Decades down a path littered with more than 100 failed experimental drugs for Alzheimer's disease, a growing chorus of scientists are saying it's time to admit defeat and start fresh.

Before Virginia Morris of Sarasota died at 92, Christine Docter, her only child, struggled for a year and a half to help her mother qualify for Medicaid benefits and get the memory care she desperately needed.

Her own family challenges were daunting enough, Docter said. Then one day at her mother's facility, she watched another caregiver wrangle first a wheelchair and then a walker from her car. The woman loaded her elderly mother into the wheelchair, and then pushed the chair while using the walker herself.

"That's the thing that stood out so much to me in this whole process," Docter said. "Everybody’s living so much longer, it’s like the old are taking care of the elderly."

Along with so many who must pay the price that dementia exacts from a loved one — in terms of identity, relationships, health and finances — Docter said she often felt helpless as her mother declined.

"I could only do so much," she remembered. "When it got bad with her, she would call me five times a night, asking for the same thing. I would finally unplug the phone, just so I could get some sleep."

Caregivers like Docter discover that the medical community, too, can only do so much. Enlightened, effective treatment for people with dementia is hard to find, and medications to combat the ravages of cognitive loss are temporary solutions at best.

Now, decades down a research path littered with more than 100 failed experimental drugs for Alzheimer's disease, a growing chorus of scientists are saying it's time to admit defeat and start fresh. As pharmaceutical companies like Merck, Lilly and Biogen press on despite costly clinical trial disappointments, researchers question the wisdom of pouring good money after bad.

"We need to go beyond a drug discovery model," said Neal D. Barnard, a medical professor at George Washington University. "We’re not seeing new drugs, and the ones we have don't change the progression of the disease. We need to stop looking at the Alzheimer's mouse, and concentrate on the healthy human."

The amyloid cascade

Alzheimer's disease, the most studied and most prevalent form of age-related dementia, affects some 5.5 million Americans — 520,000 in Florida alone. According to the latest report from the Alzheimer's Association, the national cost of their care has swollen to $259 billion a year.

Barnard is founder and president of the Physicians Committee for Responsible Medicine, a doctors' organization that promotes ethical research and preventive health strategies. Speaking recently at the annual meeting in Boston of the American Association for the Advancement of Science, an influential gathering of scientists from every discipline, he highlighted human studies that have explored links between cognitive health and lifestyle behaviors.

Instead of funding more lab experiments using mice that are genetically manipulated to show some, but not all, symptoms of Alzheimer's disease, Barnard said dementia researchers should pay attention to growing evidence that "what's bad for the heart is bad for the brain."

Laboratory mice that mimic some aspects of Alzheimer’s disease are a useful first step in exploring new therapies, scientists say, but drawing conclusions from this basic research is misleading. One major distinction: The mice can be programmed to develop the telltale buildup of plaque in the brain — sticky accretions of beta amyloid proteins that are early markers of the disease. But they do not go on to show the tau protein pathology that accompanies later stages of the disease in human brains — toxic “tangles” of tau that can be seen in neuroimaging and are always present in full-blown Alzheimer’s.

Barnard believes human subjects offer a better avenue for progress, with vigorous testing of recent observations about the effects of food, fitness, environmental factors, chronic diseases and sleep quality on dementia.

"I am going to make a pitch that the excitement of these findings be translated into more research studies," he said. "We have these discouraged post-docs" — recent Ph.D. graduates working in labs — "who are tired of killing animals all afternoon. Get them involved in human studies! We can look at risk factors and see which ones apply, including ones we haven’t thought of yet."

But with hundreds of millions invested in pharmaceutical products, and a potential $30 billion payoff in the United States alone for a medication that actually works against Alzheimer's, drugmakers are reluctant to abandon their quest. Many of these latest therapies target beta amyloid, the protein long thought to be the first sign or even the cause of the disease. While these drugs succeed in removing amyloid from the brain, there has been no payoff in terms of halting the progress of cognitive decline.

So they talk of tinkering with the dosages, and recruiting younger, healthier subjects for clinical trials, in hopes of intervening before the plaque can accumulate. They draw analogies to cancer research, reasoning that a drug that has no effect at stage four can be a lifesaver at stage one.

Other researchers believe that these drugs' failures are evidence that amyloid buildup is not the critical development in Alzheimer's, and the focus should be on what happens next: the appearance of tangles formed by tau proteins. The amyloid-vs.-tau argument has generated publicity, but many feel it represents a false choice.

Michael Mullan, a pioneering Alzheimer's scientist and director of the independent Roskamp Institute in Sarasota, has been following this debate with a sense of frustration. He, too, believes it's time to rethink the research questions on dementia, even though his early work was instrumental in formulating what's now called the amyloid cascade hypothesis, a belief that this protein buildup is the disease's crucial trigger.

