How Aluminum Causes Alzheimer’s Disease: The...

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IntroductionAluminum has been identified as a

neurotoxin for over 100 years.1 Its toxicimpacts were demonstrated most dra-matically when long-term hemodialysispatients (with chronic renal failure) weretreated with aluminum-containing phos-phate binders, and/or dialysate made us-ing water with high dissolved aluminumlevels.2 Many of these kidney patients de-veloped dialysis dementia and other com-plications including osteomalacia andosteoporosis.

There are similarities between thebrains of Alzheimer’s and dialysis demen-tia patients. Senile plaques have been ob-served in both, as have decreased levelsof choline acetyltransferase activity andgamma-aminobutyric acid concentra-tions.3-6 Such similarities have providedfurther support for the hypothesis thataluminum toxicity is the key to Alzheim-er’s disease, although many researchersreject this suggestion.7 Opponents of thisviewpoint argue that aluminum deposi-tion in the brains of Alzheimer’s patientsonly occurs late in the disorder, becausethe blood-brain barrier preventsaluminum entry until it is damaged byextensive nerve cell death or by othercauses, such as amyloid deposition. Sec-ondly, they claim that even when incor-porated into the brain, aluminum is rela-tively benign. Thirdly, they point out thatpathological changes caused experimen-tally in animals by aluminum are notidentical to those seen in the brains ofAlzheimer’s disease patients.9 This arti-cle provides evidence to refute suchobjections.

Geographical and Epidemiological Evidenceof Aluminum’s Involvement in Alzheimer’sDisease

Drinking water usually contains be-tween 0.01 and 0.15 mg per litre ofaluminum, but some potable water mayhave as much as 0.40 mg per litre or more.9

While this represents only a small percent-age of total dietary aluminum, it is possi-ble that because of repetitious exposureand increased species solubility, aluminumfrom drinking water may provide a largecomponent of the total aluminum ab-sorbed. Priest10 has shown that the fractionof dietary aluminum entering the tissuesmay vary from as much as 0.01 for aluminumcitrate to 0.0001 for insoluble species, suchas aluminum silicates and oxides. Most ofthis absorbed aluminum tends to be ex-creted if kidney action is normal, but about5 per cent is deposited in the body, mainlyin the skeleton.11 It was established by Sohlerand coworkers12 as early as 1981, however,that in 400 psychiatric outpatients in NewJersey, memory loss increased as bloodaluminum levels rose.

It has been shown that, in Norway,13-14

England and Wales15 and Canada,16 theprevalence of Alzheimer’s disease rises asdissolved aluminum in potable water sup-ply increases. Conversely, there is some evi-dence that where drinking water containsthe aluminum antagonist fluoride, Alzhe-imer’s disease prevalence may be de-pressed.17-18 This latter point is open to de-bate since the acidity of drinking watergreatly affects the aluminum speciesformed when fluoride is present, some ofwhich are easily absorbed and others not.19

Other sources of exposure to aluminuminclude tea, certain food additives (such asthose often found in chocolate), aluminum

How Aluminum Causes Alzheimer’s Disease:The Implications for Prevention and Treatment

of Foster’s Multiple Antagonist Hypothesis

1. Department of Geography, University of Victoria P.O.Box 3050, Victoria, BC V8W 3P5

Harold D. Foster, Ph.D.1

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Journal of Orthomolecular Medicine Vol. 15, No. 1, 2000

foil, cans and cookware, antacids, enteric-coated aspirin and some antiperspirantsand deodorants.20

Aluminum also is always present inambient air but numerous industrial work-ers inhale far more than the 4.4 microgramaverage daily intake from the air.10 Inhaledaluminum appears to be neurotoxic undercertain special conditions. To illustrate,silica has a well known ability to protectagainst aluminum and vice versa. For thisreason, between 1944 and 1979, many min-ers were given aluminum powder as aprophylaxis against silicotic lung disease.An aluminum “bomb” was let off after eachshift and the miners inhaled its dust in aneffort to protect themselves against silica.During a study21 conducted during 1988and 1989, miners who had been exposedto aluminum dust in this way were foundto show abnormal cognitive deficits, theirneurological problems increasing with theduration of their exposure.

Probably the most significant evidenceof the possible link between dementia andaluminum comes from an Ontario study in-volving 668 autopsy-verified Alzheimer’sdisease brains. These showed that the riskof developing Alzheimer’s disease is about2.5 times greater in individuals from com-munities drinking water containing morethan 100 mcg per litre of aluminum, thanit is in individuals from communities wherethe potable water contains less than thislevel of aluminum.22

It is not the author’s objective here topresent all the epidemiological and geo-graphical evidence that is available to sup-port a role for aluminum in Alzheimer’s dis-ease. Readers wanting a more comprehen-sive introduction to this literature are di-rected to Doll’s9 “Review: Alzheimer’s dis-ease and environmental aluminum” in Ageand Ageing and to the double edition ofEnvironmental Geochemistry and Healththat was devoted largely to this topic.23

Foster’s Multiple Antagonist Hypothesis

Numerous hypotheses have attemptedto explain the neurodegenerative processesthat ultimately culminate in Alzheimer’sdisease. These focus, for example, on cal-cium homeostasis,24 beta-amyloid proteinand the apolipoprotein- E4 allele.25 None ofthese hypotheses, however, appear able toaccount for all the diverse geographical, so-ciological, pathological, biochemical andclinical aspects of the disease. For this rea-son, the author is presenting a new multi-ple antagonist hypothesis which appearscapable of explaining more fully theetiology of Alzheimer’s disease.

Antagonism among elements is widelyestablished. To illustrate, many diseases inlivestock occur because fodder, enriched inparticular minerals, results in shortages ofothers. Cobalt deficiencies, which causewasting in sheep and cattle, for example, canusually be linked to a high iron and manga-nese soil content.26 Such relationships be-tween minerals are commonplace and ap-pear to occur because ions with similar va-lence of electronic shell structures, or simi-lar electronic configurations,27-30 are antago-nistic towards each other. Aluminum showsthis type of antagonism towards divalentmetals including zinc, phosphorus, calciumand magnesium.31-34 Aluminum’s biologicalactivity is influenced further by at least twoother elements, silicon and fluorine, somecompounds of which are able to chelate itwhile others promote its solubility. Dietarylevels of minerals formed from these six el-ements greatly affect aluminum’s absorptionby the digestive tract and its ability to crossthe blood-brain barrier. If it reaches thebrain, aluminum’s negative impact again isdue largely to its antagonism with calcium,magnesium, phosphorus and zinc, since ithas a strong tendency to replace them inimportant enzymes and proteins. The result-ing novel compounds then create cascadesof biochemical dysfunctions which eventu-ally cause neuronal degeneration, ultimatelyculminating in Alzheimer’s disease. Evidenceto support this hypothesis is presented now,

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How Aluminum Causes Alzheimer’s Disease

together with a discussion of its implicationsfor the prevention and treatment of thisform of dementia.

Alzheimer’s Disease: the ChallengeAlzheimer’s disease affects at least 4

million people in the United States andprobably over 11 million more world-wide,chiefly in the developed world.25 It is mostcommon in the elderly, but between 2 and7 percent of cases are associated with in-herited genetic mutations which can causethe disease in people as young as 30 yearsold. Three rare genes have been implicatedin such early-onset Alzheimer’s cases, butthese stand apart from the major suscepti-bility genes linked to Alzheimer’s in the eld-erly. Most Alzheimer’s patients, however,develop the disease after age 65, withoutany previous family history of this disor-der.25 Apart from genetic susceptibility andaging, other identified risk factors for thedisease are malnutrition, lack of educationand head trauma.25, 35-36

Alzheimer’s disease, a normally irre-versible brain disorder, is characterized byinsidious onset and progressive loss of in-tellectual capacity. This decline in the abil-ity of the brain to function is linked to theformation of senile plaques, neurofibrillarytangles and to the granulovascular degen-eration of neurons in the cerebral cortex.37

Other nerve cell degeneration in the sub-cortical area of the brain also has been re-corded.38 Such brain abnormalities weredocumented first by the German physicianAlois Alzheimer in 1907,39 hence the nameof the disease.

Biochemically, Alzheimer’s disease isknown to involve malfunctions in thecholinergic and catecholaminergic systemswhich are linked, for example, to deficien-cies of the neurotransmitters acetylcholineand dopamine. Another hallmark of Alzhe-imer’s disease is a decrease in brain glucosemetabolism. Such changes in the brains ofAlzheimer’s patients are not typical of ag-ing. Indeed, Byell and Coleman40 suggest

that while degenerative dendritic changesdo occur in some cells as a usual conse-quence of aging, these seem associated witha simultaneous thickening of branches inother cortical neurons. This suggests thatin normal aging there is an attempt to com-pensate for neural degeneration which doesnot occur in Alzheimer’s brains.41

Typically, memory loss is the first ob-vious sign of the early stage of Alzheimer’sdisease. Then subtle personality shifts be-gin to appear, including signs of apathy andwithdrawal. By the middle stage of the dis-ease appearance and behaviour tend to de-teriorate and wandering may become moreapparent. Intellectual personality distur-bances increase and depression or delusionsmay appear, followed by delirium. As pro-gression occurs, the patient may becomemute, incontinent and incapable of self-care.Death ultimately follows. From onset tomortality, the average course of Alzheimer’sdisease is usually between 5 to 8 years.

