Age-related human neurodegenerative diseases are a major social and medical problem. It is therefore logical to take into consideration every theory with an overall approach to neurodegenerative diseases. This environmental proposal relies mainly on data concerning the Western Pacific amyotrophic lateral sclerosis-Parkinsonism-dementia complex (WP ACS-PD) considered as a prototypal human neurodegenerative disease' and on extrapolation from it to the bulk of neurodegenerative diseases (NDD). NDD would be due to an accelerated ageing process in certain populations of neurons due to the noxious synergy of (1) increased environmental slow deleterious factors (such as slow toxins) and of (2) decreased environmental protective factors (Mg deficient intake particularly). First, it was observed that three apparently dissimilar conditions occurred at extraordinary high rates in the Guam area: motoneuron disease (ALS), Parkinson's disease (P) and Alzheimer's-like dementia (D). Next, several other foci of endemic ALS-PD were found in Asia and Oceania in three Western Pacific population groups. These included the Chamorro people in Mariana Islands (Guam and Rota), the Auyu and Jakai people of West New Guinea and the Japanese residents of the Kii peninsula (Honshu island). The post-Second World War decline of the occurrence of WP ALS-PD in all three high incidence disease foci coupled with the absence of demonstrable heritable or transmissible factors had led to focus the search for the cause of this degenerative disease on nontransmissible environmental factors that are disappearing as the susceptible population groups acculturate to modern way. Epidemiologic study has shown that preference for traditional Chamorro food is the only one of 23 tested variables significantly associated with an increased risk for PD. An early suggestion incriminated the toxic seed of the false sage palm (Cycas circinalis L) which was used in traditional food and medicine. Laboratory investigation of cycad seed revealed the presence of various toxins and particularly of an 'unusual' non protein aminoacid: L-BMAA (beta-N-methylamino-alanine), an excitotoxic aminoacid. This slow toxin presents some structural similarity to another 'unusual' excitotoxic aminoacid: L-BOAA (beta-N-oxalyl-amino-L-alanine), an exogenous neurotoxin present in the grass pea (Lathyrus sativus) whose excessive consumption may cause lathyrism. The excitotoxicity of both L-BMAA and L-BOAA mainly concerns non-NMDA receptors. The neurotoxicity of these aminoacids varies with experimental models failing to induce an experimental model akin to WP ALS-PD or displaying many of the motor-system and behavioral changes of WP ALS-PD. It may be due to the presence of physiological levels of bicarbonate or of various toxic cofactors: bio-organic such as cycasin or inorganic such as pollutant metals e.g. aluminum or manganese, together with the lack of protective factors (e.g. calcium and magnesium deficiencies). Combined Al intoxication with Ca-Mg deficiencies is a reasonable model to investigate the pathogenesis of neurodegenerative diseases and eventually to screen their treatments. It may also be considered as a model of magnesium deficit, but it does not concern simple magnesium deficiency reversible with mere oral physiological magnesium supplementation. Magnesium deficiency cannot result in neurodegenerative disease. Combined Al intoxication with Ca Mg deficiencies is not reversible through physiological oral magnesium supplementation. It therefore constitutes a type of experimental magnesium depletion model, instrumental in the investigation of the pathogenesis of magnesium depletion and in the screening of its still unknown possible treatments. As a rule, no changes have been found in brain magnesium concentrations during the course of magnesium deficiency in adult rats, but in the experimental and clinical type of magnesium depletion related to pollutant metal load combined with low Mg and Ca dietary intake, magnesium concentrations were decreased in various structures of the nervous central system. Ca deficiency plus Al load seems less deleterious than Ca/Mg deficiencies plus Al load and magnesium deficiency plus Al load appears more noxious than Ca/Mg deficiencies plus Al load. Neuronal morphometric alterations were observed only in the low magnesium groups. It is speculated that magnesium depletion, by increasing the Ca/Mg ratio in the CNS tissues, further accelerated the uptake of Al into the CNS which promoted the neurodegenerative processes. Lesser noxiousness of magnesium deficiency when combined with Ca deficiency might be mainly ascribed to a lower increase in cellular calcium. The physiopathological mechanisms of neurodegenerative and neurotoxic insults associate several intricated and interactive factors: e.g. excitotoxicity, depolarization, decreased energy metabolism and cationic gradient, increased Na and Ca cellular influx, oxidant and arachidonic cascades. Magnesium depletion due to systemic kainic acid (KA) plus magnesium deficiency appears as the model most closely linked to the main basic mechanisms of age-related neurological disorders. It associates low dietary magnesium intake (the most noxious decrease in neuroprotective factors) to the most deleterious excitotoxicity in elderly: kainic acid, an agonist of non-MDA receptors such as L-BMAA and L-BOAA. Relying on these data on endemic WP ALS-PD complex a general environmental theory of the bulk of the age-related neurodegenerative diseases has been hypothetized: NDD would be due to an accelerating ageing process caused by the sum of increased environmental slow deleterious factors and of decreased environmental protective factors (a low magnesium intake particularly). The very value of the environmental pathogenesis of the endemic prototypal neurodegenerative complex is not yet firmly established. Postulated nutritional deficiencies of Ca and Mg have only been inferred from indirect and therefore questionable data. Direct evaluation of Mg, Ca and heavy metal status in patients with ALS-PD and in Chamorro control subjects showed very similar results. It is even more hazardous to extrapolate from physiopathological data concerning endemic WP ALS-PD to sporadic cases,of amyotrophic lateral sclerosis (ALS), Parkinson's disease (P) and dementia of the Alzheimer's type (D). It has never been observed that patients with ALS or P or D had low Ca and Mg dietary intake. In these neurodegenerative diseases investigation of magnesium status disagrees with the hypothesis of magnesium deficiency, but stresses the possible role of some various types of magnesium depletion, with possible aetiopathogenic importance of chronic pollutant metal toxicity. More criticism can be expressed concerning extrapolation from environmental data on WP ALS-PD complex to other degenerative diseases presenting no common symptomatology such as multiple sclerosis or spongiform encephalopathies. From these studies mainly based on endemic WP ALS-PD data, it appears difficult to infer a general environmental scheme of the bulk of neurodegenerative diseases. But they have generated various experimental acquired models of magnesium depletion whose pathogenic mechanisms are linked to those of neurodegenerative diseases, particularly when excitotoxicity and magnesium deficiency were combined. Today, magnesium supplementation carried out with the usual magnesium salts either at physiological or at pharmacological doses appears of little help as a curative treatment of neurodegenerative diseases. It might even be contraindicated in such cases as Alzheimer's disease and multiple sclerosis. But the experimental models of magnesium depletion related to neurodegenerative diseases should constitute promising tools for the screening of effective treatments.
