I Can't Remember
AUGUST 21, 2003
COVER STORY
By Catherine Arnst
"I Can't Remember"
Drugs to stave off age-induced memory impairment -- perhaps even to foil Alzheimer's disease -- may be on the horizon
"We are
who we are in good measure because of what we have learned and what we
remember."
-- Nobel Laureate Dr. Eric R. Kandel
The 76-year-old California lawyer appears to be the very model of healthy aging.
C.L., who asked that his name not be used, hikes two miles up a nearby mountain
four times a week, is always reading two or more nonfiction books at a time, and
boasts that his waist and chest measurements haven't changed since he was 25.
This take-charge guy expects a lot of himself. But for the past six years, his
memory hasn't measured up. He occasionally forgets a name, he loses his train of
thought when there are distractions, and he has walked away from six pairs of
expensive sunglasses. "People who are very well-trained intellectually notice
when they begin to lose that ability to grab onto every word, every concept," he
says. "It's like a significant part of your life is erased."
C.L. yearns for some kind of treatment -- and his determination sends a powerful
message to the drug industry. Although he is functioning very well for his age,
he lobbied hard to enter a clinical trial for an experimental memory drug
developed by Cortex Pharmaceuticals Inc. (COR
) of Irvine, Calif. The compound, called CX516, is in Phase 2 clinical trials
for people who suffer from frequent short-term memory lapses, a condition called
mild cognitive impairment (MCI). It is an ominous diagnosis, even though the
condition doesn't interfere significantly with daily living, because it can be
an early warning sign of something much worse. Every year some 15% of people
with MCI go on to develop Alzheimer's disease.
HUMAN TRIALS. C.L. took nine capsules
of CX516 daily for 12 weeks this spring. The impact was immediate. "At the start
of the trial, I could remember less than five words out of a list of 20. By the
second week, I could get 14 out of 20. There was a very, very appreciable
enhancement." He has since finished his part in the study and says it was
"heartbreaking" to go off the drug. "I've been thinking of some other way to get
it, and I don't give a damn if it's legal or illegal."
If he waits a few years, C.L. should be able to solve his problem legally. At
least 60 pharmaceutical and biotech companies around the world are working on
novel memory pills. Some 40 are in human trials, and the first of these could be
on the market within the next few years. These drugs aim to do far more than
relieve the occasional "senior moment." Neuroscientists are hoping that any pill
that improves memory in the elderly will also protect against Alzheimer's
disease, the diagnosis old people fear most.
"Within five years, we will have treatments that slow the rate of decline or
even delay the onset of Alzheimer's by five years or more," predicts Dr. Leon J.
Thal, chairman of the Neurosciences Dept. at University of California-San Diego.
The drug industry is spending billions of dollars to come up with such a pill,
and it's not hard to see why. In 10 years, all 77 million baby boomers will be
50 or older, and as many as 25% of them may develop some form of dementia. They
do not, however, show any interest in going gently into that good night. As
Harry M. Tracy, publisher of the newsletter NeuroInvestment, notes: "This
is a generation that does not accept decline."
FINAL FRONTIER. It's also a
generation that is approaching the danger zone. The brain reaches its maximum
weight by age 20 and then slowly starts shrinking, losing 10% of its volume over
an average lifetime. It's virtually inevitable that mental glitches will show up
by the time we are eligible for senior-citizen discounts, and people are
noticing. Surveys have found that 75% of people over 50 believe they suffered
memory problems over the prior year. Some of these people may be overreacting --
but a large proportion aren't. At least 20 million Americans over 60 have some
level of memory impairment short of dementia. Another 4.5 million are victims of
Alzheimer's, a progressive brain disease that over the course of a decade
destroys memory and other cognitive functions until its victims are virtually
helpless. The longer one lives, the greater the danger -- 50% of people age 85
and over end up with Alzheimer's.
Since more of us are living to an old, old age, trend lines for memory loss all
point upward. The Alzheimer's Assn. estimates that by 2050 -- when the number of
people over 65 will have doubled, to 70 million -- there will be 13.2 million
Alzheimer's victims. Run the numbers, and it's obvious that a pill that promises
to protect against this terrible malady would dwarf the $1.7 billion a year
pulled in by Viagra, that other salve for an aging body.