Any hypothesis attempting to explainthe etiology of Alzheimer’s disease must,therefore, be able to account for the disor-der’s known risk factors (such as its in-creasing frequency with age), its links togenetic aberrations, its associated neuro-logical and biochemical abnormalities andits clinical symptoms.25 The rest of this ar-ticle is an attempt to meet this challenge.

Aluminum’s Absorption by the IntestinalTract

While exposure to aluminum is ubiq-uitous, how much of it is absorbed by theintestinal tract and how easily this is ex-creted depends upon a variety of complexinterrelationships. To illustrate, there isconsiderable evidence to show that whendietary calcium intake is low, or whenaluminum intake is very high, the lattermay substitute for the former, or may usesome of the same transport mechanismsto gain access to the brain.42 This is mostlikely to occur in individuals drinkingacidic water, which may explain why the

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prevalence of Alzheimer’s disease increasesin areas that experience acid rain.43 Rela-tionships between aluminum and calciumare complex, as illustrated by the impactof aluminum-containing antacids on theabsorption of calcium and other minerals.44

Even small doses of such antacids signifi-cantly increase fecal fluoride, indicating adecline in its intestinal absorption. Antac-ids that contain aluminum also impact onphosphorus and calcium metabolism, andtheir primary effect is the complexation ofintestinal phosphorus, which results in itsdepletion. This change in phosphorus me-tabolism results in a rise in urinary andfecal calcium excretion, which often is suf-ficient to produce a negative calcium bal-ance. Animal experiments suggest thataluminum absorption also is greatly af-fected by parathyroid hormone and activevitamin D levels, both of which are involvedin calcium homeostasis. Rats45 fed on a dietcontaining elevated aluminum, for exam-ple, produced high levels of parathyroidhormone, which in turn increased gastro-intestinal aluminum absorption. This ele-ment was subsequently deposited in thebrain. Chickens given supplements of ac-tive vitamin D also developed increasedaluminum brain content.46 In contrast, dogswith low levels of vitamin D suffered sig-nificantly more aluminum accumulation intheir bones, independently of parathyroidhormone status.47

Such animal studies also demonstratethat diets deficient in calcium alone, or lowin calcium and magnesium (with or with-out added aluminum) can reduce absorp-tion of magnesium and increase that ofaluminum.48 Low calcium and highaluminum diets in rats, for example, dimin-ish magnesium in the bone and in the cen-tral nervous system, and induce loss of cal-cification in the former and tissue degen-eration in the latter.49 Furthermore,aluminum has been shown to decrease thezinc concentration of the bones and softtissues of rats fed a low calcium-magne-

sium diet.50 Beyond this, it has been estab-lished that in rats fed magnesium-deficientdiets there is diminished kidney function,51

which seems likely to provide greater ac-cess of aluminum to soft tissues. This de-cline in kidney function is associated withcalcium deposition in tubules. The antago-nism between magnesium and aluminum,therefore, is clearly established52 but itwould appear that magnesium intake alsoinfluences the bioavailability of both cal-cium and zinc.

Aluminum also has a high affinity forsilicon which influences its absorption bythe intestinal tract. This was demonstratedby a British clinical trial, conducted byEdwardson and coworkers,53 in which vol-unteers were given an aluminum tracer(26Al) dissolved in orange juice. Elevatedlevels of this element were later detectedin their blood. Six weeks later the same vol-unteers drank orange juice, again contain-ing aluminum but to which sodium silicatealso had been added. After this secondchallenge, blood aluminum level rose toonly 15 percent of that previously reachedin the absence of silica. Edwardson andcolleagues argued that the geographicalassociation between Alzheimer’s diseaseand levels of aluminum in water suppliesreflects this inverse relationship betweenaluminum and silicates. It is believed silicapromotes the formation of aluminosilicatespecies, limiting the gastrointestinal ab-sorption of aluminum.

Fluorine also has an affinity foraluminum and influences its absorption.Fucheng and coworkers,54 for example, havedescribed high incidences of osteoporosis,osteomalacia, spontaneous bone fracturesand dementia in certain villages in GuizhouProvince, China. These diseases are verysimilar to those occurring in European di-alysis patients, treated with water and gelscontaining aluminum.55 Fucheng and col-leagues discovered that such Chinesehealth problems stemmed from eatingmaize which had been baked in fires of coal

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mixed with kaoline. The latter contained19.3 percent aluminum and 7000 ppm fluo-rides. In this area, fluoride levels in drink-ing water also were elevated. Bonealuminum and fluoride levels were foundto be 25 times higher in maize-eating vil-lagers than they were in controls. Tests withrats confirmed that in the presence of el-evated fluorides, the toxic dose of aluminumin food may be reduced to 100 ppm or less.The implications of this fluoride-aluminumrelationship to Alzheimer’s disease are un-clear, but demonstrate that aluminum canbe neurotoxic in individuals who do notsuffer from kidney malfunction.

The solubility of aluminum and prob-ably the ease with which it is absorbed var-ies markedly with pH, being lowest at aboutpH 6.5.56 Aluminum’s solubility, therefore, isgreatest in highly acid or highly alkalinewaters. However, since the latter usually con-tain elevated calcium and/or magnesium ittends to be the greatest health threat whendissolved in acidic water. It is also believedthat fluorine complexes aluminum at acidicpH values, forming species such as solvatedAlF2+ and AlF2.57 At a higher pH, the pre-dominant form of aluminum is Al(OH4)

_.

These relationships have been discussed atlength by Forbes and coworkers.19 In general,therefore, aluminum is most soluble inacidic water, especially if it contains fluo-rides. Tennakone and Wickramanayake58 forexample, have shown that the presence ofonly 1 ppm of fluoride in water adjusted withsodium bicarbonate or citric acid to pH3,and boiled in an aluminum vessel, releasesnearly 200 ppm aluminum in 10 minutes.Prolonged water boiling can elevate dis-solved aluminum to 600 ppm. In contrast, ifsuch water contains no fluoride, only 0.2ppm aluminum levels are reached. In addi-tion, in 10 minutes, 50 grams of acidiccrushed tomatoes cooked in 200 ml of wa-ter containing 1 ppm fluoride produced apaste containing 150 ppm aluminum. Insummary, acidic food or water, especially iffluoride is present, can leach excessive

aluminum from cooking vessels. Further-more, tea brewed in soft (acidic) water or fla-voured with lemon juice contains significantlyhigher levels of bioavailable alum-inum59-60 thannormal. These links between fluorine andaluminum may be of great significance inAlzheimer’s disease since, in a recent study,Varner and co-workers61 have demonstratedthat the chronic administration of thefluoraluminum complex (AlF3) to rats, indrinking water, resulted in elevatedaluminum levels in brains and kidneys.These high levels of aluminum were associ-ated with damage to rat neuronal integrity,not seen in controls drinking double distilleddeionized water.

Beyond such antagonistic andsynergistic relationships with specific bulkand trace elements, it is clear that certainaluminum compounds inherently are moreeasily absorbed than others. McLachlan andKruck,62 for example, have fed a wide vari-ety of aluminum compounds to rabbits toestablish variations in absorption rates. Theydiscovered that aluminum citrate, formedwhen aluminum reacts with the citric acidin oranges or tomatoes, caused the absorp-tion of aluminum to increase by a factor of2.5. This is of particular interest becauseoranges and tomatoes also are known toincrease calcium absorption, which needsacid for assimilation.63 McLachlan andKruck’s rabbit experiments further estab-lished that aluminum maltolate, producedwhen this metal reacts with maltol (an ad-ditive that usually is found in hot choco-late, beer and some commercially bakedgoods), raised aluminum uptake someninetyfold. Aluminum citrate and alum-inum maltolate, therefore, seem particu-larly capable of entering the body.

Aluminum and the Blood-Brain BarrierInvestigators who oppose the patho-

genicity of aluminum in Alzheimer’s dis-ease have claimed that the blood-brainbarrier will prevent this neurotoxic metalfrom impacting on the brain until after se-

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rious damage already has occurred fromother causes.64-65 This argument is incorrect.Yumoto and coworkers66 injected the radio-isotope 26Al into healthy rats and show-ed that a considerable amount of thisaluminum isotope was incorporated intothe cerebrum within five days after one in-jection and continued to show a gradualincrease in the brain for a further 70 days.This accumulation of aluminum was ac-companied by a decline in dendrites incortical nerve cells and in attached spines.These changes implied a decrease in theamount of information that could be re-ceived. Many similar changes have beenreported from Alzheimer’s brains.

