Alzheimer's Stepchild

A neuropathologist defies conventional wisdom when he swears there's a connection between aluminum and Alzheimer's.

By Peter Radetsky|Tuesday, September 01, 1992
Daniel Perl remembers the incident vividly. I was downtown and had some time to kill, so I went into the housewares section of Bloomingdale’s. There on sale was a set of aluminum pots and pans--big, heavy, fancy stuff, much reduced. I said to the saleslady, ‘This is a great buy. You must have trouble keeping them in the store.’

‘No, nobody will buy them,’ she said. ‘That’s why they’re on sale.’

‘What do you mean, nobody will buy them?’ I said. ‘They’re beautiful.’

She said, ‘It’s because they give you Alzheimer’s disease.’

‘Oh, really?’ I walked out shaking my head, thinking, ‘What have I done?’

Perl shrugs, eyebrows raised, palms out, a hometown Queens, New York, gesture that says, Whadaya think of that?

The irony is appropriate. By pinpointing the location of abnormally large concentrations of aluminum in the brains of patients with Alzheimer’s disease in the late 1970s, Perl and a handful of colleagues helped establish a connection between the metal and the disease. But they have never claimed that aluminum causes the problem; even if it did, cookware would be an insufficient source.

Scientists don’t know what causes Alzheimer’s. This thief of a disease, which robs people of their minds--and which attacks one in ten individuals 65 years of age and older, or 4 million people in this country alone--is an affliction without known origin, treatment, or cure.

But Perl, a 50-year-old neuropathologist at the Mount Sinai School of Medicine in Manhattan, can live with the pots and pans thing, as he puts it. If it is an overreaction, no one is hurt by it (except aluminum manufacturers, that is). Harder to swallow is that while much of the public may be convinced that aluminum is in some way associated with Alzheimer’s, and while Perl and other researchers feel that the connection is real and significant, reaction in the scientific community has ranged from ho-hum indifference to outright skepticism. A majority of scientists are instead directing their attention toward other possible factors, in particular a fragment of a little-understood protein called beta-amyloid that occurs naturally in the body. Aluminum research is the stepchild of Alzheimer’s investigations, receiving relatively little credence, little attention, little funding. In Perl’s view, the reasons tend to be less than scientific.

Alzheimer’s research has become like religion, he says. You go to meetings and it’s like you just entered church--everybody wants to know if you’re a true believer. In one room are the high priests of amyloid preaching to the converted. In the meeting next door are the genetics believers. There’s even an aluminum temple, I admit it. But it’s small, let me tell you. We can all sit around one table.

Perl shrugs. But that’s fine. There’s nothing wrong with having these revival meetings. To get funded and get attention, you have to sell your hypothesis. The problem is when people start putting down everything that’s happening in those other rooms.

And nothing gets put down as much as the aluminum hypothesis. The bottom line is that the majority of us think that aluminum is not a primary player, says neurologist Donald Price of the Johns Hopkins School of Medicine. Neuropathologist Henry Wisniewski, director of the New York State Institute for Basic Research in Developmental Disabilities, says, Aluminum is simply not important in the development of the lesions of Alzheimer’s disease.

Yet there is evidence that aluminum is poison to the nervous system. When injected directly into the brains of certain experimental animals like cats and rabbits, aluminum compounds produce symptoms resembling those of Alzheimer’s disease: a reduced ability to learn and remember, loss of coordination and muscle control, seizures, and death. Upon examination these brains are found to be riddled with abnormalities similar to those of brains with Alzheimer’s. The mechanism by which aluminum destroys neurons is not fully understood, but at least in some cases it is clearly effective.

Moreover, aluminum is everywhere. It never occurs in pure form like other metals, but in combination with other substances, particularly oxygen, it makes up about 8 percent of Earth’s crust; in fact, it is Earth’s eighth most abundant element. (It was only relatively recently, in the late nineteenth century, that a commercial process to purify the metal was developed, thus giving rise to the aluminum industry.)

Aluminum is present in our bodies as well, though in minuscule amounts. In Alzheimer’s brains, however, the metal shows up in huge quantities, up to 50 times the normal amount in some cells. Perl and others are laboring mightily to clarify just how the metal is able to make its way in there. But most Alzheimer’s researchers don’t seem all that concerned. They focus instead on the mysterious beta-amyloid protein.