That such pills are even in the pipeline is something of a scientific miracle.
The human brain is medicine's most daunting frontier. Made up of more than one
trillion highly complex neurons, it remained obdurately opaque long after the
body's other tissues had given up many of their mysteries. But in the past
decade, the code has been partially cracked. Using sophisticated imaging
technologies, animal experiments, and genetic insights, scientists now have a
road map of the complex process that is memory formation.
Products follow knowledge. The first drug able to improve the thinking abilities
of people with advanced Alzheimer's disease was approved in Europe last year and
is widely expected to win the nod from the Food & Drug Administration this fall.
Memantine, developed by the German company Merz, is no miracle cure, and it has
shown no effect in Alzheimer's patients in the earliest stages of the disease.
But clinical trials demonstrated that the drug allows the most desperately
confused patients to live independently for six months to a year longer than
they would otherwise, with no debilitating side effects.
Memory clinics are springing up around the U.S.
That's more significant
than it may sound: Alzheimer's is the No.1 cause of institutionalization in the
U.S. Memantine marks the first big payoff of brain research carried out over the
past decade. The three treatments for Alzheimer's now on the market -- Pfizer's
(PFE ) Aricept, Novartis' (NVS
) Exelon, and Reminyl from Johnson & Johnson (JNJ
) -- all boost the levels of a brain chemical called acetylcholine, and first
appeared in the early 1990s. These drugs can delay the downward trajectory of
patients in early stages of the disease for several months, but they do not
improve thinking power and can cause nausea, loss of appetite, and frequent
bowel movements.
Memantine is a smart bomb by comparison. It targets a cell receptor that
controls the intake of glutamate, a neurochemical that scientists believe is
responsible for 75% of the communications between brain cells. "Memantine
represents real progress, a meaningful therapeutic advance," says Dr. Pierre
Tariot, a University of Rochester psychiatrist.
Neuroscientists eagerly anticipate more such advances. Even now, the contours of
an enormous memory industry are coming into view. Just look at the herbal
supplement ginkgo biloba: Annual sales reached an estimated $500 million in the
U.S. last year, although clinical trials have disproved claims that it can boost
memory. The three Alzheimer's drugs now available had combined U.S. sales of
more than $1 billion, despite their shortcomings. Memory clinics are springing
up around the nation, headed by everyone from top-ranked neurologists to New Age
practitioners, while bookstore shelves are stuffed with how-to guides on memory
maintenance.
A CURE IN CURRY? Even the federal
government is in on the act. The cost of caring for Alzheimer's victims in the
U.S. will total over $100 billion this year, making the disease a top priority
of the National Institutes of Health. It is sponsoring a dozen or more clinical
trials of potential memory enhancers in the hopes that something, anything, will
be found that can delay the slide into dementia. Anti-inflammatory treatments
such as aspirin and Celebrex are particular favorites for study, because
inflammation in the brain is a hallmark of Alzheimer's disease. Vitamin E also
has attracted interest in the hope that it may protect brain cells from damaging
molecules called free radicals that course through the blood and batter healthy
cells.
Plenty of other potential remedies are being tested as well, among them
estrogen, blood-pressure medications, cholesterol-lowering drugs, memory
exercises, and special diets -- including curry (because India has the lowest
incidence of Alzheimer's in the world).
Most experts, though, believe that a drug specifically designed for memory loss
will be far more effective than any jerry-built treatment -- and more lucrative
for the inventor. Medical experts estimate that about 8 million people in the
U.S. over age 50 suffer from mild cognitive impairment, and drugmakers do not
plan to stop there. Any pill that wins FDA clearance for cognitive impairment
will surely be tested against the next gradation of fuzzy thinking:
age-associated memory impairment. The signs of this condition include the
occasional misplacing of car keys or failure to recall a well-known name. As
many as 12 million Americans suffer from such lapses.
Are "smart pills" for younger people next?