"This is going to be a very long funeral: Nobody wants to bury the amyloid cascade hypothesis," Mullan said. "It looks like it plays a very important role early in the disease as a trigger, but it doesn’t look like it’s a driver for the disease once you’ve passed a certain point. Once you’ve got mild Alzheimer’s or above, these anti-amyloid approaches just don’t work. We just have to absorb that and get real."

At this stage, no one is ruling out the possibility that preventing amyloid buildup could slow or halt Alzheimer's progression. But proving this is impractical, Mullan said, because it would require young, healthy people to spend years taking drugs that have unwanted side effects such as brain swelling, on the chance that they will fend off dementia.

But that's not the only thing bothering Mullan.

"The second problem that worries me an awful lot is that we have five and a half million people with mild-and-above Alzheimer's," he said. "This would be pushing the boat out on them and saying, 'We’re just going after amyloid still.' We shouldn’t be out there trying to prove a theory. We should be curing Alzheimer’s disease."

Shifting the focus

Christine Docter is now in her 60s, around the same age when she first noticed a change in her mother's personality.

"It was hard to tell at first; she was always a funny, eccentric woman," Docter recalled. The females in her mother's family tended to live long and develop dementia, she said: "It wasn’t a bad kind of thing with them. They would have imaginary boyfriends, but they were kind of peaceful."

As Virginia Morris aged, she began to fall often. Doctors prescribed an antidepressant to help with mood swings, but never made an official diagnosis of Alzheimer's disease. When she was hospitalized at 89 or 90, however, Docter saw the results of an MRI scan.

"There was so much space around her brain that there wasn’t any brain," she said.

This physical deterioration, Mullan explained, is the clearest indicator of Alzheimer's.

Like many adult children of dementia sufferers, Docter wonders what lies ahead for her.

"So far I think my head’s still glued on," she said, proof that she inherited her mother's sense of humor. "I don’t seem to be exhibiting any of the early signs of dementia my mother had. It has crossed my mind quite a bit. My dad was lucid to the end; I hope I take after him."

In their push to prove their drugs can work, pharmaceutical companies are enrolling symptom-free adults like Docter in clinical trials. They're betting that removal of amyloid from the brain before it has inflicted too much damage might stop the disease in its earliest stage.

Mullan and other researchers support studying human subjects before any signs of dementia emerge, but they tend to see the current clinical trial model as a trap. Instead of trying to understand the disease process, they suggest, researchers should concentrate on mitigating its terrible effects.

"Just because something causes a disease, that doesn’t mean it’s a good clinical target," Mullan said. "We don’t know what causes diabetes, but we still know what some of the treatments are. I think maybe it’s a shift away form the disease-modifying concept to the symptom-modifying concept, but let’s be honest: That would be just fine."

Rhoda Au, a professor at Boston University Alzheimer’s Disease Center and director of neuropsychology for the Framingham Heart Study, also spoke at the Boston meeting. Experience from the Framingham study, now in its 69th year and following a third generation of human subjects, has convinced Au that Alzheimer's has to be studied as a lifelong process.

"This is an insidious-onset disease," she said. "It’s not like the week before you were fine, or five years before, you were fine. If we start to focus on the earliest symptoms, we can actually start thinking about a different strategy. And if you can delay the onset of symptoms by five years, you can cut a person’s risk of the disease by 50 percent."

Au's team is working on ways to quantify cognitive loss by using digital technology, with devices like wearables to collect data on factors like sleep, balance and heart rate. The privately funded study, "Precision Monitoring of Preclinical Alzheimer's Disease," will track 2,200 people over three years.

Au said she has received pushback from the research community for collecting data without a theory about which measures will predict dementia. But she sees this as an approach that is necessary to shift the paradigm.

"Right now there is a lot of focus on the concept of precision medicine," she said. "I think the conversation needs to focus on precision health. Aging is a lifelong process. It’s really about development and change, not decline and impairment: How do you optimize that person’s health at every stage?"

Studying healthy subjects for clues about dementia, said Mullan of Sarasota, would place the science of this age-related disease where it belongs: on the aging process. This could help solve the mystery he first encountered in his work with families whose genetic mutations predispose them to develop the disease.

"Why didn’t they get it when they were 2 years old? Why weren’t they born with Alzheimer’s disease?" he asked. "Clearly, you have to have aging. Other things are changing in the brain. We have worked on a lot of those other downstream pathways for years, but we can’t get them funded and the commercial world hasn’t been interested either."

Because a brain marked by Alzheimer's disease "looks like a huge, raging inferno, in terms of information," he said, the answer is not going to be found in a single protein molecule, like beta amyloid or tau. He agreed with the scientists in Boston that researchers need to push their inquiries beyond the molecular level, at least for now.

"Nobody’s going to welcome this news," Mullan said. "But I think they’re going to welcome a change."