Replies to post #40056 on Biotech Values

[biophud]

Great Article Dew-Thanks.

Happy New Year!

biophud

[DewDiligence]

Prevalence of Alzheimer’s Rises 10% in 5 Years

[An egregious error in the first paragraph makes me wonder what other stats in this article might be wrong.]

http://www.nytimes.com/2007/03/21/us/21alzheimers.html

>>
March 21, 2007
By JANE GROSS

More than five million Americans have Alzheimer’s disease, a 10 percent increase from the last official tally five years ago, and a number expected to more than triple by 2050, absent a cure, as the 85-and-over population soars and the baby boomers move into their late 60s and 70s. [Huh? In 2050, the baby boomers will be between 86 and 104!]

The updated estimates, based on the rising occurrences of the disease with age, not new disease research, were released yesterday by the Alzheimer’s Association, along with a compilation of other information about a progressive brain disease that afflicts 13 percent, or one in eight people 65 and over, and 42 percent of those past 85.

Much of the report is a synthesis of existing research on the prevalence and costs of the disease. But the report includes the startling finding that 200,000 to 500,000 people younger than 65 have some form of early onset form of dementia, including a rare form of Alzheimer’s disease that strikes people in their 30s and 40s.

Mary Mittelman, an Alzheimer’s researcher at New York University, had mixed feelings about disproportionate attention to early onset Alzheimer’s disease. On the one hand, Dr. Mittelman said, these cases are such a small minority that she fears will take focus and resources “from the majority who are much older.” On the other, she said, "because of the ageism of this society” far too many people still believe dementia to be part of normal aging and attention to this younger group will clarify that it is a "real disease.”

Apart from early onset cases, the primary risk factor for Alzheimer’s disease is age.

Alzheimer’s disease, the most common form of dementia, affects memory, reasoning and communication. In the advanced stage, people need help dressing, using the bathroom and eating. In the final stages, they cannot speak or recognize family members. The disease is ultimately fatal.

Currently, there are five drugs approved by the Food and Drug Administration that slow the disease’s symptoms for 6 to 12 months in half the individuals who take them. Nine other drugs are in late-stage trials.

Etc.
<<

[DewDiligence]

The current issue of Barron’s has a cover story
on the various players in the Alzheimer’s arena.
Among the companies mentioned are ELN MYGN
NRMX and WYE. This makes a good companion
piece with the 2006 article in BW (#msg-15892303).

http://online.barrons.com/article/SB117529931082755269.html

>>
Alzheimer's Cure

By BILL ALPERT

About a year ago, James Smith's life changed. "At age 46," he says, "something like Alzheimer's disease wasn't even on my radar screen."

Smith was an information-technology director for a big financial firm near Minneapolis, a globetrotting "tech weenie." But he started forgetting things, losing his sense of time. He could no longer multitask. More recently, following the Alzheimer's diagnosis, Smith has noticed his personality changing. Flashes of anger come and go, for no reason. And his awareness is slipping: He'll think he's having a good day, only to find out he's forgotten something really important.

The disease forced him to retire on disability last summer, just after his twin daughters entered Northwestern University. Smith's wife Juanita doesn't have a job with health insurance. His corporate health-insurance coverage will run out in about a year. It's too late for them to get long-term-care insurance, so they'll have to spend down to the poverty level when he finally needs full-time care.

James and Juanita watched her grandmother die of Alzheimer's complications, so they know what's ahead. "Neither of us has any illusions about where this goes," he says. "It's 100% fatal."

But those odds may soon improve for Alzheimer's sufferers like Smith. Large drug companies such as Wyeth have progressed to the point where they're conducting human studies for numerous treatments that stem the underlying biological causes of Alzheimer's disease. Smaller firms like Myriad Genetics and Neurochem are actually in their final phase of testing drugs aimed at Alzheimer's causes. Smith is desperate to participate in one of those clinical studies, but the test designs exclude people under the age of 50.

So Smith is in a race against time -- the most advanced experimental drug candidates are still a couple of years from Food & Drug Administration consideration. But when Alzheimer's drugs arrive, they will do much good for the estimated 440,000 Americans that develop the disease each year. More than 5 million suffer from Alzheimer's in the U.S., according to the latest estimates from the Alzheimer's Association, and perhaps 24 million suffer worldwide. Smith's disease had an unusually early onset, given that Alzheimer's risk increases with age: 1% of those in their early '60s have it, while more than one-third of those older than 85 have it. [I find this stat hard to believe, but I keep seeing it in reputable publications, so presumably it’s true.] With the cohort of 78 million baby boomers that began turning 60 last year, the prediction is that 16 million Americans will have Alzheimer's by mid-century. The worldwide number by then would be 80 million.

