Imagine that you live in a house with dozens of holes in the roof, says Dr. Dale Bredesen, an expert in degenerative brain diseases and Alzheimer's in particular.

"And when it rains, the floor gets wet," he says. You can repair one hole, but it's not going to keep the place dry - you've got to repair all of them.

The same could be said for Alzheimer's.

"If you look at the basic mechanisms that lead to abnormalities and disease, there might be 36 different mechanisms," said Bredesen, a scientist with the Buck Institute for Research on Aging in Novato.

In other words, he said, "maybe we need to do more than patch one hole at a time."

Alzheimer's scientists are starting to believe that a main reason they haven't yet found a treatment - not a single drug that will significantly slow down or stop the disease - is because they've been focusing on just one hole in the roof.

That hole has a name: amyloid beta. For decades, it's been the primary target of Alzheimer's research, and for good reason. The protein is a hallmark of the disease, forming distinctive clumps of sticky plaque in the brains of people with Alzheimer's.

But efforts to tackle amyloid beta - to remove the plaque from the brains of people whose cognitive function and memory have started to fade with disease - have failed. Patients in clinical trials don't improve, or the drugs have side effects that make them unsafe.

A pressing issue

The pressure to find treatments and preventions for Alzheimer's disease has been building steadily over the past decade, and it's becoming critical as the United States prepares for the crush of Baby Boomers who are approaching their 70s, when the disease is most likely to strike.

Aside from the personal losses to individuals and families, the needs of those patients will be an enormous burden on the nation's health care system, doctors say. In California alone, almost half a million people are living with Alzheimer's now, and that number is expected to climb to 660,000 by 2025, according to the Alzheimer's Association.

"All of us who take care of patients wish that things could move at a faster pace," said Dr. Gil Rabinovici, a neurologist in UCSF's Memory and Aging Center. "In Alzheimer's we're really pretty far behind the curve. This is an impending public health crisis, and it would be very rational for us to invest in a lot of different ideas about how to treat the disease."

The focus on amyloid beta has been a twofold problem.

Long chain of events

First, amyloid beta is probably just one piece of a long chain of events that go wrong in the brains of people with Alzheimer's. And second, that plaque buildup likely has been going on for years, even decades, before people are symptomatic. By the time doctors introduce a drug to attack amyloid beta, the disease has already progressed to the point that almost any treatment is bound to fail, scientists now believe.

"In the past 10 years amyloid therapies have failed, one after another and quite spectacularly, to provide any benefit to people even with mild dementia," Rabinovici said. It may be that "there's been a lot of end-organ damage and it's too late."

That's not to say that scientists are giving up on amyloid beta, and it's still the primary focus of Alzheimer's research in the United States. But that may be largely due to the investments that already have been made, Alzheimer's experts said.

The scientific community and the major drug developers have devoted decades of resources into studying amyloid beta. There's little doubt that the protein is important, and it may indeed be a viable target for drugs to treat the disease someday.

But in the meantime, scientists are looking for other targets, and they're trying to dig much deeper into the history of the disease and identify the earliest signs of it in people who aren't yet symptomatic.

At Stanford, several scientists are zeroing in on the communication lines, called synapses, that allow neurons in the brain to talk to one another.

Pruning synapses

The formation, and destruction, of synapses is a necessary part of early childhood development. Synapses are created to help build memories and learn new skills, but synapses also must be pruned to keep brain activity healthy and efficient.

Scientists are coming to believe that in brains afflicted by Alzheimer's disease, that pruning process - which should be mostly inert by the time people reach adulthood - becomes overactive. Synapses that help people retain memories and create new ones are snipped and cannot be repaired. Eventually, the neurons on either end of the synaptic connections die.

"The current idea is the sickness starts earlier" than previously thought, said Carla Shatz, a Stanford neurobiologist. "The real loss is in the loss of synapse connections."

Shatz, who has spent much of her career studying early brain development, stumbled into the dementia field when her lab identified a protein that seemed to promote memory loss and synapse destruction in mice with Alzheimer's-like symptoms. Further research showed that the protein, called PirB in mice and LilrB2 in humans, is very attractive to amyloid beta, which tends to clump around it.

She's now studying whether removing the LilrB2 protein or altering it in some way might halt the chain that eventually leads to amyloid beta buildup.

"Maybe in neurodegenerative disorders this molecule is being turned on too much," she said.

Another pruner

Her colleagues, meanwhile, are studying yet another protein, called C1Q, that is known to trigger immune responses in the brain. It, too, is involved in synapse pruning - part of its job is to latch on to synapses that are due to be destroyed and send a call out to other immune proteins to kill that synapse.

It may be that C1Q builds up in the brains of people with Alzheimer's, not necessarily causing much damage on its own, but creating a setting in which the synapses are on the brink of destruction - as though they have a cocked gun pointed at them with a twitchy finger on the trigger.

Some small injury - a case of pneumonia or an asymptomatic stroke, for example - could be enough to set off a "cascade" of immune responses that leads to mass destruction of synapses, said Dr. Ben Barres, chair of neurobiology at Stanford. Barres has created a company, Annexon, to develop drugs to stop the immune reaction that begins with C1Q.

"There is actually a whole series of neurodegenerative diseases, and in every one of them the cascade is activated prominently," Barres said. "In Alzheimer's disease, it's entirely plausible that if we block this activation, if we stop this fire burning through the synapses," the brain will be able to recover before symptoms of dementia ever set in, he said.

Genetic risk factor

Naturally, in order to study the earliest phases of a disease, scientists need to be able to identify future patients long before they complain of symptoms like memory loss. That's why the most attractive targets for early Alzheimer's interventions may be found in people who are known to have a genetic risk for the disease.

There's been growing interest in the gene called ApoE in particular. There are three versions of the gene, and one of them - called ApoE4 - is associated with a massive increased risk of developing Alzheimer's. People with two copies of the ApoE4 gene are up to 14 times more likely to get Alzheimer's than someone with a healthy variant.

Scientists at San Francisco's Gladstone Institute of Neurological Disease have identified a potential drug that alters the ApoE4 variant to make it behave more like its healthy siblings. The drug is in the earliest stages of laboratory and mouse study and is not yet ready to test in humans.

"One of the most under-investigated and underexploited areas in Alzheimer's research is ApoE - it's nature's clue in how to avoid the disease," said Dr. Lennart Mucke, director of the Gladstone Institute.

"If we want to find out how to delay the disease or stop it, nature has already taught us," he said. "Now we just need to learn from it."