PHOENIX -- For years, scientists and drug companies zeroed in on clumps of brain plaques as a trigger for Alzheimer's disease.
Scientists theorize that these clumps, known as beta amyloid plaques, crowd the brains of Alzheimer's patients, killing nerve cells and scuttling memory and thinking.
But pharmaceutical companies have come up empty on developing a drug that removes these plaques and slows or halts memory deterioration, despite spending billions of research dollars.
Some scientists now question whether amyloid is the correct target.
"There really hasn't been any clinical benefit," said Dr. Richard Caselli, a professor of neurology at Mayo Clinic in Arizona. Tests showed that some drugs could clear amyloid plaques, "but, lo and behold, the dementia continues to progress, and people continue to die."
Still, amyloid believers, such as Banner Alzheimer's Institute in Phoenix and Washington University in St. Louis, aren't ready to give up the fight for a blockbuster, plaque-clearing drug to beat a disease that is projected to afflict 8 million Americans by 2030.
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The pro-amyloid camp argues that, in the past, these drugs have been prescribed too late, after the disease had already wrecked brains and scrambled cognitive and motor skills. Prevention trials underway seek to target amyloid, which develops in the cerebral cortex and then floats to the interior of the brain, before symptoms appear. The idea is that you can delay or prevent the disease if you treat it soon enough, much like statin drugs are prescribed to prevent heart or vascular disease.
"It would be a terrible mistake to throw the baby out with the bathwater," said Eric Reiman, executive director of Banner Alzheimer's Institute. "Give it a better test at an earlier stage at which it might have a more profound effect."
Researchers now have diagnostic tools that were not available before - brain scans, blood tests and spinal taps - to identify people at risk and give them the drugs before memory and thinking problems start.
"By the time symptoms appear, there is already an irreversible loss of nerve cells," said Dr. John Morris, a professor of neurology at Washington University. "By the time you are giving a patient drugs, you are treating a damaged brain."
Elsewhere, researchers are attempting to develop drugs based on protective genes that may prevent the disease altogether. Others are targeting potential disease triggers such as tau protein in brain cells and promoting vascular health to ensure the brain gets a steady supply of oxygen.
Yet another camp of experts promotes diet, exercise and memory games as a way to slow the insidious disease.
Maria Carrillo, vice president of medical and scientific relations for the Alzheimer's Association, said amyloid in the brain was among the industry's first discoveries. It's been an easier target because amyloid plaques are found freely in the brain of Alzheimer's patients, unlike tau protein, which is embedded in cells.
Still, Carrillo said the idea of attacking amyloid at its earliest stages is worth pursuing.
"The thought is if we go in earlier, we can increase the odds of (delaying or preventing) the disease," Carrillo said. "The landscape looks promising."
To prime the research pump, groups such as Banner Alzheimer's Institute in Phoenix are recruiting tens of thousands of volunteers to participate in national drug trials sponsored by the pharmaceutical industry, patient groups and the federal government. The Alzheimer's Association has its own registry, called TrialMatch. Several pharmaceutical companies also operate registries.
Nancy Hetrick, 46, of Avondale, and her three sisters have joined Banner's registry, hoping the research will help families ravaged by the disease for generations. Hetrick's father, grandfather and her grandfather's 13 siblings all suffered from Alzheimer's. Hetrick realizes that participating in clinical trials can be a gamble, but she and her sisters feel that such participation is critical to bringing at-risk families closer to a cure.
"I'm all for it," said Hetrick, a financial adviser. "We've got to have people who are willing to put themselves out there for the benefit of science."
Banner aims to recruit a robust group of 250,000 volunteers from across the country to test different experimental therapies. If one drug trial does not work, researchers can test the next one in rapid fashion. More than 70 Alzheimer's drugs are now being tested in clinical trials, according to the Alzheimer's Association.
The Banner study will include an extended Colombian family whose members carry a rare mutation of the presenilin 1 gene, a trigger for Alzheimer's.
Washington University is coordinating a national study that will recruit up to 400 volunteers who carry a genetic risk that makes it virtually certain they will develop early-onset Alzheimer's in their 40s or 50s. Early-onset Alzheimer's represents just 1 percent of Alzheimer's cases, but this sample gives researchers a powerful tool because they reach normal-thinking people who are destined to get the disease.
