Holding on to Memory
Strategies from vaccines to genetic manipulation may one day halt the ravages of Alzheimer’s disease and other dementias
Of all the marvelous organs we humans possess, the brain, with its capacity for self-awareness, reasoning, learning, creativity and emotion, most defines us. It endows us with remarkable abilities — to compose symphonies, write novels, solve scientific conundrums, ponder ethical dilemmas, fall in love and remember past loves — and its failure threatens more than physical health; it challenges our very sense of ourselves. No wonder Alzheimer’s disease and other dementias, which assault the brain and rob us of our most cherished abilities, both terrify us and impel us to search for cures and preventive therapies.
That search is becoming even more urgent today, as aging baby boomers expand the ranks of the elderly. Already dementias, more common in older people, affect one in seven Americans over age 70, and the prevalence is increasing. According to the Alzheimer’s Association, someone in America develops Alzheimer’s disease — the most common cause of dementia — every 71 seconds. By mid-century, the rate will be one every 33 seconds.
“It’s an avalanche, an epidemic,” says Sid Gilman, M.D., director of the Michigan Alzheimer’s Disease Research Center. “And not just in the U.S. The same thing is happening in Western Europe, Japan and other parts of the world.”
Thanks to advances made over the past couple of decades, medical scientists know a lot about the workings of the healthy brain and the malfunctions underlying Alzheimer’s disease and other dementias. “The harder part is figuring out how we can intervene in the disease process in a safe and effective manner,” says geriatric neurology specialist Judith Heidebrink, M.D. A number of approaches, informed by basic research on the biology of dementias, are being explored at the U-M and elsewhere, and although no definitive cure has yet been found, early results are promising.
In simplest terms, dementias occur when nerve cells (neurons) deteriorate and die, wreaking havoc on the brain’s circuitry. A healthy adult brain is a vast and highly interconnected switchboard with some 100 billion neurons connecting to one another at 100 trillion points known as synapses. Each synapse is an information channel across which signals, in the form of chemical pulses, pass from neuron to neuron. Those pulses are the cellular underpinnings of thought, learning and memory.
In Alzheimer’s, the lines of communication break down. Synapses fail, triggering a cascade of events that ultimately destroys neurons. As neurons die and debris accumulates, the brain shrinks and becomes more compromised.
What kicks off the devastating process? Scientists are still exploring and debating answers to this question, but the prime suspect implicated in one leading theory is a snippet of protein known as beta-amyloid. According to the “amyloid hypothesis,” things start going awry when beta-amyloid accumulates, either because the brain produces too much or because mechanisms for disposing of it fail. The buildup creates roadblocks at synapses — obstructing information flow and triggering the damage that leads to neuron death.
Clumps, or plaques, of beta-amyloid are one telltale sign of Alzheimer’s disease; another is tangles of a protein called tau. In addition, brains of people with Alzheimer’s disease show signs of inflammation and oxidative damage. There’s no doubt these abnormalities occur in Alzheimer’s disease, but is any one of them the root cause?
The evidence is conflicting, explains Gilman. “In tissue culture, beta-amyloid is toxic to cells,” he says, and excess beta-amyloid is found both in individuals with garden-variety Alzheimer’s disease and those with the less-common, early-onset form that strikes people in their 30s and 40s. However, even people whose brains work perfectly well may have significant beta-amyloid deposits, autopsy studies suggest. “Only when they acquire tau abnormalities do they develop dementia,” Gilman notes. Also, the severity of dementia seems to be related more to the density of tau tangles than to the amount of beta-amyloid deposited.
So some researchers consider tau tangles the real villains and beta-amyloid an innocent bystander, while others still suspect amyloid involvement. “It could be that both pathologies are important,” says Gilman. “It doesn’t have to be either-or.”
Even though the issue isn’t resolved, studies of beta-amyloid, tau, and normal brain function are pointing the way to new treatments and prevention strategies. Current therapies are aimed at the end of the degenerative cascade, and thus can only ease symptoms, not alter the course of the disease, says Heidebrink. “What we really want to do is look at the front of the cascade and figure out how to stop the process altogether.”