The families of the five million Alzheimer's disease sufferers in the U.S. are all too familiar with the erratic neurodegenerative disorder. "Mom seemed almost like herself this morning and then she drifted away form me," recounts senior investigator Lennart Mucke, describing a conversation with a patient's daughters.
The root of these heart-wrenching fluctuations between cognizance and confusion has eluded scientists for years. But Mucke, director of the Gladstone Institute of Neurological Disease at the University of California, San Francisco, and colleagues believe they may finally have pinpointed the cause of these puzzling personality twists as well as other cognitive deficits associated with Alzheimer's: petite mal (nonconvulsive) seizures similar to those exhibited in some types of epilepsy.
They reached this conclusion during studies of mice engineered to build up protein fragments in their brains known to cause the disease. The animals had alternating stages of overexcitement and inhibition in several regions of their brains, seizures of activity that resulted in swift rewiring to dampen the sudden surges.
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"We were quite struck to find anatomical and pathological hallmarks of overexcitation" observed in epilepsy without the convulsive, physical reaction, says Mucke. "We would have thought that everything was shutting off."
The surprising finding indicates that antiseizure medications given to epilepsy patients may also help lower or even reverse cognitive decline in Alzheimer's disease, a treatment option that could be available relatively quickly.
A protein fragment called amyloid-beta (Aβ) is known to aggregate and create plaque in the brains of Alzheimer's patients. Plaque hinders neuronal activity by gumming up synapses (spaces between cells through which chemical or electrical information is transmitted), eventually damaging nerve cell branches and leading to neuronal death.
In the current study, a collaborative team of researchers at the Gladstone Institute and the Baylor College of Medicine in Houston, created a strain of mice that overproduces a precursor of Aβ known as amyloid precursor protein. Five to six months after birth, as plaque built up, these animals showed learning and memory deficits illustrated by their difficulty navigating mazes. During autopsies, researchers observed that rewiring had occurred in the late subjects' brains.
"What tipped us off to the excitation was actual anatomical rewiring in the hippocampus—or learning centers—that looked like the cells wanted to protect themselves from overexcitation," Mucke says.
Using electroencephalography (EEG)—in which electrodes placed in the brain measure neural activity—the team saw a sharp wave of action in the mouse brains from the hippocampus in the midbrain to the neocortex (the outermost brain layer). The whole network of nerve cells seemed to activate simultaneously and synchronously. "The hippocampus then clamps down because it doesn't want to receive all that excitation, so it clamps down its portals by engaging its inhibitory cells," Mucke says. "In the process, they probably disable some normal, excitatory functions; part of this inhibitory rewiring that happens probably accounts for the fact that there's no physical seizure activity."
He says it is no doubt difficult for the neurons to do their usual jobs in the face of the sudden bursts of activity and overcompensation to correct them. Given that the hippocampus is associated with episodic memory, he says that this may account for some of the cognitive deficits of Alzheimer's, including the spells of confusion. "I could imagine that this abnormal activity may go on throughout the course of the disease,'' Mucke notes, "and not just mess up cognition but contribute to the neurodegenerative process."
Next up: the team plans to study whether human patients with early stage Alzheimer's or a mild cognitive impairment experience this same nonconvulsive seizure activity. "Interestingly, anticonvulsive drugs are already sitting on the shelf, approved by the FDA and used daily by hundreds of thousands of people for epilepsy," he says. "They have not been tested for Alzheimer's disease, to my knowledge." But he notes that it is possible one or more of these drugs could offer some benefit to the Alzheimer's community in as little as two years.