Without successful treatments, Alzheimer's will become a crushing economic burden for the country, and not just for families like the Smiths. Patient care already costs Medicare $91 billion a year, plus another $21 billion for Medicaid programs. That makes it the country's third most costly illness, after heart disease and cancer.

"I'll be 60 this year," says Wyeth chief executive Robert Essner. "And there are no really effective treatments out there...This will be a huge health-care problem for my generation."

Essner's company (ticker: WYE) has made a broad investment in Alzheimer's research, bringing 11 drugs into clinical human testing. Its lead compound is a genetically engineered antibody developed with the Irish firm Elan (ADR ticker: ELN) that actually clears away the toxic protein that clots Alzheimer's patients' brains. Other Wyeth compounds inhibit the formation of those Alzheimer's clumps.

Wyeth's experimental drugs certainly could fail, but it wouldn't cost investors much to find out. The Madison, N.J.-based company has one of the cheapest big drug stocks, trading at about 14.5-times this year's consensus earnings estimate, at the recent share price of 50.

Yet its business is improving. Wyeth has gotten its arms around the expensive litigation surrounding its pfen-fen diet drugs, so currently successful products like the anti-arthritic Enbrel and Prevnar, a strep vaccine, should start lifting cash flow and profits. It is also one of only a handful of drug firms that might be attractive merger partners for giants like Novartis (NVS) or Pfizer (PFE). So Wyeth shares could rise into the 60s -- and that's without considering that its Alzheimer's program could yield some of the most important new drugs in our lifetimes.

Other companies with large Alzheimer's bets include Eli Lilly (LLY) and Pfizer, as well as the Salt Lake City-based genetic- testing pioneer Myriad (MYGN) and tiny Neurochem (NRMX) of Laval, Quebec.

Just over 100 years ago, the Bavarian psychiatrist Alois Alzheimer described autopsies of dementia patients' brains, where he found nerves caked with sticky plaque and filled with tangled fibers. In the last 20 years, scientists have gained much understanding of the biology underlying these features of what is known as Alzheimer's disease, the cause of at least half of all dementia. After losing memory and language skills, patients become unable to care for themselves and die bedridden -- sometimes as long as 20 years after diagnosis, but typically after about eight years.

Drugs to combat Alzheimer's have been slow to arrive, with many failed efforts. The five medications approved since 1993 only treat the symptom of weak memory -- offering a moderate boost that lasts for less than two years. Pfizer's Aricept and Novartis' Exelon prevent the breakdown of the neurotransmitter acetylcholine that's part of the mechanism of memory (as does Cognex, which Pfizer no longer actively markets). Johnson & Johnson's Razadyne works similarly, but also makes the so-called nicotinic receptors produce more acetylcholine. Namenda, from Forest Labs (FRX), prevents another neurotransmitter called glutamate from overexciting memory receptors of nerve cells.

Smith has taken Aricept for a year, and is adding Namenda. Aricept helped him regain a lot of his mental clarity. "It's like the difference between driving during the day...and driving at night," he says. "Within the space of my mental headlight, with Aricept, I can do pretty well."

But none of these approved drugs has been shown to actually change the downward course of Alzheimer's. The search for drugs that can slow the disease has focused largely on the source of the plaque first reported by Alois Alzheimer. The plaque consists of a misfolded variant of a common cellular substance known as amyloid. This rogue version is called amyloid-beta42 -- or A-beta42 -- and it tends to clump together inside nerve cells, interfering with nerve function and eventually killing brain cells.

Researchers have been able to reproduce features of human Alzheimer's in the laboratory cell cultures and mouse experiments that precede clinical studies in humans. "There has been a lot of preclinical evidence that amyloid deposition is upstream of the other effects of the disease," said Harvard Medical School neurologist Dennis Selkoe, in a recent conference call with clients of CIBC World Markets.

The farthest along of the anti-amyloid experimental drugs are Myriad's Flurizan and Neurochem's Alzhemed, both of which are in the Phase 3 trials that come just prior to seeking FDA approval. Myriad already has a genetic cancer-testing business that ran up $132 million in sales in calendar 2006 -- and a stock-market valuation of more than 10-times that amount, at a recent share price of 34, despite its lack of profits. The company's been plowing research dollars into developing drugs like Flurizan, an anti-inflammatory designed to inhibit formation of the amyloid-beta42 that's prone to clumping.

Flurizan seemed to work in mice, but it failed to show a statistically-significant benefit during a 12-month Phase 2 study involving 207 patients. The endpoint combined tests of patients' cognitive performance and caregiver ratings of the patients' ability to carry out daily activities.