If a pill that treats
such minimal memory loss wins FDA approval, it's not hard to imagine the next
step down this slope. A drug that can stave off age-associated memory impairment
will surely appeal to the enormous cohort that the medical establishment refers
to as the "worried well."
These healthy, well-functioning individuals share a common fear: that forgetting
a name every now and then is the first step toward dementia. "About half of my
patients are around 50 and self-referred because they are just worried," says
Dr. Gayatri Devi, director of New York Memory & Healthy Aging Services, a
Manhattan-based clinic. "Because their functioning seems impaired, some of them
come in convinced that they have Alzheimer's."
Next in line for memory pills could be college students seeking to improve test
scores. Drug developers all insist they have no interest in selling memory pills
to the young and healthy, but that may not matter: There is already evidence
that even nimble memories can be improved. In a groundbreaking study published
last year, Peter J. Whitehouse of Case Western Reserve University gave nine
healthy aircraft pilots -- mean age 52 -- a daily dose of Aricept, Pfizer's drug
for mild Alzheimer's. They were matched with another nine pilots who received
placebos. After 30 days, the Aricept pilots were measurably better able to
perform a set of complex flight-simulator tasks than the placebo group.
Far more tests will be needed to determine if Aricept, or any other drug, would
have the same effect in a larger population. Besides, given its unpleasant side
effects, it's unlikely Aricept would ever become a popular "smart pill."
Nevertheless, the success of the pilots' study does demonstrate that
memory-enhancing pills are possible. It won't be all that easy, however, to push
through a medication that tampers with the body's control center, the brain.
PERPETUAL PRESENT. "The FDA is going
to be very careful about the safety profile of any drug that might be taken by
millions of otherwise healthy people," says NeuroInvestment's Tracy. "These
drugs have a very high hurdle to leap, much higher than Alzheimer's
[medications]." Experimental brain drugs have often failed in clinical trials
because of dire side effects. Witness the fate of a promising Alzheimer's
vaccine by Elan Pharmaceuticals (ELN
). Development was halted last year, even though the drug was able to reduce
levels of the disease in a clinical trial, because some patients died of brain
inflammation.
The Elan experience was not the only time that doctors harmed the patient while
trying to heal the brain. A breakthrough insight into memory was borne out of an
attempt to cure epilepsy that went terribly wrong. In 1953, a Hartford surgeon,
in an effort to rid a 27-year-old man of seizures, removed a small structure
deep in the brain called the hippocampus. He cured the seizures, but the
patient, known as H.M., never formed another memory. He can recall events from
before the operation but has no memory at all of a conversation held minutes
earlier. He lives in a perpetual present.
H.M.'s tragic case proved that the hippocampus is where fleeting impressions
turn into permanent memories. Each sensation that enters the hippocampus, be it
a spoken name, some visual impression, or the instructions for a new cell phone,
sets off electrical charges inside neurons, the cells that make up the brain.
The charge stimulates the cell to release a roiling stew of neurotransmitters,
which carry the information across tiny gaps called synapses that connect the
neurons to one another. The longer these millions of signals flash back and
forth, the stronger the connections become and the more synapses are created --
a single neuron can have as many as 10,000 synapses. Finally, a set of neurons
bands together to retain the data, and the brain remolds itself to create
storage space.
"Use it or lose it" may apply to memory
The entire process, from
the time a number is heard until it is permanently stored, can take hours or
even days. As we age, the brain cannot execute this complex dance so quickly. A
recent study from the University of Kentucky suggests that the genetic changes
behind the mental slowdown may start by age 40, with the results showing up a
decade or two later. That doesn't mean we have no choice but to grow
continuously dumber. Even while the brain's ability to absorb new information
slows, it gets better at storing and calling up information it already has,
based on past experience. Age really does beget wisdom.
Continued mental activity might also ward off dementia. Several studies have
lent credence to the "use it or lose it" strategy. The most recent, published in
June by the Albert Einstein College of Medicine in New York, followed 469 people
age 75 or older for five years. Those in the top third of mental activity had a
63% lower risk of dementia than those in the bottom third. Taking part in a
single absorbing mental activity one day a week reduced the risk by 7%. However,
some scientists wonder if Alzheimer's may have already taken root in the study
participants who weren't as mentally engaged, which would explain their lower
ranking.
