The threat of sticky plaques and toxic A-beta strands lurks in family trees // Millions fear the fog of an endless present // Waiting on “a new therapeutic age for Alzheimer’s disease.”
Not Fade Away
Every Sunday of his childhood, Sam Gandy witnessed the effects of dementia, visiting his grandmother in a nursing home even as the disease corroded her memory of him. Relatives said she was senile and thought her condition was just what happened when you got old. Now, four decades later, there’s an awareness that Alzheimer’s disease, like other maladies associated with aging, is not inevitable. But that makes it no less terrifying, and as tens of millions of baby boomers enter their later years, they monitor parents, one another and themselves for signs of what could be the start of a slide into oblivion.
Less than a year ago, 38 years after “senility” claimed Gandy’s grandmother, his father-in-law began to suffer from forgetfulness and confusion. Gandy, director of the Farber Institute for Neurosciences at Thomas Jefferson University in Philadelphia, told him it was the same disease. “It was horrible to admit we can do nothing to stop it,” he says.
Alzheimer’s is the bad news about our new, longer life spans. At age 65, fewer than 3% of people show signs of the disease, but after age 85, as many as 40% suffer its effects. Today, there are 5.1 million diagnosed sufferers of Alzheimer’s disease in the United States. That number is expected to rise to 7.7 million by 2030 and to 13 million by 2050—and caring for those patients could bankrupt Medicare and Medicaid.
Yet against this backdrop, researchers are strikingly sanguine, confident they’re close to finding ways to slow the ravages of the neurodegenerative disease. During the past 15 years the field has seen revolutionary advances, the fruit of some of the largest dementia research studies ever funded. “I’m very optimistic that we’ll be able to arrest the progression of Alzheimer’s disease in my lifetime,” says Gandy, who is 53. “And I think our ability to diagnose the disease early will become so good that eventually we’ll be able to prevent it.” With nine drugs currently in the final phase of clinical testing, adds Paul Aisen, an internist and professor of neurology at Georgetown University in Washington, D.C., “we are on the verge of a new therapeutic age for Alzheimer’s disease.”
The landscape of devastation that Alzheimer’s disease causes was first revealed in 1906, when Alois Alzheimer, a German psychiatrist and neuropathologist, described what he found in the autopsied brain of a demented 51-year-old woman. Inside her neurons were tangles of twisted protein threads. Clumped between the neurons were sticky plaques of protein, decayed neuron remnants, and whole cells called microglia that digest damaged cells or foreign substances.
Both the plaques and tangles appear to be linked to a brain substance known as amyloid precursor protein (APP) that is thought to play a role in the normal function of brain cells. Enzymes clip APP into fragments of different sizes—peptides of beta-amyloid, or A-beta—that float freely in the brain until they are cleared by the bloodstream. There is debate about what function, if any, A-beta serves, but some fragments—of a particular type called A-beta 42—seem to be toxic. People with Alzheimer’s have higher than normal concentrations of A-beta 42, and some researchers believe these protein clumps do the chief damage of Alzheimer’s as they find their way into the synaptic gaps among neurons, short-circuiting signals between brain cells. (The clumps then form long, spaghetti-like fibrils, which in turn condense into the gooey plaques of Alzheimer’s.) Although many scientists consider the plaques themselves just as dangerous, others now theorize that they could be protective, absorbing A-beta 42 strands to keep them from further impairing cell-to-cell communication.
Once plaques start forming, neurodegeneration worsens with the abnormal accumulation of the protein tau. Normally, tau stabilizes microtubules, structures inside neurons that transport nutrients through brain cells. But in the brains of Alzheimer’s sufferers, tau pulls away from the microtubules to twist with other strands of tau, causing the neuron’s transport system to collapse.
As neurons lose connection with one another and their food source, they die. Alzheimer’s first destroys neurons in the parts of the brain, particularly the hippocampus, that form and store memory. Then it attacks areas in the cerebral cortex responsible for language and reasoning before finally causing so much of the brain to atrophy that the person with Alzheimer’s becomes helpless and unresponsive.
Therapies do little to stem this decline. Drugs developed during the 1970s and 1980s—three of only four FDA-approved Alzheimer’s medications now on the market—increase the level of the neurotransmitter acetylcholine, the chemical used by neurons in forming memories, by inhibiting an enzyme that breaks it down. (The fourth drug blocks the action of the neurotransmitter glutamate, which is overactive in people with Alzheimer’s.) But the drugs do not slow the inevitable death of neurons—they treat just the symptoms, not the disease.