Alzheimer’s Remains a Puzzle a Hundred Years After It was First Identified

We know what happens to those afflicted with Alzheimer’s, but not why it comes about. A century after it was first identified and after billions of dollars sunk in research, it still baffles scientists.

David Bennett of the Rush Alzheimer's Disease Center in Chicago persuaded more than 2,000 older people who had no signs of dementia to undergo cognitive testing, beginning in 1992. As they aged, some of the people developed cognitive difficulties. Some had mild cognitive symptoms. Some none. Some developed full-bore Alzheimer's.

The participants agreed that after death their brains would be available for autopsy. Bennett has examined 660 of the brains. Only about a third of the people had developed symptoms of dementia, notes Terry McDermott writing in  Los Angeles Times.

Alzheimer's first afflicts the areas where new memories are encoded. Early symptoms include the incidental episodes of forgetfulness often brushed off as "senior moments." The symptoms progress, slowly at first, to more frequent memory disruptions, to broader cognitive problems -- confusion, disorganization, disorientation. Eventually, as the disease works its way through more areas of the brain, it alters personality and destroys the self, reducing the victim to little more than a warm body greatly in need of care.

The leading hypothesis of the cause of Alzheimer's, called the amyloid hypothesis, is centered on the overproduction, or inadequate clearance, in the brain of a protein called beta amyloid. Fragments of the protein aggregate into clumps called plaques. These plaques were first observed more than a century ago by the man after whom the disease is named, Alois Alzheimer.

For most of the century since, scientists have believed the plaques were associated with the disease. But to date, they don't know whether amyloid plaques are the cause of the disease or a result. They don't know whether they are vital to the progress of the disease or incidental. They don't even know whether their presence is indicative of the disease.

A rival idea, called the tau hypothesis, is no more definitive. Where beta amyloid generally aggregates outside brain cells, the protein tau aggregates into fibrous structures, called tangles, inside the cells.

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The processes by which either amyloid or tau cause brain cells to malfunction, and in some cases die, are neither well understood nor completely coincident with observations of the disease itself.

Inconveniently for scientists, there are no definitive physical markers for Alzheimer's in living patients. There is no blood test or tissue sample that can be taken and examined. It is diagnosed by the symptoms a patient exhibits, and there is no way to know definitively what is going on inside a patient's brain.

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Yet Bennett found that more than 90% of the brains bore the plaque/tangle hallmarks of the disease. Some people who had the symptoms did not have the tau tangles or the beta amyloid plaques. Some who didn't have the symptoms had the plaques or tangles; some had both.

The implications of this are confounding and frightening. Could it be that Alzheimer's is not a specific disease, but a normal part of growing old?

Bennett recoils at the implication. Alzheimer's might be associated with aging; that doesn't mean it is caused by it, he said. "Alzheimer's disease is extremely common. The estimates are probably gross underestimates. Is it statistically normal? Yes. But if you use normal to mean the same as puberty, something inevitable, no, absolutely not."

He notes that ancient Egyptians all developed tooth decay by age 40. "But there was nothing normal about it -- it was the environment," he said.

Marcelle Morrison-Bogorad, associate director of the National Institute on Aging's neuroscience and neuropsychology of aging program, finds Bennett's data deeply disturbing.

She said "the distinction is getting fuzzier and fuzzier between normal aging and diseases like Alzheimer's disease. This brings into question if these people are normal or not. I don't think we can tell anymore who is normal.

"It worries me a lot, actually, because we've been trying to reassure people who are older that small lapses in memory are part of normal aging. . . . This research is suggesting, not proving, that it might be a sign of something down the road. That's not good news."

To say that Alzheimer's is normal is not something anyone wants to hear. Medicine can't stop people from getting old. And you can't fix old age. Other than the simple arithmetic of it, no one really even knows what aging is. They know what accompanies it; they haven't a clue what causes it. Some people, of course, live to be 100 and never suffer dementia. But dementia is clearly associated with old age. Any individual's probability of having Alzheimer's is the sum total of a variety of factors.

Gary Lynch of UC Irvine summarized those factors as a combination of an individual's genetic endowment, pre-birth conditions, life experiences, environmental conditions and health accidents. If, for example, you were born with a mutation of a particular lipid transport gene and you had banged your head on the pavement when you were 12, your chances of having Alzheimer's would be many times greater than someone who had the right genes and wore a helmet religiously when skateboarding. Eric Karran, chief scientific officer at pharmaceutical giant Eli Lilly & Co., states the obvious when he says his industry is "in a lot of trouble at the moment." New drug candidates are failing trials. Old drugs are the subjects of lawsuits. The industry is accused of having insufficient concerns about the safety of its products while being urged by specific patient groups to take more risks to develop medicines for them. Patents are expiring on successful drugs, meaning revenue for many companies is about to fall off what is darkly referred to within the industry as the patent cliff.

The failure to learn what causes Alzheimer's has made development of ways to treat it problematic, but the pharmaceutical industry has already sunk billions into Alzheimer's programs. The disease is too tempting a financial target to ignore.

There are currently five medications approved for treatment of Alzheimer's in the United States, one of which causes severe problems and is rarely prescribed. The other four take in an estimated $4 billion a year. They do nothing to stop the disease and have only marginal, often transitory effects on its symptoms. They're on sale because there is little else to offer people afflicted with the mind-crippling disease.

There are 56 more drugs in some stage of the clinical trials regulated by the Food and Drug Administration; few people other than their creators have great hopes they will work. Sometimes, not even the creators are optimistic.

Wyeth, a New Jersey-based pharmaceutical company, has 10 candidate Alzheimer's drugs in clinical trials. Drug companies have had such difficulty translating their research into effective neural disease treatments that Wyeth has decided to push everything it had into trials and see what, if anything, worked. Internally, Wyeth calls this the "fail faster" approach.

Neil Buckholtz, chief of the dementias of aging branch of the National Institute on Aging, said the pharmaceutical industry had little choice. "This is basically a 'throw the spaghetti against the wall' strategy. . . . We just have to try these various approaches. It's very time consuming, very expensive, but it's the only way we'll know if things work or not."

As Eli Lilly's Karran despaired, "If the pharmaceutical industry had known what this looked like, we never would have started working on it."

An estimated 5 million Americans have Alzheimer's. That number has lately been growing exponentially; ironically, as medical care improves and people live longer every decade, it will continue to do so.

By 2010, Alzheimer's care will cost Medicare about $160 billion a year. By 2035, it could overtake the defense budget. One analysis has estimated that by 2050, Alzheimer's will cost Medicare more than $1 trillion annually. Those numbers do not include privately insured and uninsured costs.

"From a social and economic view, it is about the money, the growing diversion of resources to sustain life in those increasingly unaware of their own lives," Harry Tracy wrote recently in NeuroInvestment, his industry newsletter. "There is no greater public health issue looming in the developed world."

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