After the study, however, researchers followed some of the Phase 2 patients who had the mildest Alzheimer's and who continued taking Flurizan for two years. Those on the highest dose of Flurizan stabilized their mental test scores. This post-hoc analysis of a subset of patients doesn't prove much, but it encouraged Robert C. Green, a Boston University neurology professor. "If you can preserve function up to two years in some people," he says, "that suggests to me that the drug's doing something."

Green is lead investigator in one of Myriad's two Phase 3 studies of Flurizan, each of which is following 1,600 patients over 18 months. Myriad recently cancelled plans for an interim analysis after 12 months, so Green won't have his results until 2008.

The future of Canada's Neurochem basically rides on Alzhemed, an experimental drug that's like an anti-coagulant that binds to single copies of A-beta42 and reduces their tendency to clump together. Like Myriad's drug, it seemed to work in mice and is safe in humans. But in a Phase 2 trial in 58 patients, Alzhemed yielded no measurable benefit in memory tests -- although the study period was an admittedly short three months.

It did reduce levels of an A-beta biomarker in patients' cerebrospinal fluid, however. That impressed Paul Aisen, a professor of neurology at Georgetown University Medical Center who is leading the large 18-month Phase 3 study of Alzhemed in North America. But cerebrospinal biomarkers have been hard to interpret in Alzheimer's. "We really have no idea how much a reduction in [cerebrospinal] peptide over 12 weeks will translate into clinical and cognitive gains over 18 months," he told listeners on CIBC's recent conference call. "It could be anything from zero to a major difference."

In more than 1,000 patients, the Phase 3 trial will look for a difference in standard measures of mental and everyday functioning. Over half the patients have also gotten MRI scans to check for the shrinkage in brain volume that's characteristic of Alzheimer's. The study's done, but its results have not yet been revealed.

Neurochem could announce top-line results within the next few weeks. Georgetown's Aisen should report the detailed Phase 3 data at a couple of neurology conferences in early June. "This is a tremendously exciting stage in Alzheimer's disease research," Aisen told CIBC's clients. "We are quite close to disease-modifying drugs."

If Alzhemed succeeds in its pivotal North American trial, Neurochem is unlikely to seek FDA approval until it has the results from a European trial in late 2008. Even so, Neurochem Chief Executive Francesco Bellini has made big bets on its success. Last year he took out millions of dollars in margin loans, secured by his shareholdings, to buy Neurochem shares and squeeze the skeptics who had sold the stock short. The share price climbed from less than $10 to more than $25, before settling at a recent $15.42. CIBC analyst Brian Lian (whose firm is a Neurochem investment banker) thinks the company merits a speculative bet.

Less risky bets on Alzheimer's drugs are Elan and Wyeth. In 1996, Elan acquired a pioneering Alzheimer's research firm called Athena Neurosciences. It has since collaborated with Wyeth on developing a number of treatments. The companies' first human trial vaccinated patients with a synthetic version of amyloid-beta to get their immune systems to attack A-beta42 accumulations. In rodents, vaccination cleared A-beta from brain cells, improved performance in maze tests and extended life spans. But the human study was halted after just two doses in 2002, when 6% of the 300 patients suffered brain inflammation from their hopped-up immune response. Researchers still followed the test patients, however, and some showed stable or improved memory tests. Autopsies of patients who died of other causes revealed that amyloid plaque had shrunk.

"What we know is that the immunotherapeutic approach to Alzheimer's works," declared Elan Chief Executive Kelly Martin at a recent SG Cowen health-care conference. Wyeth and Elan have returned to human trials with a reformulated vaccine code-named ACC-001. It uses a shorter, more specific fragment of A-beta and a carrier protein from Wyeth's vaccine business that shouldn't overexcite patients' immune systems.

Further along is the companies' Phase 2 trial of a so-called passive immunotherapy. About 240 patients are enrolled in the test of bapineuzumab, a genetically engineered antibody. It's designed to tag amyloid for clearance by patients' immune systems. In mice, these antibody infusions cleared amyloid as effectively as did vaccination.

Patients in the study have experienced no adverse events so far, says Menelas Pangalos, who heads up Wyeth's neuroscience research. Results should come out this year. If they're good, Pangalos says a Phase 3 trial could start within 6-18 months. A successful Phase 3 study could support an application for FDA approval as early as 2010.

Outside of its Wyeth collaboration, Elan has other Alzheimer's projects. Those include a potential anti-amyloid pill called AZD103, developed with Toronto Stock Exchange-listed Transition Therapeutics (TTH.TO), which has reduced amyloid levels and improved learning performance in rats.