Aluminum’s ability to cross the blood-brain barrier is influenced by the form inwhich it is absorbed and the levels of othercompounds in the blood. To illustrate, it hasbeen discussed previously that aluminummaltolate is absorbed easily by the intesti-nal tract. It appears also to be capable ofquickly crossing the blood-brain barrier.67

Furthermore, as it does, it increases thepermeability of this barrier, a process withsubsequent serious toxicity implication.That is, aluminum maltolate may affect theblood-brain barrier adversely, making itpermeable to other damaging toxins. Thismay account for the variety of symptomsseen in subtypes of Alzheimer’s disease andeven in some other forms of dementia. In-terestingly, Rao and colleagues68 have sug-gested that maltolate-treated, elderly rab-bits can be used as a good animal model ofAlzheimer’s disease because of their neu-rofibrillary pathology.

Aluminum maltolate is not the onlysubstance that can enhance aluminum’sability to cross the blood-brain barrier. Toillustrate, Deloncle and coworkers69 haveshown that when there is an increase insodium L-glutamate in whole blood,plasma aluminum penetrates red bloodcells. This suggests that aluminum crossesthe erythrocyte membrane as a glutamatecomplex. Experiments with rats have dem-

onstrated that similarly, aluminum canpass the blood-brain barrier as a glutamatecomplex and then be deposited in the cor-tex. This aluminum-L-glutamate complexis neurotoxic in vivo.70 Nevertheless,aluminum enters neurons and alone in-duces possible conformational changes intau which are detected by the Alz-50 anti-body. Aluminum combined with glutamateor glutamate by themselves do not.71

Aluminum and the BrainOn reaching the brain, aluminum be-

gins to antagonistically replace calcium,magnesium, zinc and phosphorus in vari-ous enzymes and proteins. As a conse-quence, it sets in motion a series of bio-chemical cascades involving abnormalprocesses, which together eventually cul-minate in the pathologic and clinical symp-toms known as Alzheimer’s disease. Severalexamples will now be provided, but noclaim is made here that all such antagonis-tic relationships have been identified, orthat they are necessarily limited to calcium,magnesium, zinc and phosphorus.

(i) Aluminum and glucose metabolismDecreased glucose metabolism is a

hallmark of Alzheimer’s disease.72 It appearsto occur because of aluminum’s bindingwith the phosphate enzyme, glucose-6-phosphate dehydrogenase and its interfer-ence with hexokinase.73 To illustrate, Choand Toshi74 purified two isozymes from pigand human brains and established thatthey contained an enzyme-aluminum com-plex. They were then able to demonstratethat glucose-6-phosphate could be com-pletely inactivated by aluminum, but thatthis enzyme’s potency could be restored bythe three aluminum chelators: citrate,sodium f luoride and apotransferrin.Aluminum’s negative impact on glucosemetabolism, however, is not limited to in-hibiting the glucose-6-phosphate enzyme.Lai and Blass75 have shown that this metalalso inhibits hexokinase activity in the rat

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brain, but that high levels of magnesiumcan reverse this process. Aluminum alsoappears to inactivate hepatic phosphofruc-tokinase, an important control site in theglycolytic pathway.76

(ii)Aluminum and the cholinergic systemCholinergic neurotransmitter deficits

are characteristic of Alzheimer’s disease.25

Indeed, a deficiency of acetylcholine is thebasis for a recognized diagnostic test forthis disorder.77 Such malfunctioning of thecholinergic system appears to be caused byaluminum’s ability to inhibit the activities ofthe enzyme choline acetyltransferase,78-80 adeficiency of which has been confirmed inAlzheimer’s disease by several researchersincluding Perry,81 Gottfries80 and Quirionand coworkers.82 In addition, some neuriticplaques have been shown to contain ace-tylcholinesterase-beta amyloid proteincomplexes, further compromising the func-tioning of the cholinergic system.83 As is de-scribed in the following discussion, the de-velopment of such plaques is also the re-sult of aluminum’s disruptive influence.

Interestingly, Gottfries and colleagues84

have established that in the early stagesof Alzheimer’s disease, elevated serum ho-mocysteine appears to be a sensitivemarker for cognitive impairment.85

Choline deficiency raises homocysteinelevels by altering the metabolism of me-thionine86 and would, therefore, accountfor both homocysteine’s presence at highlevels in the serum and associated cogni-tive impairment. Certainly, there is an ex-tensive literature 87-91 that indicates thatthe malfunctions that occur in the cholin-ergic system in Alzheimer’s disease are ac-companied by selective degeneration ofcholinergic neurons in the cortex, hippoc-ampus and base of the forebrain. This ishighly significant because such acetylcho-line-containing neurons play a key role inmemory and affect the highest levels ofcognitive functioning.(iii) Aluminum and the catecholaminergic

systemAltman and coworkers92 have shown

that, in patients on hemodialysis, levels ofthe enzyme dihydropteridine reductase areinversely related to serum aluminum con-centrations. When such patients were giventhe aluminum-chelating agent desferri-oxamine, their dihydropteridine reductaseactivity doubled. This depression ofdihydropteridine reductase by aluminum isextremely significant since this enzyme isessential for the maintenance of normalbrain concentrations of tetrahydro-biopterin, which is itself required for thesynthesis of the neurotransmitters,dopamine, norepinephrine and serotonin.

As might be expected, if Alzheimer’sis caused by aluminum neurotoxicity, lev-els of tetrahydrobiopterin are depressedsignificantly in the cerebrospinal fluid ofpatients suffering from this disease.93 As aconsequence, the brains of Alzheimer’spatients contain more neopterin94 and lessdopamine, norepinephrine and serotoninthan those of controls.95-96

Several studies have demonstrated thatthe subnormal production of theseneurotransmitters appears to be linked tothe death of dopamine receptors andnoradrenergic and serotonergic neurons inthe cortex and elsewhere in the Alzheim-er’s brain. Joyce and coworkers,97 for exam-ple, argued that the loss of the D2 receptor-enriched modules in the brains of Alzhe-imer’s patients contributed to disturbancesin information processing that may be re-sponsible for cognitive and non-cognitiveimpairments. Similarly, Palmer98 has sug-gested that the absence of noradrenergicand serotonergic neurons probably contrib-utes to the non-cognitive impairments inbehaviour seen in Alzheimer’s patients.

It is possible that aluminum impactsmore directly on the catecholaminergic sys-tem. Marinho and Manso,99 for example,have studied the effects of different con-centrations of aluminum sulphate on thenonenzymatic oxidation of dopamine, con-

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ducting these experiments to evaluate theaction of aluminum on neuromelanin syn-thesis. Their results indicate that aluminumpartially inhibits dopamine self-oxidation,decreasing the formation of such interme-diate compounds as dopaminequinone anddopaminochrome. This suggests that if, asbelieved, neuromelanins have a cyto-protective function in the central nervoussystem, where they are thought to act asfree scavengers of redox metal ions and freeradicals, then their reduction by aluminumcould accelerate the damage of neuronaltissues by oxidative stress.

Furthermore, Singh and colleagues100

have described the high toxicity ofaluminum phosphide which is used widelyas a fumigant in India. Accidental poison-ing with this aluminum compound is rela-tively common and its dominant clinicalfeature is severe hypotension related todopamine. This appears to further confirmthat aluminum has a direct impact on thecatecholamine system.

Wenk and Stemmer101 have shown that,in rats, the neurotoxic effects of ingestedaluminum are dependent on the dietaryintake of copper, zinc, iron and magnesium.To illustrate, norepinephrine levels in thecortex and cerebellum are depressed in ratsreceiving a high aluminum, low copper diet.Similarly, suboptimal iron levels reducenorepinephrine in the cerebellum. Further-more, diets containing aluminum but lit-tle copper or zinc decreased cortexdopamine levels. These data suggest thataluminum’s impact on the catechola-minergic system is complex and dependsvery much on the presence, or absence, ofadequate levels of various bulk and traceelements in diet.

(iv) Aluminum and parathyroid hormoneAdenylate cyclase is a catecholamine

sensitive enzyme102 that plays a significantrole in parathyroid hormone secretion. Cal-cium inhibits adenylate cyclase activity butmagnesium promotes it, so stimulating the

production of parathyroid hormone.103 In-deed, Zimmerman and colleagues104 havesuggested that the adenylyl cyclase cata-lytic mechanism involves two magnesiumions. Animal studies have established thataluminum can cause an irreversible acti-vation of adenylate cyclase that Ebstein andcoworkers have suggested may be one rea-son for this metal’s neurotoxicity.105 Indeed,although while adenylate cyclase activitydeclines in the non-demented elderly, nosuch reduction is seen in Alzheimer’s pa-tients, who typically show abnormally highbrain adenylate cyclase activity.106

(v) Aluminum and the glutamatergic systemThere is a profound reduction in

glutamatergic neurotransmission in Alzhe-imer’s disease that results from the loss ofpyramidal neurons and cholinergic inner-vation.107 This deficit is associated with sig-nificantly depressed plasma glutamate lev-els and abnormally low glutamine cerebro-spinal fluid/plasma ratios.108 Furthermore,there appears to be a strong correlationbetween behaviour and coping ability inAlzheimer’s patients and cerebrospinalfluid glutamate levels, which provides clearevidence of a role for the disruption ofamino acid metabolism in the disease.

