The defective proteins that are widely thought to kill brain neurons and cause, or at least indicate, Alzheimer’s disease do not always have that calamitous result, scientists reported on Monday, raising more doubts about conventional approaches to diagnosing and finding treatments for Alzheimer’s.
The researchers analyzed the brains of eight people who died in their 90s and who had excellent recall until then. Three of the eight brains had the defining amyloid plaques and tau tangles of Alzheimer’s, yet somehow were “immune to [their] effects,” said neurologist Changiz Geula, of Northwestern University Feinberg School of Medicine, who led the study and presented the results at the annual meeting of the Society for Neuroscience in San Diego. “What’s significant about these findings is that they show there can be high densities of plaques and tangles in the brains of some elderly individuals who are cognitively normal or even superior.”
Although the study was small and preliminary, outside scientists were impressed. “This is an exciting paper,” said Dean Hartley, director of science initiatives at the Alzheimer’s Association, adding that Geula and his colleagues were “producing very solid work.”
Previous studies have shown that some people with numerous amyloid plaques did not have Alzheimer’s or other signs of cognitive pathology before they died, but “these findings are clearer than prior ones because the patients are older,” said George Perry, dean of the College of Sciences at the University of Texas, San Antonio. That is, by 90-something, amyloid plaques and tau tangles should have wreaked their terrible havoc.
The findings raise the obvious question of why some people are immune to molecules widely thought to be lethal to brain neurons and synapses. Geula and his colleagues plan to look for genetic, dietary, and environmental factors that might protect against both amyloid plaques, the sticky blobs that form between neurons, and tau tangles, twisted strands of a protein that build up within neurons.
Two main explanations for “Alzheimer’s brains” that don’t develop Alzheimer’s are emerging.
One, known as cognitive reserve, holds that if people are well-educated and intellectually engaged throughout life, they won’t show the memory and cognitive impairments that otherwise come with the loss of synapses and death of neurons in the brain’s memory and thinking regions. Such people have enough backup neurons and redundant synapses to withstand some losses, much as an external hard drive lets a computer withstand the loss of, say, the Word files in a computer’s internal memory.
“What you do in your life somehow protects against these otherwise toxic molecules, allowing you to lose cells and synapses and still function,” said Hartley.
The other possibility is even more intriguing. Perhaps biochemical or genetic mechanisms prevent cognitive decline even when the brain is riddled with pathological amyloid and tau. For instance, some people might produce molecules that make amyloid nontoxic, in which case even if plaques build up they don’t destroy synapses. Or, some genetic or other factor might make synapses strong enough to endure even the toxicity of amyloid. If such protective molecules were discovered, they might inspire lab-made versions to prevent or treat Alzheimer’s.
Scientists are intently looking for such molecules, but in the meantime the finding that an amyloid-ridden brain is not necessarily a brain with Alzheimer’s underlines a longstanding concern about the brain scans sometimes used to diagnose Alzheimer’s.
Since 2012, US health regulators have approved three molecular tracers that bind to amyloid and can be used to visualize it via PET or other neuroimaging, which costs from $3,000 to $7,000 and is not covered by Medicare. Some experts have called for screening everyone older than about 50 for signs of amyloid. But even before this study, research as far back as 1991 showed that “many people have amyloid plaques in the brain but have no symptoms of cognitive decline or Alzheimer’s disease,” according to the Alzheimer’s Association.
Scans can therefore “give false positives,” said Perry, a longtime skeptic of the idea that amyloid plaques are the chief cause of Alzheimer’s. “The value of the tests as a public health measure is questionable,” he said, and the Alzheimer’s Association does not recommend their routine use to diagnose the disease.
Geula’s team studied the brains of eight people older than 90 who were part of the 90+ Study at the University of California, Irvine. Soon before their deaths, the volunteers scored extremely high on memory tests compared to 90-somethings with a normal (for their age) score. After they died, their brains were scrutinized for telltale signs of Alzheimer’s.
Three had the characteristic amyloid plaques and tau tangles. (The other five brains looked normal.) But cells in the memory-forming hippocampus and the higher-order-thinking frontal cortex were relatively intact, somehow withstanding the toxic effects of amyloid and tau. The search is on for what’s protecting them.