Wyeth, too, has separate Alzheimer's projects. It's running Phase 1 trials of GSI-953 and PAZ-417, two oral drugs. The first interferes with the enzymes that help form A-beta42, while the second prevents clumping. Enzyme-inhibition strategies have proven effective in stemming diseases like AIDS. In Alzheimer's the approach would attack the disease process farther "upstream" than other treatments, by preventing harmful amyloids from even forming.

Wyeth is testing drugs for Alzheimer's symptoms, as well. It has a Phase 2 trial of a compound called Lecozotan that boosts multiple neurotransmitters. Three other cognitive boosters are in Phase 1 studies. "The disease is ultimately going to be treated by multiple drugs," says Wyeth researcher Pangalos, who foresees Alzheimer's patients getting immunotherapy infusions, pills for enzyme inhibition and several symptomatic drugs...hopefully, from Wyeth.

Despite its achievements in neuroscience, Elan has steadily lost money over its history. So Wyeth is by far the safest bet on Alzheimer's drugs. Its best-selling products like the antidepressant Effexor (which faces generic competition in the next few years), the strep vaccine Prevnar and the arthritis treatment Enbrel (partnered with Amgen) helped Wyeth grow sales 9% last year to $20.4 billion. Earnings per share grew 14% in 2006, to $3.08.

Wyeth could generate 4 bucks a share in 2008, says Bear Stearns analyst John Boris, while continuing to buy back billions of dollars worth of shares and paying a dividend of $1.18 (for a yield of 2.5% on the current share price). Yet Wyeth shares trade at a price-earnings ratio that's 15% cheaper than its peers.

Wyeth's chief exec, Essner, attributes his company's valuation discount to investors who worry that the company hasn't resolved the legal problems over its discontinued phen-fen diet drugs. But after a nationwide settlement program and $21 billion in charges, Essner believes Wyeth is nearing the end of its diet-drug costs. The company is also defending against the claims of some 5,200 women who blame their cancer, stroke or heart disease on Wyeth's hormone-replacement drugs. The company's liability won't be easy to demonstrate, however, because its labels warn of the cancer risk and both products remain FDA-approved. So Wyeth's billions in annual cash consumption for litigation could subside next year.

Wyeth stands to grow its earnings at about a 15% annual rate, whether or not its Alzheimer's drugs pay off. But if it succeeds with only a few of its dozen Alzheimer's drugs in development, the payoff will be big. If a large percentage of America's 5 million Alzheimer's patients spend a few thousand bucks a year for disease-modifying treatments, Alzheimer's will easily become a multi-billion-dollar market. Needless to say, an effective drug would also be a wonderful thing for people like James Smith.
<<

[DewDiligence]

Finding Alzheimer’s Before a Mind Fails

http://www.nytimes.com/2007/12/26/health/26alzheimers.html

>>
December 26, 2007
By DENISE GRADY

For a perfectly healthy woman, Dianne Kerley has had quite a few medical tests in recent years: M.R.I. and PET scans of her brain, two spinal taps and hours of memory and thinking tests.

Ms. Kerley, 52, has spent much of her life in the shadow of an illness that gradually destroys memory, personality and the ability to think, speak and live independently. Her mother, grandmother and a maternal great-aunt all developed Alzheimer’s disease. Her mother, 78, is in a nursing home in the advanced stages of dementia, helpless and barely responsive.

“She’s in her own private purgatory,” Ms. Kerley said.

Ms. Kerley is part of an ambitious new scientific effort to find ways to detect Alzheimer’s disease at the earliest possible moment. Although the disease may seem like a calamity that strikes suddenly in old age, scientists now think it begins long before the mind fails.

“Alzheimer’s disease may be a chronic condition in which changes begin in midlife or even earlier,” said Dr. John C. Morris, director of the Alzheimer’s Disease Research Center at Washington University in St. Louis, where Ms. Kerley volunteers for studies.

But currently, the diagnosis is not made until symptoms develop, and by then it may already be too late to rescue the brain. Drugs now in use temporarily ease symptoms for some, but cannot halt the underlying disease.

Many scientists believe the best hope of progress, maybe the only hope, lies in detecting the disease early and devising treatments to stop it before brain damage becomes extensive. Better still, they would like to intervene even sooner, by identifying risk factors and treating people preventively — the same strategy that has markedly lowered death rates from heart disease, stroke and some cancers.

So far, Alzheimer’s has been unyielding. But research now under way may start answering major questions about when the disease begins and how best to fight it.

A radioactive dye called PIB (for Pittsburgh Compound B) has made it possible to use PET scans to find deposits of amyloid, an Alzheimer’s-related protein, in the brains of live human beings. It may lead to earlier diagnosis, help doctors distinguish Alzheimer’s from other forms of dementia and let them monitor the effects of treatment.