Rabbit studies with intracisternally ad-ministered aluminum-powder have shownthat this element causes significant de-creases in glutamate decarboxylase activ-ity in the cerebellum.109 In addition,aluminum impairs the glutamate-nitricoxide-cyclic GMP pathway in neurons110

and appears to inhibit glutamate releasefrom the rat hippocampus.111 Aluminumchloride also has been shown to slow therate of accumulation of L-glutamate in ratforebrain nerve-ending particles, in a dose-dependent fashion, so influencing neuro-transmitter substance transport.112 As hasbeen discussed previously when reviewingaluminum’s ability to cross the blood-brainbarrier, aluminum can react with glutamateto form an aluminum L-glutamate complex

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that is neurotoxic in vivo.69,70 This may bebecause aluminum, as has been shown,potentiates both glutamate-induced cal-cium accumulation and iron-induced oxy-gen free radical formation in primary neu-ronal cultures,113 suggesting that thealuminum-glutamate association may in-crease neuronal oxidative stress.

(vi) Aluminum and neuritic plaquesThe brains of Alzheimer’s patients are

characterized by neuritic plaques, whichare composed of abnormal proteins. Thecores of such plaques consist of beta-amy-loid, a sticky snippet of a larger protein,amyloid precursor protein. It has been es-tablished that beta-amyloid involved insuch plaques is created when the brain isdeficient in acetylcholine, a shortage thatcauses amyloid precursor protein to breakdown.78, 114 As has been discussed previously,acetylcholine deficiency is a hallmark ofAlzheimer’s disease because of aluminum’sability to inhibit the activities of the en-zyme choline acetyltransferase,78 so inter-fering with the normal operation of thecholinergic system.83 In addition, as pointedout already, some neuritic plaques containacetylcholinesterase-beta amyloid proteincomplexes, which further disrupt thecholinergic system.83

Perry115 has demonstrated that in post-mortem Alzheimer’s brain tissue, there isan inverse relationship among the activi-ties of choline acetyltransferase and acetyl-cholinesterase and senile plaque numbers.Furthermore, plaques that contain acetyl-cholinesterase have a higher resistance tolow pH and to anti-cholinesterase inhibi-tors and are more cytotoxic than normalplaques.116

(vii) Aluminum and neurofibrillary tanglesNeurofibrillary tangles also are a char-

acteristic of Alzheimer’s brains. Such tan-gles consist mainly of an abnormal form ofthe protein tau which is highly and unusu-ally phosphorylated.117 Calcium/calmodulin

kinase II acts as a catylist in the phospho-rylation of tau,118 a process that is stimu-lated by two phospholipids,119 phospha-tidylserine and phosphatidyl-ethanolamine.However, aluminum interacts withcalmodulin by displacing the Ca-ion to forma stable Al-calmodulin complex.117-120 Underthese circumstances, calmodulin becomesless flexible, is prevented from reacting withseveral other proteins and is inhibited in itsregulatory functions. In addition, aluminumcreates fatty acid abnormalities in thephospholipids, which normally stimulate thephosphorylation of tau.117,121

Beyond this Yamamoto and collea-gues122 have shown that aluminum appearsto inhibit the dephosphorylation of tau inthe rat brain. It seems likely, therefore, thatin the presence of elevated aluminum bothphosphorylation and dephosphorylation oftau are disrupted, largely by the replace-ment of calcium by aluminum incalmodulin.

Furthermore, hemodialysis patientsexposed to elevated aluminum develop de-pressed serum alkaline phosphatase lev-els.123 Abnormally low phosphatase concen-trations also have been reported fromAlzheimer’s patients’ brains.124 Aluminum-induced abnormalities in levels ofphosphatases, enzymes required to removephosphate groups from protein, also appearto be involved in the formation of neurofi-brillary tangles. It would appear that suchaluminum-induced lack of phosphatase,125

in the brains of Alzheimer’ patients, occursbecause of an excess of phosphates in tauthat prevent this protein from performingits normal role of securing vital parts of theneuronal cytoskeleton. The cell, therefore,is harmed and hyperphosphorylated tau isprecipitated to form tangles. According toRoushi126 animal studies suggest that suchextra phosphates may cause neural dam-age even before tangles form, by interfer-ing with one of tau’s normal functions, as-sembling and stabilizing the microtubulesthat carry cell organelles, glycoproteins and

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other vital substances through neurons.It has been demonstrated that the

more phosphate groups that are attachedto synthetic neurofilament fragments, theeasier it is for aluminum ions to bind andcross-link neurofilaments.125 The presenceof aluminum, therefore, appears to changethe paired helical filaments that make upneurofibrillary tangles so that they accu-mulate and are not removed, in the nor-mal way, by protein-digesting enzymes.

Interestingly, a laser microprobe studyof the elemental content of neurofibrillarytangles in Alzheimer’s disease, conducted byGood and coworkers,127 established that theonly metallic elements found to be consist-ently present were aluminum and iron.

(viii) Aluminum and brain cell membranesIn Alzheimer’s patients, cellular brain

membranes display abnormal viscositywhich appears to disrupt the activities ofvarious enzymes, receptors and membranecarriers and may be linked to dendriticspine loss.128 These abnormalities seem as-sociated with irregularities in the biochem-istry of the phospholipids that concentratein such brain cell membranes. Corrigan andcoworkers,130 for example, have shown thatin Alzheimer’s disease phospholipids fromthe parahippocampal cortex, includingphosphatidylcholine, phosphatidylserineand phosphatidylinositol, contain belownormal levels of alpha-linolenic acid. In ad-dition to this depression of the level of n-3polyunsaturated fatty acid, abnormalitiesalso occur in levels of n-6 essential fattyacids. It has further been demonstrated fur-ther that, not only are the biochemical com-positions of phospholipids from Alzheimer’spatients abnormal, but that total concentra-tions of such membrane phospholipids arelow130 and that their regional distribution inthe brain is irregular.131

It has been suggested that the bio-chemical abnormalities seen inphospholipids in Alzheimer’s disease resultfrom elevated oxidative stress.121 However,

aluminum also appears more directly in-volved. To illustrate, aluminum chloride hasbeen shown to inhibit the incorporation ofinositol into phospholipids.132 Deleers andcoworkers133 also have demonstratedaluminum-induced lipid phase separationand fusion of phospholipid membranes.However, it seems more likely that disrup-tion of phospholipase A2 by aluminum 134

is probably the main cause of the biochemi-cal abnormalities seen in phospholipids inAlzheimer’s disease, and the chief cause ofassociated brain membrane dysfunctions.Certainly, phospholipase A2 plays a key rolein the metabolism of membrane phospho-lipids,135 is decreased in Alzheimer’s dis-ease136 and is inhibited by aluminum chlo-ride.134

In addition, aluminum has a direct effecton cell membranes. Dill and coworkers, 137 forexample, have proved that the addition ofmicromolar quantities of aluminum chlorideto phospholipid membranes containingVDAC channels greatly inhibits the voltagedependence of the channels’ permeability,encouraging them to remain open. It wouldappear, therefore, that both through its an-tagonism with phosphorus and by its owndirect impact, aluminum adversely affectsthe functioning of cellular brain membranesin Alzheimer’s disease.

(ix) Aluminum and oxidative stressThere is overwhelming evidence that

Alzheimer’s disease brain cells are sub-jected to elevated oxidative stress and thatamyloid plaques are a focus of cellular andmolecular oxidation. Much of the destruc-tion of neurons which characterizes Alzhe-imer’s disease has been linked to the lipidperoxidation of cell membranes caused byfree radicals. This process seems to occurbecause of disturbed defense mechanismsin Alzheimer’s disease which are associatedwith a self-propagating cascade ofneurodegeneration.138-139 It has been estab-lished, for example, that Alzheimer’s pa-tients display depressed plasma antioxi-

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dant status associated with significantlylow vitamin E levels.140

There is considerable evidence thataluminum itself reduces the body’s defenseagainst free radical damage. In dialysispatients, for example, serum glutathione-peroxidase levels are significantly de-pressed.141 Similarly, animal studies havedemonstrated that the oral administrationof aluminum sulphate, especially in thepresence of citric acid, inhibits brainsuperoxide dismutase and catalase activi-ties.142 Interestingly, vitamin E, which isdepressed in Alzheimer’s patients, can pro-tect rats against associated aluminum-in-duced free radical damage.143 Other evi-dence of the significance of oxidative stressincludes a significant increase in erythro-cyte Cu/Zn superoxide dismutase and cata-lase activity in the blood of Alzheimer’spatients144 and a pronounced increase insuperoxide dismutase immunoreactivity inolfactory epithelium.145