"The stakes couldn't be higher," Reiman said. "By the time today's young adults are senior citizens, it's destined to take an overwhelming financial toll. We have the responsibility to do everything we can to address this problem in the most fundamental way now."
The cost of providing care adds up quickly. The Alzheimer's Association estimates that Medicare will spend $107 billion on Alzheimer's-related health care this year. That is more than half of the $203 billion that government programs, private insurers and families will spend to care for Alzheimer's patients, a figure projected to swell to $1.2 trillion in 2050.
If families need to send a loved one to an assisted-living center or a nursing home, costs can spiral. The average annual cost of basic services for a loved one in a nursing home was $41,724, according to a 2011 survey by MetLife Mature Market Institute. For a private room in a nursing home, the annual cost more than doubled, to $87,235, the survey found.
Amyloid and enzymes
A half-dozen drugs tested by pharmaceutical companies in recent years have targeted amyloid. Some drugs removed amyloid from the brain but did not improve patients' memory or thinking.
Banner will use $100 million from the federal government, South San Francisco-based drug company Genentech and Banner Alzheimer's Foundation for its Colombian study. Family members who carry the mutated gene will get either Genentech's experimental drug, crenezumab, or a placebo.
They typically show cognitive trouble at age 44, but the study will enroll family members as young as 30, before symptoms appear, said Pierre Tariot, director of Banner Alzheimer's Institute. An additional 100 Colombian family members who are non-carriers of the gene will receive a placebo.
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ON THE WEB: Sign up for the registry
Banner also plans a larger study that will recruit people who carry a gene called ApoE4. The gene does not guarantee people will get the disease, but those who inherit copies of the gene from both parents have much higher odds of getting Alzheimer's later in life than the general population.
Tariot said future research could target amyloid found in other parts of the body, such as the eye.
"It may be that the plaque is not the most important part of the pathway," Tariot said.
In future trials, Tariot said, Banner scientists hope to use a diagnostic tool called the Alzheimer's Prevention Initiative composite test score. That tool assigns a score to patients based on measures such as amyloid levels in cerebrospinal fluid and brain scans as well as cognitive assessments such as memory, thinking and reaction time. Tariot said the test can detect subtle memory and thinking difficulties years before obvious signs appear.
"These are things that are not visible to the naked eye," Tariot said.
The Washington University study will test Eli Lilly's solanezumab and Roche's gantenerumab, two drugs that are designed to clear amyloid. The study also will test a third drug that blocks an enzyme that makes amyloid.
Researchers abandoned plans to test Eli Lilly's experimental "beta-secretase inhibitor" drug after the pharmaceutical giant halted an unrelated study in June based on abnormal liver-test results from patients. The Washington University study also is evaluating two other experimental drugs, which Washington University's Morris did not identify.
"We're all very hopeful that this early intervention before the brain is damaged can delay or prevent the onset of symptoms," Morris said. "Worst-case scenario, if it doesn't work, that will be an indication the amyloid hypothesis must seriously be reconsidered."
Hetrick, of Avondale, has never taken a test to see whether she inherited genes that make her susceptible to the mind-robbing disease. But she said she would be willing.
"With the genetic advances that are coming out now, I can't help but be very hopeful," Hetrick said.
She vividly recalls her father's struggle with the disease.
Tymen "Tim" Hofman was an engineer and 35-year veteran of the U.S. Forest Service in Montana. He cleared logging roads and mastered the tiniest of details. He began showing signs of forgetfulness in his mid-50s and was diagnosed with Alzheimer's at 70.
Hetrick said her mother took on the burden of caring for her father, and she often finished his thoughts and sentences. Hofman was frustrated that the disease progressed so completely that he lost his ability to communicate.
"He would talk to me and say, 'I have the words in my brain. I can see them and feel them, but they will not come out of my mouth,'" Hetrick said. "It was difficult watching him slip away."
At 74, he was spending his last days at a rehabilitation facility recovering from a minor infection. He could no longer talk, and he did not recognize Hetrick during her frequent visits.
About two weeks before he passed away, he reached over, tickled Hetrick's knee and grinned. It was a show of affection that he had done often over the course of her life, and it moved Hetrick to tears.
She returned to her car in the parking lot and began to sob. It was the last time she saw her father.