Both the amyloid group and the aluminum group are looking for the connection between their chosen substances and the characteristic abnormalities of the disease, abnormalities described at the turn of the century by the German neuropathologist Alois Alzheimer. While performing an autopsy on a demented 55-year-old woman, Alzheimer found a brain riddled with fantastic structures. In the cerebral cortex, the hippocampus, and other regions essential for cognitive function he found what looked like snarls of string--he called them tangles. Adjacent to the tangles Alzheimer found even more grotesque formations called plaques. They resembled gobs of glue, 10 to 15 times the size of nerve cells.

Later others would determine a critical component of the stringy tangles to be proteins that normally make up the skeletons of nerve cells. Researchers would also find that the plaques were composed primarily of amyloid. Then Perl and colleagues would discover that lurking inside the tangles were deposits of aluminum.

But were these bizarre formations and the substances found within them actually involved in the workings of the disease? Or were they nothing more than unfortunate side effects, tombstones marking the site of the damage? In the early 1900s Alzheimer had no way of knowing, and in the 1990s the debate rages on.

Last year came still another striking development, and it broke in the direction of the amyloid believers. A research team led by John Hardy of St. Mary’s Hospital Medical School in London discovered a genetic defect in a family with hereditary Alzheimer’s disease. No one knows how often Alzheimer’s is inherited--estimates vary from about 20 percent of the time to most of the time. In this case Hardy found that a gene on chromosome 21 was mutated. Which gene? The one that produces the amyloid precursor protein, or APP, the source of the unwelcome amyloid.

Previous investigations had hinted at this--that at least in some cases Alzheimer’s is a genetic disease and that the production of amyloid is at its core. And recent studies have found clues as to the way the protein may function to cause the disease. But in the great tradition of Alzheimer’s research, there is little unanimity concerning the matter. Other studies have shown no involvement of the APP gene, while suggesting that different genes may be implicated in the disease process. Still other studies have found no genetic involvement at all.

Nevertheless, most people in the field suspect that amyloid is at the heart of the problem. There’s no question that the amyloid protein is the important player in this business, says Price. It is amyloid that is driving Alzheimer’s pathology, agrees Wisniewski. Accordingly, it is amyloid research that receives the bulk of attention and funding.

All of which rankles Dan Perl. He thinks people are jumping on the amyloid bandwagon with insufficient evidence. As he sees it, while amyloid deposits do indeed show up in Alzheimer’s brains and so should be studied, they’re also common in normal aging brains. I can show you plenty of brains from perfectly normal people that have a hell of a lot of amyloid, even more than in some cases of Alzheimer’s disease. There have been studies looking for a correlation between amyloid and dementia--they can’t find it.

Tangles, on the other hand, are consistently associated with dementia, and, contends Perl, where you see tangles, you find aluminum. The first inkling of the metal’s involvement in Alzheimer’s disease came several decades ago. In the late 1950s, while studying autoimmune reactions in the brain, a group of investigators at the National Institutes of Health injected rabbits with a mixture that included aluminum; within days the rabbits developed seizures and died. Later dissection of those brains showed masses of tangles resembling those of Alzheimer’s disease. In the mid-1960s Henry Wisniewski, then a young investigator, showed that aluminum was responsible for those dramatic changes. And although subsequent studies found that the aluminum-induced tangles were not precisely the same as those associated with Alzheimer’s--the latter developed as two protein filaments wrapped around each other, while aluminum caused the creation of only single filaments--still, the suspicion remained that aluminum might somehow be involved in the formation of the Alzheimer’s tangles.

These experiments caught the eye of a University of Toronto neurologist named Donald McLachlan. He determined to look for aluminum in Alzheimer’s brains--and he found it. In the mid-1970s McLachlan published evidence that Alzheimer’s brains contained twice as much aluminum as was normal.

That work in turn piqued the interest of Perl, who was then at the University of Vermont. He and his colleagues exposed sections of Alzheimer’s brains to a technique called X-ray microprobe analysis. The method uses electrons to excite the atoms within tissue to produce an X-ray fingerprint that identifies the substance generating it. By analyzing these patterns, the team was able to track precisely the abnormally high concentrations of aluminum to those regions that contain tangles. When the news was published in the influential journal Science in 1980, the connection between aluminum and Alzheimer’s was here to stay.

