Illustration by Arun Misra 96P

Closer to a Cure
Genetic research is providing clues to the origins of Alzheimer’s

One hundred winters ago, a German doctor named Alois Alzheimer autopsied the brain of a patient who had fascinated him for years. Auguste Deter’s husband had brought her to Alzheimer’s hospital in Frankfurt five years before, where she was admitted for memory and speech problems, anger, and paranoia. Over the years, she had grown progressively more confused and immobile. “I have lost myself,” she told her doctor. In 1906, at age fifty-five, she died.

When Alzheimer, a psychiatrist and neuropathologist, looked at a section of her brain through a microscope, he saw abnormal clumps and tangled bundles of fibers—symptoms he later termed a “Curious Disease of the Cerebral Cortex” when he presented the case at an annual psychiatric conference in Tübingen.

These plaques and tangles would become telltale signs of Alzheimer’s disease: a progressive dementia with no known cause or cure. The incidence of Alzheimer’s is steadily increasing along with Americans’ rise in longevity. The disease, which now affects 4.5 to 5 million, usually begins after age sixty. One in five people age seventy-five to eighty-four develop Alzheimer’s, and nearly half of those eighty-five and older.

A devastating, degenerative illness that often unfolds over a decade, stealing a person’s memories, ability to communicate, and independence, Alzheimer’s is extremely costly. Already, estimates are $100 billion annually, and—demographically, at least—the future holds the promise of more cases and higher costs.

“The changes in the brain that cause Alzheimer’s begin ten to twenty years before symptoms appear,” says Sam Gandy, a leading researcher of the disease’s pathology who joins Emory this summer as a Georgia Research Alliance Eminent Scholar and director of Emory’s Center for Neurodegenerative Diseases. “Baby boomers will start entering the age of greatest risk in 2010. To prevent the looming epidemic, answers have to come before it is too late for seventy-seven million Baby Boomers.”

Gandy, director of the Farber Institute for Neurosciences at Thomas Jefferson University in Philadelphia before coming to Emory, says the basic mechanisms of Alzheimer’s disease are now known. Advances in genetics and imaging have allowed researchers to discover risk factors, he says, but much work remains if Alzheimer’s is to be stopped “before it ravages the brain.”

This is the very work that Emory hopes to pursue with Alzheimer’s research that cuts across disciplines. In 2005, the National Institute on Aging awarded a highly coveted Alzheimer’s Disease Research Center designation to the University, along with $7.4 million in funding over the next five years. Faculty from genetics, neurology, psychiatry, biostatistics, public health, nursing, and neuropathology participate in the center.

“For so long, Alzheimer’s has been seen as a hopeless disease,” says Allan Levey, chair of the Department of Neurology, who directs the center. “That is no longer the case.”

Scientists at Yerkes National Primate Research Center are investigating potential vaccines for Alzheimer’s, developing a transgenic model of the disease, conducting comparative aging studies, and improving early symptom detection.

Lary Walker, a research professor in Yerkes’ division of neuroscience, has dedicated his career to Alzheimer’s research, currently focusing on its protein structure and chemistry, developing more representative transgenic models (animals whose genetics have been altered), and researching the development of an Alzheimer’s vaccine using squirrel monkeys.

Walker and colleagues have discovered that proteins taken from the brains of Alzheimer’s patients and injected into the brains of genetically engineered mice trigger Alzheimer’s-like lesions in the mouse brains.

This suggests that the disruptive plaques seen in Alzheimer’s disease can “seed” themselves, spreading in a way that is similar to other neurodegenerative diseases such as “mad cow” disease. What isn’t clear, says Walker, is whether the proteins themselves are responsible for this effect. To investigate, his team used genetically engineered mice to carry the human gene with a mutation that caused the animals to develop plaques in old age.

When young mice received brain extracts either from humans who had died with Alzheimer’s disease or from older mice with the mutation, the young mice developed brain plaques within weeks instead of the usual year.

“For the first time we showed that the likely seed is [the protein] beta amyloid itself,” says Walker. There is no evidence, he adds, that the protein alone can accelerate Alzheimer’s-like plaques in mice that are not genetically predisposed to the illness.

“These mice were going to get Alzheimer’s anyway,” he says. “The seeding merely hastened the process.”

Associate Professor of Neurology James Lah and his colleagues are continuing research on their discovery of a new risk factor for late-onset Alzheimer’s disease—variants in a gene that influence how proteins are moved through cells.

Improper protein trafficking contributes to the development of Alzheimer’s by producing abnormal amyloid protein deposits, which are thought to underlie brain neuron degeneration.

“A lot of the focus on the genetics of Alzheimer’s disease has been on rare forms of the disease that are inherited in a fairly straightforward way,” Lah says. “The genetics associated with the more common form of the disease are a lot more complicated—a couple of dozen genes are implicated as risk factors.”

A few years ago, Levey and Lah examined genetic samples from patients collected at Emory and discovered the protein trafficking link, which led to a boon of research.

“Evidence is piling up that this is a bonafide susceptibility gene,” Lah says. “That’s where the story stands right now. Changes in the amount of this key protein are associated with very early stages of the disease and mild cognitive impairment.”

Lah and other Emory researchers, through the Emory Chemical Biology Discovery Center, are working on finding drug-like compounds that will alter the level of this protein in the brain.

“Are we closer to finding a cure than we were a century ago? Without a doubt,” says Walker. “The next decade will be an exciting and rewarding period in the development of therapies that actually slow or halt the progression of Alzheimer’s disease.”

Or, as Chief of Psychiatry Larry Tune said during a community forum on Alzheimer’s research at the Nell Hodgson Woodruff School of Nursing in April, “If we push the age of onset back to ninety-five, and the patient dies on his motorcycle at age ninety-two, we’ve done our job.” —M.J.L.

Forget about it

Tennis teammate’s name on the tip of your tongue? Puzzling over your Paypal password?
Mild memory loss is perfectly normal, especially as one ages, says Professor of Psychiatry and Behavioral Sciences Stuart Zola, director of Yerkes National Primate Research Center.

“If we have forgotten an appointment, we begin thinking, ‘Uh oh, is this the first sign of Alzheimer’s disease?’ We become much more conscious and [memory lapses] get a disproportionate amount of attention when they really may be something quite benign,” Zola told WebMD. “It is often the case that people will start to report in their fifties that they think their memories are slipping. They have to use more kinds of reminders or strategies to remember things.”

Memory is tricky, says Zola, and time is its worst enemy. Shortly after taking information in, memory traces begin
to fade.

“If your encoding isn’t good because you’re stressed or distracted, you’re going to have difficulty retrieving the information because it isn’t there in good form,” says Zola, who has spent much of his career researching memory and its vagaries.

Alzheimer’s disease can, indeed, cause devastating and progressive memory loss, but far more likely causes are:

• stress or anxiety
• multitasking
• depression
• fatigue
• metabolic diseases
• Vitamin B-12 deficiency
• infections
• prescription drugs or over-the-counter medications

“The rule of thumb is that if you’re worried about your memory loss, it’s probably not serious,” Zola says, “but if your friends and relatives are worried, it’s probably more serious.”





© 2007 Emory University