[ExI] LA Times: Scientists can't get their minds around Alzheimer's

[PJ Manney]

Apparently, no one can come up with agreement as to the causes or
mechanisms behind Alzheimer's.  And that's causing problems.

"...after listening to scientists discussing Alzheimer's and how to
fix it, it is hard to come to any conclusion but that, at least for
the moment, the Alzheimer's endeavor is a mess."

"More common are sentiments such as that expressed by Eli Lilly's
Karran in the talk he gave to open the San Francisco conference. After
describing his notion of what the Alzheimer's disease process was, he
said: 'If the pharmaceutical industry had known what this looked like,
we never would have started working on it.'"

@#$%... (fill in your favorite profanity)

PJ

http://www.latimes.com/news/nationworld/nation/la-na-alzheimers27dec27,0,1354769.story?coll=la-home-center

>From the Los Angeles Times
Scientists can't get their minds around Alzheimer's
They still aren't sure what causes the disease or how to cure it. And
the stakes have never been higher.
By Terry McDermott
Los Angeles Times Staff Writer

December 27, 2007

SAN FRANCISCO — On a warm autumn afternoon, toward the end of a
daylong barrage of PowerPoint presentations, a white-haired,
gentlemanly fellow named Michael Merzenich faced a room full of
neuroscientists and pharmaceutical executives and declared that,
really, they could all pack up and go home. He thought he could stop
Alzheimer's disease by doing nothing more than sitting old people down
for a few months in front of computer screens and retraining their
brains.

What was odd about Merzenich's pronouncement was that it hardly seemed
odd at all. He had been preceded to the stage -- and was followed the
next day -- by a procession of researchers who offered widely variant
prescriptions for confronting the disease, many as complicated as
Merzenich's was comparatively simple.

The scientists blamed Alzheimer's on misfolded proteins, broken neural
pathways, misprinted gene maps, everything, it seemed, but the stage
of the moon. Here and elsewhere for years they have laid plans to
fight the disease with all of the Big Pharma firepower they could
muster. But they also talked about inhaling insulin, eating turmeric,
fixing vitamin deficiencies, injecting stem cells and inventing
neuro-protective vaccines. They couldn't all have been talking about
the same disease, could they?

A month after San Francisco, at another conference (this time in New
York), some of the same participants delivered much of the same data,
but with yet more novel approaches piled on. A month later, the road
show moved on to San Diego, where even more alternate explanations
were added to the roll.

As with Merzenich, when someone stands in front of a crowd of
excessively bright and dedicated scientists and delivers a theory
radically different from what everyone else in the room has been
saying, nobody blinks. Or even seems to notice. It wasn't that the
other scientists thought Merzenich was wrong or right or crazy. He is
a highly respected neuroscientist. In Alzheimer's research, lots of
people seemed to have quit believing anything is wrong or right or
crazy. Mainly, they shrug.

Surveying the ideas proposed at the New York meeting, Grant Krafft,
chairman of Acumen Pharmaceuticals Inc. of South San Francisco, shook
his head and sighed. "There was a lot of mucked-up science here
today," he said.

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."

Spaghetti or not, after listening to scientists discussing Alzheimer's
and how to fix it, it is hard to come to any conclusion but that, at
least for the moment, the Alzheimer's endeavor is a mess.

What's at stake

The individual devastations of Alzheimer's disease are by now well
known. It is one of several, and by far the most common, of so-called
neurodegenerative diseases; literally, diseases that destroy the
brain.

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.

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."

While the cost of Alzheimer's soars, federal money spent on research
has flattened and is expected to decline in real terms in the future
as the competition for federal money heightens. The rising costs of
treating the disease coupled with reduced research funding is, to
some, a foreboding combination.