It is almost certainly helpful to start the mental challenges much earlier.
Study after study has shown that people with limited or no formal education
before the age of 10 are at a higher risk of Alzheimer's later in life. It may
be that intensive learning when the brain is young and plastic greatly increases
the number of synapses. The brain can call on these reserves as it ages, or in
case of injury, such as a stroke. This is when those piano or French lessons
your parents forced on you as a child might pay off. "The more synapses you form
in your lifetime, the more you can tip the balance in your favor as you age,"
says Dr. Majid Fotuhi, a neurologist at Johns Hopkins Hospital and author of the
book The Memory Cure.
"ACTS OF DESPAIR." Unfortunately,
memory can slip away from even the best and the brightest. W.D., a 78-year-old
doctor in Maryland, retired in 1993 but continued to be very active. Four years
ago, he started noticing problems. He would forget where he was going in his car
or what restaurant he had just eaten in. "I used to be clear as a bell, and now
I have to stop and think about where things are," he says. His doctor ruled out
Alzheimer's, but that just makes him wonder what is going wrong. "It's
depressing."
In trials, healthy pilots who took an Alzheimer's
drug experienced memory improvement Mental challenges early in life--such
as piano lessons--may enhance memory later on
Doctors have no way of predicting who is at risk for such debilitating memory
loss. They can't even diagnose Alzheimer's with certainty until after the
patient's death: It is then that clumps of rock-hard plaque in the brain can be
detected during autopsy. This plaque is caused by the buildup of a protein
called amyloid, which slowly destroy neurons, starting in the hippocampus. It is
unclear whether amyloid is a cause or a symptom of Alzheimer's, but scientists
are fairly certain that it starts accumulating 10 to 20 years before mental
decline is evident, by which point it is too late to reverse the process.
The
current Alzheimer's treatments are an act of despair," says Dr. Eric R. Kandel,
professor of psychiatry at Columbia University. "We have to start [intervening]
much earlier if we want to make a difference." Ergo the focus on early memory
loss, when the brain may still have a chance to save itself. Success in this
area will owe much to the study of animals that likely have far less to remember
than humans. It seems that brains of insects, apes, and people work in much the
same way. Kandel shared the 2000 Nobel prize for medicine for his breakthrough
discoveries about memory that grew out of painstaking work with sea slugs.
Kandel's discoveries were amplified by Tim Tully, a fellow of Cold Spring Harbor
Laboratories on Long Island, whose research is based on the brains of fruit
flies.
Work on these two lowly life forms led to a revolution in the understanding of
memory. Kandel discovered that a neurotransmitter called cyclic-amp, or CAMP,
plays a key role in strengthening synapses. Camp activates a protein called CREB,
which in turn switches on the genes that control the release of
neurotransmitters essential to long-term memory. "Think of CREB as a general
contractor that organizes the cascade of genes that build memories," says Tully.
Once CREB was discovered, Tully went to work designing a strain of fruit flies
with the CREB protein permanently activated. The result: flies with photographic
memories. The CREB flies could remember how to find sugar water in a specially
designed tank after only one try, while average flies would have to go through
multiple training sessions.
There is both an offense and a defense drug strategy
Both Kandel and Tully
have formed companies to pursue their discoveries, specifically by targeting
mild cognitive impairment and age-associated memory impairment. Kandel's firm,
Memory Pharmaceuticals Corp. of Montvale, N.J., is the furthest along, with
drugs that block the breakdown of CAMP. Memory Pharmaceuticals scored a $150
million partnership with Roche Holdings Ltd. and has six drugs in the pipeline,
including one in early-stage human testing. Tully's Helicon Therapeutics Inc.,
in Farmingdale, N.Y., is still in the lab with drugs designed to boost the
activity of CREB and has had promising results in mice.
The renowned reputations of Kandel and Tully have given their companies cachet.