Studies with the dye have already found significant deposits in 20 percent to 25 percent of seemingly normal people over 65, suggesting that they may be on the way to Alzheimer’s, though only time will tell.

“PIB is about the future of where Alzheimer’s disease needs to be,” said Dr. William E. Klunk, a co-discoverer of the dye at the Alzheimer’s research center at the University of Pittsburgh. “PIB is being used today to help determine whether drugs that are meant to prevent or remove amyloid from the brain are working, so we can find drugs that prevent the underlying pathology of the disease.”

Though PIB is experimental now, studies began in November that are intended to lead to government approval for wider use.

Currently, for the most common form of Alzheimer’s disease, which occurs after age 65, there is no proven means of early detection, no definitive genetic test. But PIB tests might be ready before new treatments emerge, making it possible to predict who will develop Alzheimer’s — without being able to help.

Researchers are also using M.R.I. scans to look for early brain changes, and testing blood and spinal fluid for amyloid and other “biomarkers” to see if they can be used to predict Alzheimer’s or find it early.

Studies of families in which multiple members have dementia are helping to sort out the genetic underpinnings of the disease.

Finally, experiments are under way to find out whether drugs and vaccines can remove amyloid from the brain or prevent its buildup, and whether doing so would help patients. The new drugs, unlike the ones now available, have the potential to stop or slow the progress of the disease. At the very least, the drug studies will be the first real test of the leading theory of Alzheimer’s, which blames amyloid for setting off a chain of events that ultimately ruin the brain.

Some scientists doubt the amyloid theory, but even a staunch skeptic said the studies were important.

Among the skeptics is Dr. Peter Davies, a professor at Albert Einstein Medical College, who said: “You’ve got to try. Somebody’s going to get this right.”

But if the amyloid hypothesis does not hold up, much of Alzheimer’s research could wind up back at Square 1.

Answers are urgently needed. Alzheimer’s was first recognized 100 years ago, and in all that time science has been completely unable to change the course of the disease. Desperate families spend more than $1 billion a year on drugs approved for Alzheimer’s that generally have only small effects, if any, on symptoms. Patients’ agitation and hallucinations often drive relatives and nursing homes to resort to additional, powerful drugs approved for other diseases like schizophrenia, drugs that can deepen the oblivion and cause severe side effects like diabetes, stroke and movement disorders.

Alzheimer’s is the most common cause of dementia (artery disease, Parkinson’s and other brain disorders can also lead to dementia). Five million people in the United States have Alzheimer’s, most of them over 65. It is the nation’s sixth leading cause of death by disease, killing nearly 66,000 people a year and probably contributing to many more deaths. By 2050, according to the Alzheimer’s Association, 11 million to 16 million Americans will have the disease. “Sixteen million is a future we can’t countenance,” said William H. Thies, the association’s vice president for medical and scientific relations. “It will bankrupt our health care system.”

The costs are already enormous, $148 billion a year — more than three times the cost of chronic lung disease, even though Alzheimer’s kills only half as many people. To a great extent, increases in dementia are the price of progress: more and more people are living long enough to get Alzheimer’s, some because they survived heart disease, strokes or cancer. It is a cruel trade-off. The disease is by no means inevitable, but among people 85 and older, about 40 percent develop Alzheimer’s and spend their so-called golden years in a thicket of confusion, ultimately becoming incontinent, mute, bedridden or forced to use a wheelchair and completely dependent on others.

“It makes people wonder whether they really want to live that long,” Dr. Klunk said.

The potential market for prevention and treatment is enormous, and drug companies are eager to exploit it. If a drug could prevent Alzheimer’s or just reduce the risk, as statins like Lipitor do for heart disease, half the population over 55 would probably need to take it, Dr. Thies said.

If new drugs do emerge, they will come from studies in patients who already have symptoms, Dr. Thies said. But he said the emphasis would quickly shift to treating people at risk, before symptoms set in. Many researchers doubt that even the best preventive drugs will be able to heal the brains of people who are already demented.

Treating preventively, Dr. Thies said, “will be more satisfying to patients and physicians, and there will be an economic incentive because you’ll wind up treating more people.”

The only thing that could slow the drive for early treatment, he said, would be serious side effects — and Dr. Morris, at Washington University, said drugs powerful enough to treat Alzheimer’s would probably have strong side effects.

Researchers are especially eager to study people like Ms. Kerley, because the children of Alzheimer’s patients have a higher-than-average risk of dementia themselves, and tracking their brains and minds may open a window onto the earliest stages of the disease.

“I want to do anything I can possibly do to help find a cure or find a way to identify it earlier,” Ms. Kerley said. “We need to stop this. I don’t know if it will help my generation, but it will help my son’s.”