You have to remember, Perl says, that this was before today’s widespread interest in Alzheimer’s. If you met someone at a cocktail party and they asked, ‘What do you do?’ and you said, ‘I do research on Alzheimer’s disease,’ the next question would be, ‘What’s that?’ He laughs. Now they say, ‘Oh. Are you working on amyloid or aluminum?’

If Perl’s revelation helped spark this awareness, the clincher was the publication of another paper two years later. This one addressed a long-standing mystery on the South Pacific island of Guam. Soon after World War II, doctors working on the island had discovered that an amazingly large number of residents were suffering from neurological disorders. One was amyotrophic lateral sclerosis, or ALS, the fatal disease best known for killing New York Yankee baseball star Lou Gehrig. Another resembled nothing less than a malevolent blend of Parkinson’s and Alzheimer’s diseases, causing severe dementia and death. Some people seemed to be plagued by all three disorders at once.

To this day no one knows for sure what caused--and continues to cause--these afflictions. But one thing is certain: If you look at the brains of these people, they show huge numbers of tangles similar to those you see in Alzheimer’s, says Perl. And when you look at the tangles, you find that they have ten times the aluminum content that occurs in Alzheimer’s disease--a tremendous amount. Furthermore, the soil on the island is especially rich in the metal. Could long-term environmental exposure to aluminum be at the heart of this strange neurological epidemic? It’s circumstantial evidence, says Perl, but you just keep finding it.

With that, the pots and pans thing was off and running. A representative salvo was fired by a Yale medical graduate in a letter to the New England Journal of Medicine. As a financially strapped medical student and intern, wrote the worried young doctor-to-be, I purchased inexpensive aluminum pots and pans. . . . More recently, I have become aware of the growing literature . . . discussing the association between aluminum and Alzheimer’s disease. . . . Large numbers of people in our aluminum-using society may be the victims of slow aluminum poisoning from several sources. Corrosible aluminum cookware may be a nontrivial source. This hypothesis needs systematic study. In the meantime, out with my corroding aluminum pots!

I didn’t respond to the letter, says Perl. I wasn’t sure at that point what I would have said. All I knew was, that was our data. But his inability to answer didn’t stop the questions. Every time I’d give a talk at a scientific conference, I’d get these questions about pots and pans. Pots and pans? Come on. We’re talking about scientific issues here and everybody wants to know about pots and pans?

Among those doing the questioning were certain parties with a particularly strong interest: representatives of the multibillion-dollar aluminum industry. You’d see them in the back of the room, says Perl. Reynolds, Alcoa, Kaiser, and the Aluminum Association lobbying guys. For them, evidence that aluminum may be involved in Alzheimer’s disease could have dire consequences. After all, Perl says dryly, nobody’s making anything from amyloid.

Consequently the wild card in aluminum-Alzheimer’s research was introduced--interests vested enough and powerful enough to deflect the impact of what people like Perl were finding out. At least such is the contention of those in the aluminum camp. They make no bones about the role of the aluminum industry and its marketing arm, the Washington, D.C., based Aluminum Association, which represents 79 aluminum producers and fabricators. After we published our first Science paper, says Perl, I started to get calls from friends saying, ‘Who are these guys asking questions about you?’ They were trying to find out who the hell this guy was. After that I knew that anything I said would be reviewed, evaluated, critiqued, and attacked in every way possible because of the issues involved. And that continues.

Donald McLachlan is equally blunt. The Aluminum Association has a very strong lobby against this hypothesis, and they’re putting money into it. For instance, a well-known anti-aluminum person is Henry Wisniewski. (The same Henry Wisniewski, ironically enough, who was among the first to implicate aluminum in Alzheimer’s disease.) McLachlan takes pains to note that Wisniewski is without question a solid scientist; but he also points out that Wisniewski gets over a half-million dollars from the Aluminum Association. People who fail to find aluminum in Alzheimer’s are more likely to receive grants from the Aluminum Association. Two researchers conspicuous for not receiving Aluminum Association money: McLachlan and Perl (although McLachlan does receive a small contribution of $15,000 a year from the Canadian aluminum producer AlCan). I certainly can’t claim that they’ve actively tried to suppress my work, says Perl. It’s that the statements of the people they fund tend to lend scientific credence to the idea that our aluminum research may not be very good work, or properly done.