But even Tully acknowledges that any memory enhancers developed by Helicon
"promise to be only one in this newly emerging sector of the drug industry."
Several other candidates are much further along.
Most of these drugs can be divided into two camps, defensive and offensive. They
either amplify neurotransmitters that strengthen memory formation or block those
that get in the way of that process. Cortex Pharmaceuticals, for example, is
investigating a group of drugs called ampakines that amplify the
neurotransmitter glutamate, stimulating it to produce more synapses. The
furthest along of these is CX516, the drug tested on C.L. In early trials, CX516
boosted memories in healthy 65- to 75-year-old volunteers more than twofold over
a placebo group. The drug also improved cognitive performance in a small group
of Swedish medical students, an intriguing hint that the drug may work on the
young as well as the old. Cortex is conducting a 150-patient clinical trial in
patients with mild cognitive impairment, in partnership with Les Laboratories
Servier of France, scheduled to finish this year.
The defense strategy is being pursued by Saegis Pharmaceuticals Inc. of Half
Moon Bay, Calif. Its drug, SGS742, blocks gaba, a neurotransmitter which can
inhibit memory consolidation. The results of a completed Phase 2 trial for MCI
have yet to be published, but Saegis Chief Executive Rodney Pearlman says: "We
did see a statistical significance over the placebo group."
CHOLESTEROL LINK. There are plenty of
existing compounds under investigation as well. One closely watched trial
sponsored by the NIH will try to determine if statins, the popular
cholesterol-lowering drugs such as Zocor and Lipitor, can slow memory loss. Such
a connection makes sense, says Dr. Kenneth Davis, head of the Alzheimer's
Disease Research Center at Mt. Sinai Medical Center in New York, because the
plaque that clogs arteries in patients with high cholesterol has certain
commonalities with the plaque found in the brains of Alzheimer's patients. It
will take several years before any of these large prevention trials produce
definitive answers. By then, one of the many memory pills in the works could
also be available.
At that point, people who suspect declining memory might visit a special clinic
where they will take a battery of tests to assess cognitive function. Based on
the results, they will be given a set of brain exercises and prescribed a memory
drug. "This effort," envisions Tully, "will yield lasting improvements in our
abilities to perceive the world around us and remember our contributions to it."
It is a vision everyone on the far side of 40 can embrace.
Senior Writer Arnst covers
medicine for BusinessWeek
Copyright 2000-2003, by The McGraw-Hill
Companies Inc. All rights reserved.
THE MOST COMPLEX COMPUTER ON EARTH
The brain contains over a trillion neurons that constantly reconfigure themselves to form new memories or purge old ones. When everything is going right, they perform this task more efficiently than the world's fastest supercomputers.
Remembering...
1
A phone number you've just heard is captured by
the brain's cells, or neurons, as a pattern of electrical signals that transport
it to a processing center deep inside the brain called the hippocampus,
responsible for learning and memory.
Remembering...
2
Once the phone number is lodged in the
hippocampus, a cascade of brain chemicals called neurotransmitters is released.
These messenger chemicals carry the information across tiny gaps, called
synapses, connecting the neurons.
Remembering...
3
The
neurotransmitters deliver the phone number to the appropriate area of the brain
for storage. The stronger the memory, the more synapses are created,
strengthening the connections between neurons. Eventually, a group of neurons
band together to form a long-term storage space for the information, a process
that can take hours or days.
...And Forgetting
3
By
the time you turn 50, the memory-formation process slows down as neurons
naturally die off or are ravaged by disease. Age-associated memory impairment
can develop, a common condition typified by momentary gaps in recall.
• Continued memory decline, called Mild Cognitive Impairment, could indicate
that clumps of an insoluble protein called amyloid are accumulating in the
hippocampus and elsewhere. The amyloid destroys neurons and causes
neurotransmitters to surge out of control, short-circuiting the memory-forming
process. This marks the start of Alzheimer's disease, a degenerative brain
condition that begins with the loss of short-term memories and eventually
destroys all cognitive functions--a process that can take up to 12 years.