Exactly how aluminum is involved inthe catastrophic loss of neurons from freeradical damage is being established by vanRensburg and coworkers139,146 and Fu andcolleagues.147 The former have shown, forexample, that both beta-amyloid andaluminum dose-dependently increase lipidperoxidation in platelet membranes. Theirresearch has established that beta-amyloidis toxic to biological membranes and thataluminum is even more so.146 Beyond this,van Rensburg and colleagues have demon-strated that iron encourages lipidperoxidation both by aluminum and bybeta-amyloid protein. This is of consider-able interest since the only metallic ele-ments found in the neurofibrillary tanglesof Alzheimer’s disease are aluminum andiron.127 Van Rensberg and coworkers’ invitro model also showed that melatoninprevented lipid peroxidation by aluminumand beta-amyloid protein in the absence ofhydrogen peroxide. If the latter werepresent, melatonin could only slow theprocess.146

Fu and coworkers147 have begun to ex-plain how beta-amyloid specifically dam-ages neurons. Their cell culture researchhas shown that beta-amyloid interfereswith calcium homeostasis and inducesapoptosis in neurons by oxidative stress.This latter process involves the catecho-lamines (nonepinephrine, epine-phrine anddopamine) which increase beta-amyloid’stoxicity to cultured hippocampal neurons.These findings are very consistent with themuch earlier research of Hoffer, Osmondand Smythies148-149 who argued that the oxi-dation of adrenalin to adrenochrome wasresponsible for the hallucinogenic symp-toms seen in schizophrenia. More recently,Hoffer150 has suggested that the oxidationof dopamine to dopachrome lies behind thepsychotic symptoms seen in Parkinsonism,in many long-term levodopa users. Fu andcoworkers147 also have been able to showthat the antioxidants vitamin E, glutath-ione and propyl gallate can protect neuronsagainst damage caused by amyloid beta-peptide and the catecho-lamines.

Aluminum also may increase free radi-cal damage in Alzheimer’s disease by inhib-iting the protective copper/zinc metalloen-zyme, superoxide dismutase. Normally, thisis one of the major enzymes that providesprotection against free radicals. However,Shainkin-Kesterbaum and coworkers151

showed that in vitro, at the levels of the en-zyme found in dialysis patients, aluminumseverely inhibited its protective effects. Thisinhibition of superoxide dismutase’s anti-oxidant activity was directly proportionalto the level of aluminum. Silicon was foundalso to have a similar inhibitory effect onthe enzyme. The disruptive influence ofaluminum on superoxide dismutase mayaccount for the fact that, while zinc sup-plementation generally improves mentalalertness in the elderly, in Alzheimer’s pa-tients it accelerates deterioration of cogni-tion, encouraging amyloid plaque forma-tion.152 This may be because in the latterstages of Alzheimer’s disease it cannot be

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used in disrupted superoxide dismutaseproduction and so merely stimulates freeradical formation.

Aluminum and Established Risk Factorsin Alzheimer’s Disease

Any hypothesis seeking to explainAlzheimer’s disease must be able to accountfor established risk factors, namely: mal-nutrition, susceptibility genes, headtrauma, aging and lack of education.25 Anattempt will be made now to do this forFoster’s multiple antagonist hypothesis.

(i) MalnutritionThroughout this article, evidence has

been presented to show that diet influencesaluminum’s absorption, ability to cross theblood-brain barrier and likelihood of caus-ing brain damage. Furthermore, Grant153

has shown that epidemiological evidence isconsistent with the view that low fat, lowcalorie diets may lessen the risk of Alzhe-imer’s disease. Interestingly, Mazur andcoworkers154 have established that, in therat, low selenium diets increase plasmaapolipoprotein E levels. Similarly, Durlachand colleagues155 have suggested that, inhumans, vitamin E, selenium, magnesiumand other antioxidants can protect againstthe deleterious metabolic consequences ofapolipoprotein E4-4.

(ii) Genetic susceptibility to Alzheimer’sdisease

Recent studies have shown that elderlyJapanese and African-Americans living inthe United States have a much greaterprevalence of Alzheimer’s disease thanthose still residing in their ethnic home-lands. Environmental not genetic factorsmust, therefore, be the major agents re-sponsible for Alzheimer’s disease.156-157 Nev-ertheless, the likelihood of any first-degreerelative of a late-onset Alzheimer’s patientalso developing the disease is some fourtimes greater than in the population atlarge.158 There must be, therefore, at least

one genetic component to Alzheimer’s dis-ease. In fact, there appear to be several suchlinks. To date four genes have been identi-fied as playing a role in either early or late-onset Alzheimer’s: beta-amyloid precursorprotein, presenilin-1, presenilin-2 andapolipoprotein E genes.159 Workers havelinked most of these variants to familialearly-onset Alzheimer’s but the apolipo-protein E-4 allele is a relatively commondefinite risk factor for developing late-on-set Alzheimer’s disease.25

Considerable progress has been madein interpreting the significance of such ge-netic variants. To illustrate, mutations inthe presenilin-1 gene seem associated withincreased superoxide production andgreater vulnerability to amyloid beta pep-tide toxicity.160 Interestingly, mutations inthe presenilin genes, which are linked tomore than 40 per cent of all familial Alzhe-imer’s disease cases, cause enhanced pro-duction of an abnormal form of beta-amy-loid precursor protein.161 This protein islonger than normal, aggregates more rap-idly, kills neurons in culture more effec-tively and precipitates preferentially toform amyloid plaques. The same elongatedprotein is also produced as a result of mu-tations in the gene encoding beta-amyloidprecursor protein.

As has previously been described,aluminum interacts with L-glutamate toform a complex that can cross the blood-brain barrier.69 This reaction appears to leadto depressed plasma and cerebrospinal fluidlevels of glutamate and glutamine.162 Thelargest familial Alzheimer’s disease kindreddiscovered to date occurs in Antioquia, Co-lumbia.159 These individuals appear to de-velop Alzheimer’s disease because of a ge-netic mutation that results in a glutamicacid-to-alanine substitution in presenilin-1.That is, members of the Antioquia diseasekindred are short of glutamic acid. A simi-lar deficiency might be expected to be asso-ciated with aluminum-induced depressionof glutamate and glutamine.

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An apolipoprotein E variant predis-poses a significant section of the popula-tion to late-onset Alzheimer’s disease.25 Thismay occur in several ways. Pratico andcoworkers163 have shown that in apolipo-protein E deficient mice, oxidative stress inincreased, encouraging arteriosclerosis.Interestingly, the oral supplementation ofvitamin E suppresses this degenerativeprocess. Naiki and colleagues164 also havedemonstrated that normal apolipoproteinE inhibits beta-amyloid fibril formation invitro. Indeed, it would seem that in normalbrains apolipoprotein E efficiently bindsand sequesters beta-amyloid peptide, pre-venting it from forming senile plaques.165 InAlzheimer’s disease, associated with thisgenetic variant there is impaired apolipo-protein-beta-amyloid peptide binding, re-sulting in an accumulation of beta-amyloidpeptide which facilitates senile plaque for-mation.

The literature suggests, therefore, thatthe gene variants that predispose to bothearly and late-onset Alzheimer’s disease doso because they either increase susceptibil-ity to, or mimic, the aluminum-related de-generative processes previously described.That is, the genetic mutations involved inpromoting the development of Alzheimer’sdisease duplicate some of aluminum’s del-eterious impacts on the brain and in sodoing, encourage at least one of the follow-ing: the growth of neuritic plaques or neu-rofibrillary tangles, excessive free radicalformation and higher neural oxidativestress. As a consequence, unfortunate in-dividuals carrying any one of the geneticvariants are much more likely to developAlzheimer’s disease, whether or not they areexposed to the aluminum excess or vita-min and mineral deficiencies, that are nor-mally associated with its etiology.

(iii) Head TraumaControversy continues over whether or

not traumatic brain injury increases theprobability of developing Alzheimer’s dis-

ease.166 Launer and coworkers167 sought toanswer this question by performing apooled analysis of four European popula-tion-based prospective studies of individu-als aged 65 years and older. These data in-cluded 528 incident dementia patients and28,768 person-years of follow-up. Theiranalysis established that a history of headtrauma with unconsciousness did not in-crease significantly the risk of subsequentAlzheimer’s disease. Similarly, Nemetz andcolleagues168 followed up the medical his-tories of 1,283 traumatic brain injury cases,that had occurred in Olmsted County, Min-nesota, from 1935 to 1984. Thirty-one ofthese trauma patients subsequently haddeveloped Alzheimer’s disease, a numbersimilar to that normally expected in indi-viduals without head injuries. However, thedata clearly shows that such head traumahad reduced the time-of-onset of Alzheim-er’s disease by about 8 years, amongst per-sons at risk for developing it. That is, headtrauma does not appear to increase theprobability of developing Alzheimer’s dis-ease in the general population, however,those prone to it tend to suffer from it ear-lier than normally expected.

Why this happens is a question whichappears to have been answered by Nicolland coworkers.169 These researchers haveshown that the deposition of beta-amyloidin the brain had been promoted by headtrauma, in approximately one third of in-dividuals dying shortly afterwards from se-vere injury. The probability of deposition ofsuch beta-amyloid, following trauma, isgreater than would be anticipated statisti-cally in individuals with the apolipoproteinE-epsilon 4 allele, that is the allele that hasbeen linked to late-onset Alzheimer’s dis-ease. In short, in individuals with this geno-type, severe head trauma often appears toinitiate beta-amyloid deposition. Not sur-prisingly, if they survive the trauma, suchdeposition reduces the time-of-onset ofsporadic Alzheimer’s disease in those ge-netically prone to it since, of course, beta-

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amyloid is the major constituent of neu-ritic plaques.