Seymour Epstein, technical director of the Aluminum Association, dismisses such charges. There’s no reason we have to fund something we don’t agree with. There’s a lot of research to be done, and funding has to come from someplace. Ever since our critics said, ‘If you’re funding something, obviously it can’t be credible,’ we’ve had to come to grips with attitudes like that. It’s ridiculous.

He points out that the association provides three-quarters of a million dollars a year for Alzheimer’s research and sponsors international meetings devoted to the disease, to which leading Alzheimer’s researchers of every persuasion--Perl and McLachlan included--are invited. In fact, early this year the association sponsored a symposium in Florida that helped clear the air between the two rival Alzheimer’s camps. McLachlan, for one, does think tensions have eased a bit. He now believes the whole discussion is back where it belongs, in the realm of scientific debate and critical evaluation.

But as to why his organization has never funded proponents of the aluminum hypothesis, Epstein answers simply that they’ve never asked for help. Besides, it’s a no-win situation. If we provided money we’d be accused of trying to buy them off. You can’t win.

Aluminum investigators ignore such sentiments. They’ve heard it all before--and they’re having enough trouble as it is. In the best of circumstances aluminum research is very difficult. Since aluminum is a ubiquitous element, present in water, food, and even air, any experiment researchers perform runs a very real risk of contamination. Perhaps the concentrations that have been found in Alzheimer’s brains are no more than contaminants from the laboratory environment, their critics suggest. It’s a charge Perl has heard all too often. He is banking on today’s improved analytical techniques, and a recent explosion of research from his lab and others, to silence such accusations for good. As our techniques get better, he declares, the data get more precise.

Perl’s latest work involves the use of lasers that measure more accurately than ever before the aluminum in Alzheimer’s brains. We focus a high-energy laser beam onto a section of tissue in a very short, fifteen- nanosecond pulse, which converts whatever is in its path into ions, he explains. The ions then pass into a mass spectrometer that analyzes their makeup to a sensitivity more than 100 times greater than former techniques. When cells with tangles are compared with normal neighboring cells, says Perl, we’re seeing anywhere from a tenfold to a fiftyfold increase in aluminum content.

One mystery is how in the world it gets there. Because we live in a world replete with aluminum and other toxic substances, our bodies have evolved complex defenses to keep most of them on the outside where they can do no harm. The first barrier is the gut--which is a good thing because, in the case of aluminum, we are bombarded constantly with it via the things we ingest. Aluminum is naturally present in food, and it’s used in leavening agents, coloring agents, preservatives, and such commodities as processed cheeses, baking powder, pickles, and even baby food and toothpaste. Aluminum also shows up in frequently used drugs. For example, most antacids contain aluminum compounds, as does buffered aspirin. The amount of aluminum introduced into the body from such drugs can dwarf that entering by other means. In addition, aluminum is commonly used to purify municipal water supplies.

In normal circumstances, however, relatively little aluminum passes into the bloodstream--the intestinal walls intercept and dispose of most of it in feces. What does make the transition encounters the body’s second line of defense: a specialized protein called transferrin that binds to aluminum and other toxins to ferry them to the kidneys, where they exit in a stream of urine. If an oversupply of aluminum still remains, it must surmount the blood-brain barrier, an elaborate security system that filters the body’s blood before allowing it access to this vital organ.

With Alzheimer’s, however, the defenses somehow fail. The aluminum camp offers several possible explanations. One is that the process of aging weakens the barriers, causing aluminum to leak in. Another is that certain aluminum compounds more readily pass the barriers than others. For example, if you wash down your buffered aspirin or antacid with a swig of orange juice, which is rich in citric acid, you transform the aluminum in these drugs into aluminum citrate. In this form it’s up to five times better able to overcome the body’s barriers. If aluminum comes into contact with a sugarlike additive called maltol, which is used as a flavoring in many baked goods, its capacity to breach the body’s defenses is increased as much as ninetyfold.

Perl has yet another suggestion: we may breathe aluminum in. The olfactory system is the only place where nerve cells in the brain are exposed to the external environment, he says. Perl has introduced aluminum compounds through the nasal passages of rabbits, then tracked the progression of the metal into the brain. He has found that the aluminum travels along a highway of neurons to enter the brain directly, bypassing the bloodstream and its defenses and eventually ending up causing neurological damage in the very areas attacked in Alzheimer’s disease.

