Magnesium Research (1990) 3, 3, 217-218
Letter to the Editor

Magnesium depletion and pathogenesis of Alzheimer's disease

Jean Durlach

SDRM, H˘pital 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.


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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