She figures that being a research subject may have advantages, too.

“We’re the first ones in line,” she said. “If I am genetically predisposed, and they have a preventive medication, they’ll tell me right away.”

Alzheimer’s Beginnings

Some forgetfulness is normal. Distraction, stress, fatigue and medications can contribute. A joking rule of thumb about Alzheimer’s is actually close to the truth: it’s O.K. to forget where you put your car keys, as long as you remember what a key is for. But worsening forgetfulness is a cause for concern.

Doctors use standard memory and reasoning tests to diagnose dementia, along with symptoms reported by the patient and family members. The term “mild cognitive impairment” is sometimes applied to small but measurable memory problems. But its meaning is unclear: some studies find that the impairment can resolve itself, while others suggest that it always progresses to dementia.

Even if older patients think more slowly or take longer to remember, as long as they can still function independently, they are not demented, Dr. Morris said.

In her heart, Ms. Kerley suspects that her mother’s Alzheimer’s disease began long before the official diagnosis in 2001 or even the tentative one in 1995 — years before, maybe decades. She wonders if the disease might explain, at least in part, her mother’s difficult personality and lack of interest in reading or education.

When does Alzheimer’s begin? The question haunts families and captivates scientists.

Dr. Morris said, “We think that by the time an individual begins to experience memory loss, there is already substantial brain damage in areas critical to memory and learning.”

No one knows whether the disease affects thinking, mood or personality before memory fails. Researchers think that the brain, like other vital organs, has a huge reserve capacity that can, at least for a time, hide the fact that a disease is steadily destroying it.

“I’m speculating that it does affect you throughout life,” said Dr. Richard Mayeux, a professor of neurology, psychiatry and epidemiology at Columbia University, and co-director of its Taub Institute for Research on Alzheimer’s Disease and the Aging Brain. “I think there’s a very long phase where people aren’t themselves.”

If Dr. Mayeux asks family members when a patient’s memory problem began, they almost always say it started a year and a half before. If he then asks when was the last time they thought the patient’s memory was perfectly normal, many reply that the patient never really had a great memory.

Several studies in which people had intelligence tests early in life and were then evaluated decades later have found that compared with the healthy people, those with Alzheimer’s had lower scores on the early tests.

“It raises the possibility for me that this is a genetic disorder that starts early in life,” Dr. Mayeux said.

He said those findings also made him wonder about the widely dispensed advice to read, take courses, solve puzzles and stay mentally active to ward off Alzheimer’s. The advice is based on studies showing that highly educated people have a lower risk of Alzheimer’s than do less-accomplished ones. But does that mean that mental activity prevents Alzheimer’s — or vice versa?

‘I Have Lost Myself’

The disease is named for Alois Alzheimer, a German doctor who first described it in Auguste D., a 51-year-old patient he saw in 1901. Her memory, speech and comprehension were failing, and she suffered from hallucinations and paranoid delusions that her husband was unfaithful. Unable to finish writing her own name, she told Alzheimer, “I have lost myself.”

She died in 1906, “completely apathetic,” curled up in a fetal position and “in spite of all the care and attention,” suffering from bedsores, Alzheimer wrote.

A century later, patients still die in much the same way. Although Alzheimer’s itself can kill by shutting down vital brain functions, infections usually end things first — pneumonia, bladder infections, sepsis from bedsores.

When Alzheimer dissected Auguste’s brain, he found it markedly shrunken, a wasteland of dead and dying nerve cells littered with strange deposits.

There were two types of deposits, plaques and tangles. Plaques occur between nerve cells, and are now known to consist of clumps of beta amyloid, an abnormal protein. Tangles form inside nerve cells, and are made of a protein called tau that is normally part of a system of tubules that carry nutrients to feed the cell. Once tau is damaged, the nerve cells essentially starve to death.

Until the 1970s Alzheimer’s disease was considered a rare brain disorder that mysteriously struck younger people like Auguste D.

It was thought to be different from “senility,” which was assumed to be a consequence of aging. But then researchers compared the brains of younger people who had died of Alzheimer’s with those of elderly people who had been senile, and discovered the same pathology — plaques and tangles. Senility, they decided, was not a natural part of aging; it was a disease.

The Amyloid Hypothesis

The leading theory of Alzheimer’s says that beta amyloid, or A-beta, is the main culprit, building gradually in the brain over decades and short-circuiting synapses, the junctions where nerve cells transmit signals to one other. Gradually, the theory goes, the cells quit working and die.

Everybody produces A-beta, but its purpose is not known. People who develop Alzheimer’s either make too much or cannot get rid of it. Although scientists once blamed plaques for all the trouble, more recent research suggests that the real toxins are smaller bundles of A-beta molecules that form long before plaques do.