(iv) Aging and increased prevalenceIn the United States, the prevalence of

severe dementia, much of it Alzheimer’sdisease, found amongst those aged 65 to74, is roughly 1 percent, compared to 25percent for those over 84.170 There is a dis-puted suggestion that the risk of develop-ing dementia may decline after age 84 isreached,171 but this hypothesis appears tobe in conflict with results of detailed sur-veys.172 Evans and coworkers,173 for exam-ple, found that in East Boston, Massachu-setts, an urban working class communityof some 32,000 inhabitants, an estimated10.3 percent of the population aged over 65had probable Alzheimer’s disease. Theprevalence of this disorder increased stead-ily with aging, from 3.0 percent at age 65 to74 years to 18.7 percent for those aged 75to 84. This trend continued so that 47.2 per-cent of those 85 years or older were diag-nosed as suffering from probable Alzheim-er’s disease. This age-related increase in de-mentia was identified again in San Ma-rino.174 At age 67 only 1.8 percent of thepopulation suffered from it, a figure thatrose to 25.0 percent in those 87 years of age.The general situation was summarised byJorm, Korten and Henderson175 who, aftera survey of the international literature,concluded that dementia prevalence ratesreflected the age of the sample population,doubling every 5.1 years.

If the multiple antagonist hypothesispresented here is correct, this increase inrisk of developing Alzheimer’s disease withaging is inevitable. As the individual ages,intestinal absorptive capacity is reduced,and in consequence calcium absorptiondrops. In addition, kidney function declinesand with it there is a corresponding reduc-tion in the production of active vitamin D,further decreasing calcium absorption inthe intestines.36 These changes typicallylead to a loss of bone calcium and, as has

been discussed previously, make aluminumabsorption far more likely to occur.

Not only is the brain’s aluminum bur-den likely to increase with aging in this waybut its ability to protect itself also charac-teristically declines. Hypovitaminosis, forexample, is common in the elderly,176 whoare all too frequently deficient in antioxi-dants and, therefore, more prone tooxidative stress. Beyond this, two hormonesthat decline with age, melatonin andestrogen, play roles in protecting the brainfrom aluminum. As their levels fall, dam-age from this element inevitably increases.The aluminum relationship to estrogenprobably explains why, as Cohen177 pointedout, Alzheimer’s disease is more commonin women then in men, a gender bias thatcannot be explained entirely by the greaterlongevity of females.

Sleep disruption, nightly restlessnessand other circadian disturbances are com-mon in Alzheimer’s disease patients. Thisbehaviour often appears to be associatedwith abnormally low cerebrospinal mela-tonin178 Interestingly, the level of melatoninin such patients have been found to belinked to genotype. Melatonin levels inAlzheimer’s disease patients expressingapoliprotein E-epsilon 3/4, for example,were found to be more than double thoseof patients expressing apolipoprotein E-ep-silon 4/4. It has been shown also that thenormal daily variations in melatonin dis-appears in both older subjects and Alzhe-imer’s patients.179

This decline of melatonin productionin the elderly180 has many significant impli-cations for Alzheimer’s risk. Melatonin, forexample, has been shown to alter the me-tabolism of beta-amyloid precursor pro-tein,181 prevent beta-amyloid-induced lipidperoxidation and associated toxicity to bio-logical membranes, protect against gluta-mate excitotoxicity and reduce neural dam-age due to gamma-aminolevulinic acid.182

In addition, Pappolla and colleagues183 havedemonstrated that melatonin is remarkably

35


effective in preventing death of culturedneuroblastoma cells and mitigatingoxidative damage and intracellular Ca2+increases induced by cytotoxic fragmentsof beta-amyloid protein. That is, melatoninis likely to prevent neural damage causedby glutamate and by beta-amyloid protein,both of which are implicated in the neuro-nal destruction characteristic of Alzheim-er’s disease.

The decline of estrogen production inpostmenopausal women also increasestheir risk of developing Alzheimer’s disease.Confirmation of this has come from theItalian Longitudinal Study on Agingwhich provided convincing evidence thatestrogen-replacement therapy reduces theprevalence of Alzheimer’s disease.184 It hasbeen shown also that female Alzheimer’spatients receiving this hormone have im-proved cognitive skills.185 Why estrogen actsin this way is still the subject of extensiveresearch. It has been proved, however, that,in rats, estrogen acts as a growth factor forcholinergic neurons.186 Gibbs and Aggarwal187

have hypothesized that there are similareffect in humans and that, as a result, inpostmenopausal women receiving estrogenreplacement therapy, this hormone delaysthe decline in basal forebrain cholinergicfunction, typical of Alzheimer’s disease.

(v) Lack of an educationBeyond the possibility that less edu-

cated individuals may be more likely to eatinappropriate diets, there appear to bethree hypotheses that may explain why thelack of an education might increase the riskof developing Alzheimer’s disease. Firstly,it is possible that the apolipoprotein E vari-ant that predisposes a significant sectionof the population to late-onset Alzheimer’sdisease might, in some way, also adverselyeffect an individual’s ability to cope withthe demands of an education. There seems,however, to be no available evidence tosupport this hypothesis.

Secondly, education might stimulate

the brain’s development, so increasing itsability to withstand more degenerativedamage before Alzheimer’s symptoms be-come apparent. There is certainly growingevidence that stimulation affects brain de-velopment. To illustrate, Rosenzweig188

showed that the number of neurons in rats’brains were influenced by the stimuli in theenvironment. Rats that grew up in an “en-riched” milieu were found to have moreneurons in the cerebral cortex than thosethat did not. In addition a rat from an “en-riched” environment had a heavier cortexwith thicker cortical coverings. Brain en-zymes were also elevated. Globus189 furtherdiscovered that such “enriched” environ-ments increased the number of dendriticspines in the rat brain. Perhaps as Restak190

muses, learning, memory and other brainfunctions in humans may depend to a largedegree on the quality of environmentalstimulation.

A third hypothesis that may accountfor the apparent link between a lack of edu-cation and the risk of developing Alzheim-er’s disease would focus on exposure totoxic metals and inadequate dietary min-eral intake. If a child were exposed to el-evated aluminum while its calcium, mag-nesium, zinc and phosphorous intakes weredepressed, it might be unable to handle therigours of higher education. Ultimately,these imbalances might also result in thedevelopment of Alzheimer’s disease. Thereis clearly this type of negative relationshipbetween lead exposure and depressedchildhood intelligence.191 FurthermoreVarner and coworkers61 have shown re-cently that the chronic administration ofdrinking water containing aluminum-fluo-ride or sodium-fluoride to rats causes sig-nificant deficits in neuronal integrity thatshow regional brain differences. It has beenestablished also that elevated hairaluminum levels seems to be associatedwith classroom withdrawal by young chil-dren.192 Much of this aluminum may comefrom cans but it should be noted that

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aluminum concentrations in most cow’smilk-derived formulas are 10 to 20-foldgreater than in human breast milk. Theyare also 100-fold greater in soy-based for-mulas.193 Deficiencies in trace and bulk el-ements also appear to adversely influenceschool performance. To illustrate, Marloweand Palmer194 compared 26 hair trace ele-ments in two sets of young Appalachianchildren: an economically disadvantagedgroup of 106 drawn from Head Start pro-grams and 56 control group children frommore prosperous backgrounds. Develop-mental disabilities, including communica-tion and behavioural disorders were re-corded in 13 members of the Head StartGroup, but were absent from the controlgroup. Hair analysis also established thatthe mean levels of calcium, magnesium andzinc were significantly depressed in chil-dren from the economically disadvantagedgroup. Conversely, Benton195 reviewed fivestudies that suggested that vitamin/min-eral supplements improved many children’sperformances during intelligence tests. Insummary, the evidence suggests that manychildren are exposed to excess aluminum,while being simultaneously mineral defi-cient. Such individuals appear to experi-ence schooling difficulties early in life andmay possibly develop Alzheimer’s diseasewhen older. This may be particularly trueif they eat a high fat diet.153

The Prevention of Alzheimer’s DiseaseThe number of elderly is undergoing

an unprecedented increase, with the pro-portion of the very old doubling within onegeneration. In 1950, globally there were 214million people 60 or older; by 2025 therewill probably be one billion.196 Not only aremore people surviving into old age and,therefore, increasing their chances of de-veloping Alzheimer’s disease but those whodo so are living longer after its onset.Gruenberg197 termed this paradox the “fail-ure of success”, a tragedy caused largely byprogress in medical care. As he and his col-

leagues198 point out “the old man’s friend,pneumonia, is dead–a victim of medicalprogress.” In consequence, the old man isstill with us, but all too often he is de-mented.

