T., Varnes,
A.W. & Breslau, D. (1985): Trace element content of brain in
Alzheimer disease and aging. Trace Element Med.
2, 40-43.
6. Nowak, L., Bregestoski, P., Ascher, P., Herbet, A. &
Prochiantz, A. (1984): Magnesium gates glutamate-actived channels
in mouse central neurons. Nature 307,
462-465.
7. Greenamyre, J.T., Penney, J.B., D'Amato, C.J. & Young,
A.B. (1987): Dementia of the Alzheimer's type: changes in
hippocampal 1-3H glutamate binding. J. Neurochem.
48, 543-551.
8. Deloncle, R., Guillard, O., Turq, P. & Prulire, N.
(1990): Alzheimer's disease and dementia syndromes consecutive to
imbalanced mineral metabolisms subsequent to blood brain barrier
alteration. In Metal ions in biology and medicine, eds
P. Collery, L.A. Poirer, M. Manfait & J.C. Etienne, pp.
336-338. London-Paris: John Libbey-Eurotext.
9. Durlach, J. (1988): Magnesium in clinical
practice, p. 386. London: John Libbey.
10. Durlach, J., Poenaru, S., Rouhani, S., Bara, M. &
Guiet-Bara, A. (1987): The control of central neural
hyperexcitability in magnesium deficiency. In Nutrients and
brain function, ed. W.B. Essman, pp. 48-71. Basel-New York:
Karger.
11. Rayssiguier, Y., Durlach, J., Guiet-Bara, A. & Bara,
M. (1990): Aging and magnesium status. In Metal ions in
biology and medicine, eds P. Collery, L.A. Poirier, M.
Manfait & J.C. Etienne, pp. 62-66. London-Paris: John
Libbey-Eurotext.
12. Borella, P., Neri, M., Andermacher, E. & Giardino, A.
(1990): Magnesium in aging and dementia (abstract). Magnesium
Res. 3, 60.
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