Dr. Dennis J. Selkoe, a professor of neurologic diseases at Harvard, said that just as lowering cholesterol can prevent heart disease, lowering A-beta may prevent Alzheimer’s or slow it, particularly in the early stages — provided that drugs can be created to do the job.

Several drugs and vaccines are now being tested that either block the production of A-beta or help the body get rid of it.

Researchers are also testing anti-amyloid antibodies, which are proteins made by the immune system, as well as blood serum that contains the antibodies.

Eventually, Dr. Selkoe said, screening tests for Alzheimer’s “will be like getting an EKG in the doctor’s office at 45 or 50, and you’ll start treating right away to prevent Alzheimer’s rather than treat it.”

Other researchers are less enthusiastic, noting that there have been numerous failures and disappointments along the way. A vaccine study had to be halted in 2002 because 18 of 300 patients developed encephalitis, and 2 died. Some scientists worry that anti-amyloid vaccines in general could be dangerous, in part because the role of amyloid is not well understood and the brain may actually need it.

No Choice but to Cope

Even if current research yields new drugs, there is not likely to be a miracle pill that will bring people back from deep dementia. For now, there is no choice but to cope with the disease. Seventy percent of Alzheimer’s patients are cared for at home, and millions of families are struggling to look after them, piecing together a patchwork of relatives, friends, paid health aides and adult day-care programs.

Barbara Latshaw, 79, lives with her husband, David, and her sister in Crafton, Pa., near Pittsburgh. Ms. Latshaw, whose dementia was diagnosed in 1991, has not spoken in four years, and she can no longer smile. But she locks eyes with visitors and will not let go.

“There is still something alive in there,” said her sister, Fritzie Hess, 69. “I’m convinced of it.”

The family believes that, at least some of the time, she still understands them. They speak to her as if she does. She is with them, and yet gone, and they miss her terribly.

“We hope to keep her here at home until she passes on,” Ms. Hess said. “She’s a joy to us.”

Many families hope to keep Alzheimer’s patients at home, but not all can manage it, especially if family members have to go work or patients become combative, incontinent, immobile or unable to sleep at night.

“There are three of us taking care of my sister, and it works out beautifully,” Ms. Hess said. “We spell each other. I don’t know how these spouses manage, when it’s one on one.”

Ms. Hess and her brother-in-law are retired, and Ms. Latshaw’s daughter, Becky Bannon, 53, is free to visit many mornings to help them get her mother out of bed, massage and exercise her arms and legs, change her diaper and dress and feed her.

Ms. Latshaw used to be full of life. She loved to cook, played tennis and bridge, raised two children and took charge of redecorating the grand old family home. Then her memory began to slip: guests would arrive for dinner, and she would have no memory of inviting them. She forgot to look before pulling into traffic, and nearly caused an accident. She would wander out of the house, and local store clerks would take her home. She never turned hostile or angry, as many demented patients do, but she had vivid hallucinations of strings being caught in her teeth, and little men getting into her bed and jabbing her with broom straws. On especially bad nights, her husband would get up with her at 2 or 3 a.m. and make the two of them hot chocolate.

Aricept, an Alzheimer’s drug, made the hallucinations worse, while another drug, an antipsychotic used for schizophrenia, seemed to quell them. But the second drug had side effects: after taking it for several years, Ms. Latshaw began to grind her teeth, and could not stop moving her arms and legs.

Their father also suffered from dementia, Ms. Hess said, admitting that she wonders about herself.

“Naturally I’m a little bit concerned, but I think worry is such a waste of time, so I don’t dwell on it; I just don’t,” she said. “My friends always said, ‘You always had a bad memory.’ I see Barbara and David’s children having that same kind of memory.”

Ms. Hess has volunteered for studies at the University of Pittsburgh Medical Center, where she became the first person in the United States to have a PIB study of her brain.

“I’m very anxious to get to the bottom of this whole Alzheimer’s thing,” she said.

Nothing Left to Give

In an interview in the summer of 2006, Ms. Kerley described her mother this way: “She’s completely withdrawn in herself. She hasn’t recognized us for a few years. Basically she hums one line of one song over and over again. She seems to be stuck somewhere in her life between age 4 and 5.”

Ms. Kerley said she and her son Michael, then 21, visited every week or two.

“She loves getting her back rubbed, being smiled at, being hugged,” Ms. Kerley said. “She doesn’t know who we are. We’re going for us, not for her, because she doesn’t remember us the minute we walk out the door.”

She had signed her mother up for hospice care at the nursing home, meaning that she would receive medical care to keep her comfortable but no extraordinary measures like resuscitation if she began to fail. She said her mother would not want to be kept alive in her present condition.