As Khachaturian25 states the costs ofthis paradox will be enormous, “... if cur-rent demographic trends continue, thenumber of people with Alzheimer’s diseasewill double every twenty years. The US al-ready spends $100 billion a year on care forAlzheimer’s patients: with the rising costof health care, society will have a monsteron its hands”. The USA will not be alone.StatsCan predicts that by the year 2031,close to 800,000 Canadians will be de-mented, two-thirds of them suffering fromAlzheimer’s disease.199 This trend is typicalof the Developed world.200

The author believes that the preced-ing review has demonstrated that alum-inum neurotoxicity is the cause of Alzhe-imer’s disease.201 At the political level, aseries of highly unpalatable steps, therefore,must be taken if the “monster” is not tohave its way. These include setting muchlower limits for aluminum in drinking wa-ter,202 prohibiting the use of aluminum saltsas coagulants in water treatment,203 revers-ing the drive for water fluoridation andbanning the use of both aluminum cans204

and the food additive aluminum malt-olate.62 It is obvious also that the recom-mended daily allowances of many miner-als and vitamins, especially antioxidants,are too low and that this inadequacy is re-flected in the contents of the average mul-tivitamin pill.205

The chances that such changes will bemade in the near future are poor. Fortu-nately, there are many steps that the indi-vidual can take to reduce his or her ownprobability of developing Alzheimer’s dis-ease. These include drinking low aluminumpotable water, avoiding hot chocolate andacidic drinks in aluminum cans and notusing aluminum-containing antacids ordeodorants. Cooking utensils should be

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stainless steel or glass and foods should notbe cooked or stored in aluminum foil. Min-eral supplements should include calcium,magnesium and zinc. Probably the bestevidence that vitamin supplements also canreduce the risk of developing Alzheimer’sdisease comes from a prospective study of633 people aged 65 or older, whose vitaminintake was carefully established.205 After a4.3 year follow-up period, 91 of the partici-pants met criteria for the clinical diagno-sis of Alzheimer’s disease. None of the 27vitamin E supplement users suffered fromit, however, nor did any of the 23 elderlyindividuals taking vitamin C. Nevertheless,there was no relationship between the in-cidence of Alzheimer’s disease and the useof multivitamins. These data suggest thathigh dose vitamin E and C supplementslower the risk of Alzheimer’s disease; butthat multivitamin antioxidant levels are toolow to do so.

The Treatment of Alzheimer’s DiseaseVery few people ever come back from the

abyss, but it has been done. The author isaware of only two well documented cases ofthe “spontaneous regression” of Alzheimer’sdisease. Fortunately both of these individu-als have written books about their experi-ences.206-207 In the belief that Siegel208 is cor-rect that “We should be paying more atten-tion to the exceptional patients, those whoget well unexpectedly, instead of staringbleakly at all who die in the usual pattern”,their cases will now be reviewed.

Louis Blank207 was confirmed to haveAlzheimer’s disease after detailed hospitaltesting. As his disorder progressed, he lostthe ability to recognize his own family orto speak, and to dress, wash or eat withoutassistance. For six months, at the peak ofhis illness in 1993, he sat virtually motion-less. His recovery appeared to begin afterhis family replaced all its aluminum cook-ing utensils and started to avoid aluminumcans. In addition, he was fed a high mag-nesium diet, designed to chelate aluminum.

By May, 1994 Louis Blank was again ableto carry on conversations and venture out-side. By January 1996, he had written andpublished his book Alzheimer’s Challengedand Conquered?209 despite the fact that oneof his specialists continued to argue thatsince there is no cure for Alzheimer’s dis-ease, he must still have it. An interestingaspect of Blank’s description of his experi-ences is that while most of his long-termmemory remains he still has no recollectionsof his worst six months. This confirms that,as Alzheimer’s disease progresses, the pa-tient loses the ability to form short-termmemories. Older-term memories appear toremain intact for much longer.

In his book Beating Alzheimer’s: A StepTowards Unlocking the Mysteries of BrainDiseases, Tom Warren206 also describes hisexperiences with dementia. In June 1983,a computer assisted tomography scan con-firmed that Warren had Alzheimer’s dis-ease. His physicians gave him a maximumof seven years to live. Yet nearly four yearslater, a new scan indicated that the diseaseprocess had reversed. Warren’s self-treat-ment had included rectifying low hydro-chloric stomach acid, the removal of all histeeth and mercury amalgam fragmentsfrom his gums, ethylene diamine tetraceticacid (EDTA) chelation therapy and highdoses of vitamins and minerals. The latterincluded zinc, calcium, magnesium, andvitamins B3, B6, B12 and folic acid.

In summary, both Blank and Warrenattempted to reduce their exposure to met-als, especially aluminum and/or mercury,underwent chelation therapy and addedminerals to their diet, especially in Blank’scase, magnesium. These protocols seemconsistent with the hypothesis presentedhere, that Alzheimer’s disease is caused byaluminium and reflects its antagonistic re-lationships with zinc, calcium, phosphorusand magnesium. It would seem essentialthat the Alzheimer’s patient, in addition toavoiding contact with aluminum and othertoxic metals, undergoes treatment to lower

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the body’s existing burden of these ele-ments. To illustrate, clinical trials haveshown that the chelating agent des-ferrioxamine can slow the progression ofthe disorder.210 This may be because, asSavory and coworkers211 have shown in rab-bits, aluminum-induced neurofibrillary de-generation can be effectively reduced in aslittle as two days by intramuscular injec-tions of desferrioxamine. An excellent oralchelation therapy designed to remove met-als from the body has been described re-cently by Pouls.212

Campell213 has suggested that a dailysupplement of 500 mg of calcium and asimilar amount of magnesium can lower el-evated hair aluminum back to normal in ayear, while Bland214 recommended the dailyuse of 600 mg of calcium and 300 mg ofmagnesium to reduce body aluminum bur-den. Durach215-6 has argued that there aretwo types of magnesium deficit: magne-sium deficiency and magnesium depletion.Magnesium deficiency, in his view, is dueto insufficient magnesium intake and re-sponds to simple supplementation. Magne-sium depletion, in contrast, is the result ofa dysregulation in the mechanisms respon-sible for magnesium metabolism. This sec-ond form of magnesium deficit can only beaddressed by the correction of the respon-sible pathogenic dysregulation. However,since in Alzheimer’s the dysregulation is ap-parently due to excess exposure to alu-minium which itself can be corrected byelevating magnesium intake, magnesiumsupplementation alone also may correctsuch dysregulation and with it the deficit.This appears to be what happened in thecase of the “spontaneous regression” ofLouis Blank’s Alzheimer’s disease when heboth avoided aluminum and ate a highmagnesium diet.209

Once exposure to aluminum and theexisting body burden of this element havebeen reduced, the final stage of Alzheim-er’s disease treatment appears likely to in-volve attempts to buttress the patient’s

cholinergic, catecholaminergic andglutamatergic systems and associatedoxidative stress defense mechanisms(Table 1, p. 39). Scinto and coworkers,77 forexample, have used acetylcholine deficiencyas the basis for the early detection of Alzhe-imer’s disease, demonstrating that the pu-pils of patients with Alzheimer’s diseasedilate markedly in response to a dilute so-lution of the acetylcholine-blocking drug,tropicamide, while normal subjects are vir-tually unaffected by it. As a consequence,several attempts have been made to treatAlzheimer’s disease by trying to increasebrain acetylcholine levels. To illustrate, vari-ous clinical trials have been conducted todetermine whether phospha-tidylcholine orlecithin (which contains it) improve brainfunction in Alzheimer’s patients.217-8 Takenas a whole, these trials seem to suggest thatphosphatidylcholine may slow the rate ofprogression of Alzheimer’s disease. Again,in an attempt to elevate brain acetylcho-line, clinical trials also have been conductedusing acetyl-L-carnitine in the treatment ofAlzheimer’s patients.219-21 Results have beenpromising, with statistically significant im-provements being recorded in behaviour,attention and memory. It is not surprisingthat acetyl-L-carnitine may be valuable inthe treatment of Alzheimer’s disease becausepatients’ brains are deficient in carnitineacetyl-transferase, which is necessary tocatalyse interchange between L-carnitineand acetyl-L-carnitine.222 Acetyl-L-carnitinemay be of benefit in Alzheimer’s disease fortwo reasons. It is a precursor of acetylcholine,223

increasing the brain availability of this neuro-transmitter. In addition, it also seems to evokedopamine release from the vesicular pools ofnigrostriatal dopaminergic neurons.224 Acetyl-L-carnitine, therefore, may be capable of help-ing to correct deficits in both the cholinergicand catecholaminergic systems, commonlyfound in Alzheimer’s disease.