Andy Grove, the former chairman of Intel Corp., spoke at this year's
Society for Neuroscience convention in San Diego. Grove, who has
Parkinson's disease, lamented the lack of a full-scale attack on
neurodegenerative disorders: "We are about to experience an explosion
of Alzheimer's disease cases. . . . This situation is best compared to
astronomers following a meteor hurdling toward San Diego, aimed to hit
a very precisely calculated place and time. What would we do if we had
such a situation? I think we would take it a little more seriously
than we take the economic meteor that's coming just as predictably our
way."

Research confusion

It's been 101 years since Alzheimer's disease was first theorized, and
30 years since the federal government began funding research on it,
spending, to date, more than $8 billion. Private industry has spent
billions more. What has been learned?

The answer is perplexing. There have been more than 35,000 scientific
papers published on Alzheimer's just in the last decade. They include
hundreds of impressively detailed descriptions of purported disease
mechanisms. But in all that wealth of information, there are some
rather obvious gaps.

For example, 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.

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.

For a long while, the Alzheimer's field was divided between the two
warring camps -- the so-called (beta amyloid) Baptists and Tauists.
Now, the two-front war has exploded. The lack of resolution has
produced a surfeit of competing hypotheses, the most prominent of
which focuses on what happens with beta amyloid before plaques form.

Beta amyloid is common in the brain and not harmful when it exists in
single strands. Plaques contain thousands of strands. This new
hypothesis holds that much smaller accumulations of the proteins,
containing as few as half a dozen strands, are the real culprit in
Alzheimer's. These smaller accumulations, called oligomers, are,
because of their small size, able to travel between neurons in a way
that plaques cannot.

Researchers have discovered that oligomers can be toxic to brain cells
long before plaques ever form. This would explain why some people who
have been diagnosed with Alzheimer's were not found to have plaques.
The evidence that oligomers are dangerous has been so persuasive that
many of the leading proponents of the amyloid hypothesis have
incorporated them into their models.

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.

Complicating matters are preliminary results from the first long-term studies.

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. 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.

Pharma difficulties

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.

Much of the basic research of the last decade has been aimed at
building an understanding of how the normal process within brain cells
can break down. That process is an elaborate one, involving what
biologists call cascades of events -- dozens, to perhaps hundreds, of
steps long. Every step represents a point of potential failure. Each
also represents a point of potential intervention. Science has learned
to intervene in many normal biological processes by manufacturing
molecules that will disrupt one step, thus halting the cascade. That's
the theory, but it is also the biggest obstacle. The cascade wouldn't
exist if it didn't do something useful.

Here's an example. So far, the primary genetic contribution to normal,
or late-onset, Alzheimer's, the most common form of the disease,
occurs with the mutation of a gene that makes a protein called ApoE.
It might be possible to devise a way to render that protein inactive.
But that causes other, potentially larger, problems. ApoE is a lipid
transporter. Its main job is to carry lipids, including cholesterol,
from the interior of cells to be broken down, destroyed and carried
away for disposal. Think of it as taking out the garbage. A drug to
attack ApoE would destroy one of the body's natural systems of
disposing of cholesterol.

Alzheimer's has been particularly intractable, but there are
optimists. Dennis Selkoe of Harvard University, one of the most
prominent Alzheimer's researchers, thinks there might be an effective
therapy found within the next year or two. He thinks the disease
process is now sufficiently understood. "If drugs fail, it will be
because they are not potent enough," he said, not because they don't
attack the disease process.

Buckholtz, of the National Institute on Aging, said the wide variety
of proposals now in circulation reflected the vigor of the underlying
science. "The therapeutics are targeted at different pathways that may
be involved. I think that's a good thing," he said. "Although it's
frustrating they haven't been more efficacious, I continue to be
optimistic that by having all these targets available we'll have
something soon."

More common are sentiments such as that expressed by Eli Lilly's
Karran in the talk he gave to open the San Francisco conference. After
describing his notion of what the Alzheimer's disease process was, he
said: "If the pharmaceutical industry had known what this looked like,
we never would have started working on it."

terry.mcdermott at latimes.com