Just what all this means for humans is still unproved, but two recent studies reinforce the possibility that airborne aluminum may be one of the culprits. In 1990 University of Washington researchers found a slightly higher risk of Alzheimer’s among people who used aluminum- containing antiperspirants than those who didn’t. Although the study didn’t pinpoint the mode of application--spray or roll-on--subsequent investigation has led its leader, epidemiologist Amy Graves, to suspect that if aluminum is a significant risk factor, it’s through inhalation.

Another study in November 1990 from McLachlan and his colleagues in Toronto is even more intriguing. Between 1944 and 1979, gold and uranium miners in northern Ontario were dusted with a finely ground aluminum powder in an attempt to combat silicosis, a disease caused by inhaling rock dust containing silica. As they changed clothes before each daily underground shift, the miners were enveloped in a cloud of the powder for ten minutes. The Toronto team tracked down these miners, gave them a test that measured cognitive function, and found that the dusted miners performed poorly compared with those not exposed to aluminum powder. The longer the exposure, the greater the loss in function. Some were even found to have impaired memory.

Still other recent research further implicates aluminum. In one experiment published early this year, an international team led by biochemist Gerald Fasman of Brandeis University added aluminum to protein fragments from nerve cells in the brain. They found that the protein refolded itself into the same pattern found in the proteins making up the tangles characteristic of Alzheimer’s.

In yet another recent study, McLachlan and his team gave 24 Alzheimer’s patients two injections a day of desferrioxamine, a drug that binds to aluminum and neutralizes its effect in the body. After two years of this regimen, the drug dramatically slowed the progression of dementia in these people. The patients still declined mentally, but only half as quickly as 24 other patients who were not treated. The next step is to give the drug to many more Alzheimer’s patients at a number of locations around the world to test these results. If successful, the research may produce a practical way to lessen the effects of the disease.

Also, tearing a page from rivals’ books, McLachlan and his colleagues are examining the effects of aluminum at the genetic level. They’ve come up with tantalizing indications that aluminum in Alzheimer’s brains binds to DNA in neurons, thereby interfering with the process of making proteins to sustain healthy cells. When removed into test tubes, the impaired DNA appears sticky and balled up, as though the aluminum has glued the strands together. Thus constrained, the DNA may no longer be accessible to enzymes that assist in the manufacture of proteins. The result: diseased and dying neurons. The team is now beginning experiments to see if the aluminum does indeed bind to the DNA and whether neutralizing the metal with desferrioxamine might slow the process.

Naturally, the findings have provoked skepticism--nothing ever comes easy to the aluminum temple. Nevertheless, the accumulated evidence has prompted Perl to make a modest proposal. While it’s true that food cooked in aluminum pots and pans can pick up traces of the metal, don’t worry about it--the risk is so much greater from other sources. Avoid inhaling aluminum-containing aerosols or antiperspirants, he suggests, because these are preparations made for maximum absorption of an aluminum- containing product. There are alternative products that are effective.

McLachlan goes even further. He recommends that we limit our exposure to aluminum by virtually any route--food, water, drugs, cosmetics. The problem, however, is that much of the time we’re unaware that we’re actually encountering the metal. For example, while antiperspirants are labeled as containing aluminum, baked goods often are not. What’s needed is a change in public policy. All aluminum-containing foods and drugs should be labeled as such, and water treatment should be regulated to lower aluminum content. Right now, reducing our exposure to aluminum may be the only change in life-style that offers hope of lessening the incidence of Alzheimer’s disease, McLachlan says.

So Perl and his hardy fellow pioneers are finally gleaning a sense of where aluminum may fit into the Alzheimer’s picture. Ironically, it’s one that includes the other sects in the Alzheimer’s religion. Says Perl, My feeling is that Alzheimer’s is probably like the other chronic diseases of the elderly, cancer and heart disease. Namely, it’s an interaction between genes and the environment. Your genes provide you a relative resistance or susceptibility to rather common environmental factors, which over time help trigger the disease.

He shrugs, giving his eyebrows-raised, palms-out gesture. And the environmental factor we are getting the most scientific evidence on is aluminum.
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