“She has nothing left to give the world, and the world has nothing left to give to her,” Ms. Kerley said.

Nearly a year and a half later, her mother is still alive, even though Ms. Kerley has declined liquid nutritional supplements, antibiotics and flu and pneumonia shots.

Her mother does not even hum anymore, and spends much of her time in a fetal position, except when she is at the dinner table. She can still walk, if led.

“If my mother had her own choice, she would have offed herself a long time ago,” Ms. Kerley said. “There is no quality to her life.

“When she does go, it will be a blessing.”

Ms. Kerley has already arranged to donate her mother’s brain and her own to Washington University. She seriously doubts that she will develop Alzheimer’s. She is more like her father than her mother, she said, and she is the most educated person in her family, reads constantly and stays in shape by swing dancing two to five nights a week. And her students keep her sharp.

“If you want to keep up with me until you retire, that’s fine,” she said. “I’m betting I’m not going to have that problem.”
<<

[DewDiligence]

Connecting the Pieces of the Alzheimer’s Puzzle

[This write-up from Saturday’s WSJ is like a CliffsNotes account of AD.]

http://online.wsj.com/article/SB10001424052748703806304576242781646480162.html

›APRIL 9, 2011
By MATT RIDLEY

The discovery, announced this week, of several genetic mutations that predispose people toward Alzheimer's disease is intriguing, because the genes are associated with cholesterol metabolism and inflammation. The Alzheimer's jigsaw is a long way from being complete, but the pieces are emerging, and this new evidence fits quite nicely with the other pieces in suggesting a role for inflammation.

Piece 1 is the immediate cause of Alzheimer's disease: the appearance of insoluble "plaques" made of a small protein called amyloid beta (A-beta for short) inside brain cells. These plaques block the traffic of molecules in the cells. Eventually another small protein, called tau, also starts to crystallize in this way to form "tangles." Both symptoms are diagnostic of Alzheimer's, and similar ones characterize other neurological syndromes such as Parkinson's and Creutzfeldt-Jakob's.

Puzzle piece 2 is the APOE gene on chromosome 19, long known as a powerful influence on whether you will get Alzheimer's disease. Having two copies of the 4 version of the gene makes you 20 times more likely than average to get the symptoms before the age of 75. (Having at least one copy of the 2 version makes you less likely than average to get the symptoms.) One of APOE's jobs is to break down plaques, and the 4 version is inefficient at this task.

So right at the heart of the disease is the insolubility of proteins in old age. Proteins in living cells always teeter on the edge of insolubility, because with so many different proteins dissolved in the cell doing different jobs, the total concentration is high and crystallization is a risk. Solubility depends on the correct folding of each protein into a certain shape. With even slight misfolding, a protein may crystallize too easily.

Here is piece 3 of the puzzle. Prof. Chris Dobson of Cambridge University made 17 slight genetic adjustments to the A-beta protein to make it either more or less soluble. He then genetically engineered the mutant proteins into fruit flies and showed that the less soluble the protein, the less coordinated and the shorter-lived were the fruit flies. In effect, by lining up the test-tubes, he could make the dancing flies form a sort of living graph of solubility versus activity.

What makes misfolded proteins appear in elderly brains? Piece 4: Cells have an internal quality-control mechanism that both detects and refolds misfolded proteins. Research published last month by scientists at Brown University revealed that both parts of this mechanism—the detector and the refolder—are working, but overwhelmed, in diseased brains; they can't keep up with the workload of too many misfolded A-beta proteins.

Which brings us to piece 5, this week's announcement of the discovery by Jeffery Kelly and his colleagues at the Scripps Research Institute that a chemical formed when cholesterol reacts with ozone attaches to A-beta and makes the misfolding of it more likely. The ozone comes from inflammation.

Piece 6 is stress—caused by worry, fear, pain, trauma—which shows itself in the production of cortisol, a hormone made from cholesterol. Cortisol, too, is beginning to look like an accomplice in the misfolding of A-beta, according to work at the University of California at Irvine.

So we can begin to tell a coherent story. Stress and inflammation produce derivatives of cortisol and cholesterol, which trigger misfolding in A-beta proteins. This, in turn, overwhelms the cells' quality-assurance mechanism and results in growing numbers of insoluble proteins, which aggregate in plaques and tangles. And this blocks the transport of vital ingredients around brain cells, which causes the cells to die.

Somewhere along this chain, there is a link, we must hope, that can be attacked by medication—to prevent inflammation, discourage ozone reactions, encourage the refolding apparatus, improve protein solubility or boost the plaque-removal mechanism.‹