It is unfortunate that clinical trials todate have used acetyl-L-carnitine in isola-tion. The production of acetylcholine from

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Table 1. Alzheimer’s Disease and Aluminum. An Overview.

aluminum impaired consequence potential treatmentenzyme

Glucose-6-phosphate Glucose metabolism impaired Calcium, magnesium

Hexokinase Glucose metabolism impaired Calcium, magnesium

Phosphofructokinase Glucose metabolism impaired Calcium, magnesium

Choline acetyltransferase Acetylcholine deficiency Vitamin B12,[zinc],estrogen,Malfunction of cholinergic neurons folic acid, calcium, magnesiumFormation of senile plaques phosphatidylcholine, lecithin,

acetyl-L-carnitine

Adenylate cyclase Elevated parathyroid activity Magnesium

Dihydropteridine Depressed dopamine, Desferrioxamine, magnesium, copper,reductase norepinephrine and serotonin zinc, iron, calcium, magnesium

Glutamate decarboxylase Reduction in glutamatergic Calcium, magnesiumneurotransmission

Calcium/Calmodulin Loss of calmodulin flexibility, Desferrioxamine, calcium, magnesiumKinase II formation of neurofibrillary tangles

Alkaline phosphatase Neurofibrillary tangles Calcium, magnesium

Phospholipid A2 Abnormal brain cell membranes n-3 and n-6 essential fatty acids,calcium, magnesium, phospha-tidylserine, phosphatidylcholine,phosphatidyl ethanolamine,phosphatidylinositol

Glutathione-peroxidase Increased lipid peroxidation Vitamin E, vitamin C, selenium,melatonin

Superoxide dismutase Greater free radical damage [Zinc], copper, ginkgo biloba

choline involves other nutrients, includingvitamin B12 and folic acid. These substancesshould not be assumed to be readily avail-able in Alzheimer’s patients. Indeed, a B12

deficiency seems characteristic of the dis-ease,225-6 as are high levels of its meta-bolites.227 McCaddon and Kelly228 have sug-gested that when B12 levels are depressed,

a well-known biochemical process, the“methyl-folate trap” occurs. This trap di-verts folic acid from the brain, preventingthe manufacture of acetylcholine, even inthe presence of abundant choline.

Nevertheless, there is increasing evi-dence for a role for acetylcholine in thetreatment of Alzheimer’s. Recently, done-

Zinc can accelerate amyloid plaque formation in later stages of Alzheimer’s disease.152

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pezil HCI, a piperidine-based reversibleacetylcholinesterase inhibitor229 has beenused to produce an increase in central nerv-ous system acetylcholine in mild to mod-erate Alzheimer’s patients, which seemedassociated with improvements in cogni-tion. Similarly, vitamin B12 injections, whichmay increase brain acetylcholine levels,have been reported linked to significant im-provement in various neuropsychiatric dis-orders, even when anaemia is absent.230

Since the production of acetylcholine fromcholine involves folic acid, it is not surpris-ing that Snowdon’s study of postmortembrains from the School Sister’s of NotreDame, Mankato, Minnesota has identifiedthat a deficiency of this vitamin also ap-pears to occur in Alzheimer’s disease.231

Three potential treatments for Alzheim-er’s disease also rest on reducing the avail-ability of acetylcholinesterase for incorpora-tion into plaque complexes with beta-amy-loid. Tetrahydroaminoacridine (Tacrine), forexample, is a potent inhibitor of acetylcho-linesterase which reportedly improvesmemory deficits in Alzheimer’s disease.232

Similarly, in a dementia mimetic mousemodel, created with aluminum chloride so-lution, the Chinese herbal medicine oftonifying kidney depressed acetylcholineste-rase levels in the cerebral cortex, leading toan improvement in memory.233 Bonnefontand coworkers234 also have shown thatestrogen protects neuronal cells from the cy-totoxicity induced by acetylcholinesterase-amyloid complexes.

Ginkgo biloba is a herb that has beenused traditionally to treat both memoryloss and diabetes mellitus.235 Its active com-ponents are ginkgolides which have anti-oxidant, neuroprotective and cholinergicproperties. The value of ginkgo biloba ex-tracts in the treatment of Alzheimer’s havebeen demonstrated in placebo-controlledclinical trials and seems to be similar tothose of donepezil or tacrine, but withoutany undesirable side effects. One of themajor benefits of ginkgo appears to be its

ability to increase blood flow, not only tohealthy parts of the brain but also to dis-ease-damaged areas.235 Beta-amyloid, in itsinteraction with superoxide radicals con-stricts and damages the lining of the smallblood vessels supplying the brain. It is likelythat ginkgo, acting as a circulation enhancer,helps to overcome this problem.236-7 This, ofcourse, may be why the blood thinner as-pirin238-9 may also be beneficial in the treat-ment of Alzheimer’s disease. However, thereseems to be more to ginkgo biloba extractthan its antioxidant and circulation en-hancing properties since clinical trials alsohave established that it improves memoryand cognitive performance in healthyyoung females.240 In addition, in both youngand old rats it increases neurotransmitterreceptor binding.241

There appear to have been few at-tempts to correct deficits in the catecho-laminergic system in Alzheimer’s disease.One exception to this generalization hasbeen the recent testing of lisuride, adopamine receptor antagonist, more oftenused in the treatment of Parkinson’s dis-ease. Initial results suggest that this drugmay reduce the rate of decline of verbalmemory in Alzheimer’s but results were notstatistically significant.242

In contrast, several attempts have beenmade to assess the possibility of correct-ing the abnormal viscosity of cellular brainmembranes in Alzheimer’s disease. Trialshave been conducted, for example, to testthe value of phosphatidylserine in thisrole.243-4 In Italy, for example, Cenacchi,245

conducted a clinical trial involving 425 peo-ple aged 66-93 years, in 23 institutions. Allparticipants had experienced moderate tosevere cognitive decline. Phosphat-idylserine dosage was 300 mg per day andpatients were assessed when the study be-gan and three to six months later. Signifi-cant improvement in memory and learn-ing scores were reported. Interestingly,phospholipids such as phosphatidylserine,phosphatidylcholine, phosphatidyl-eth-

41


anolamine and phosphatidylinositol areavailable in healthfood stores and are widelyused as memory aids by the general public.

The potential value of antioxidantssuch as melatonin, estrogen and vitaminsC and E in the treatment of Alzheimer’s dis-ease have been discussed earlier. However,there may be more to estrogen than its abil-ity to protect against free radical damage.In addition to promoting the growth ofcholinergic neurons and decreasing neuro-nal damage by acting as an antioxidant,246

this hormone also has been shown to havepowerful protective neuronal cell effectsagainst the cytotoxicity of the acetylcho-linesterase-amyloid beta-peptide complexfound in the senile plaques that are char-acteristic of Alzheimer’s disease.116 It wouldappear that estrogen protects neuronsagainst damage from both senile plaquesand from amyloid beta-peptide fibrils. Thishelps to explain why Alzheimer’s disease isconsiderably less common in women re-ceiving estrogen replacement therapy.184

Little is known of the clinical impactof melatonin on Alzheimer’s disease. How-ever, Jean-Louis and coworkers247 describeits effects on two cases. In one patient,melatonin enhanced and stabilized thecircadian rest-activity rhythm, along witha reduction of daytime sleepiness andmood improvement. In the other patient,no significant changes were observed. In-terestingly, Pierpaoli and Regelson180 de-scribe treating a patient who suffered fromParkinsonism with melatonin and claimthat, on a dose of 5mg daily, her uncon-trolled hand shaking disappeared and tenyears later she was still completely diseasefree.

It is well established also that mela-tonin plays a significant role in normaliz-ing blood zinc levels in the elderly becauseit aids this mineral’s absorption180 Zinc de-ficiency may cause depressed glutamatedehydrogenase, resulting in an excitotoxicrise in glutamate.248 Furthermore, zinc en-zymes also are involved in the metabolism

of neurotransmitters, including acetylcho-line. A shortage of zinc, therefore, may par-tially account for the depression of thisneurotransmitter in Alzheimer’s disease.Supplementation with zinc aspartate ap-pears beneficial in preliminary trials withAlzheimer’s patients.248 However, great caremust be taken in the use of this mineralsince, although it seems beneficial in im-proving mental alertness in the elderly, ina clinical trial in Australia it caused a seri-ous deterioration of cognition in Alzheim-er’s patients within two days.152

In contrast, the available evidencesuggest that the antioxidant selenium maybe very beneficial in dementia, includingAlzheimer’s disease. In 1987, Tolonen andcolleagues249 described a double-blindclinical trial in which the demented eld-erly were given high doses of sodiumselenate, organic selenium and vitamin E.These supplements resulted in statisticallysignificant improvements in depression,self care, anxiety, mental alertness, fatigueand interest in the environment. While theroles of selenium and vitamin E in produc-ing these improvements cannot be iden-tified separately, this study suggests thathigh doses of both of these antioxidantsmay be of significant benefit to Alzheim-er’s patients.

ConclusionsIn his book Disaster Planning: The

Preservation of Life and Property, pub-lished in 1980, this author250 wrote “Com-munities, like individuals, may oftenwork towards their own destructionthrough neglect, ignorance, or a deliber-ate emphasis on fulfilling superficiallyadvantageous short-term goals. Incre-mentally, in doing so, they magnify riskand eventually suffer the disasters theydeserve.” It has been known for over acentury that aluminum is a neurotoxin.1

The unfortunate truth that its wide-spread use is the major cause of Alzhe-imer’s disease is now unavoidable.

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