For years they were flukes of the Alzheimer’s world: elderly people who died at an advanced age and, according to postmortem examinations, with brains chock-full of amyloid plaques and tau tangles, the protein fragments whose presence in the brain is the hallmark of the disease. Yet these brains were off-script. Although Alzheimer’s orthodoxy says these sticky protein clumps between and inside nerve cells destroy synapses and kill neurons, causing memory loss and cognitive decline, these individuals thought and remembered as well as their amyloid- and tau-free peers.
Because so few people donate their brain to science, it was never certain how many died with the hallmark of Alzheimer’s but never developed the disease. And there were always suspicions that maybe these seemingly resilient people did have at least mild Alzheimer’s, or would have developed it eventually; since they were no longer alive to test and track, that couldn’t be ruled out.
A funny thing happened on the way to studying brain scans to detect amyloid and tau, a $184 million government and private project called the Alzheimer’s Disease Neuroimaging Initiative. While the jury is still out on whether detection of those rogue protein fragments benefits patients (especially since there are no drugs that even slow the progression of the disease), ADNI and other large studies have unexpectedly shown something else. Not only do resilient individuals exist, but they’re not that rare.
About 30% of older adults have brains littered with enough amyloid or tau, or both, to qualify for an Alzheimer’s diagnosis but without so much as a hint of dementia, said neuroscientist Timothy Hohman of Vanderbilt University Medical Center, who is leading the largest-ever study to identify genetic explanations for that resilience.
“You can have abundant plaques and tangles without having Alzheimer’s disease,” agreed neurologist Rudy Tanzi of Massachusetts General Hospital. “The challenge is to figure out how. If we can, then the goal would be to mimic what these resilient people have with some kind of a drug.”
The National Institute on Aging has funded its Resilience-AD Program, which began in 2017, with $40 million in an effort to identify genetic and other factors that keep Alzheimer’s at bay even in people whose brains scream “Alzheimer’s,” and to somehow bottle that resilience. Experimental drugs inspired by discoveries about resilience, including four from the NIA program, are moving through clinical trials, and more are in the pipeline.
“Usually, we try to understand why people have a disease,” said the NIA’s Suzana Petanceska, who helps direct its neuroscience programs. “But by looking at these outliers who do not get Alzheimer’s, the idea is to understand the molecular pathways that drive that resilience and harness it to develop therapeutics for the rest of us.”
That represents a sea change in the understanding of Alzheimer’s resilience. For years, scientists believed it came through the side door. That is, some brains compensate for the destruction of neurons and synapses (where neurons connect) that amyloid and tau cause. It isn’t that the damage isn’t happening, but that other mechanisms counterbalance it. If the brain were a termite-infested house, the bugs are still chomping on the support beams but builders are erecting extra beams to keep the structure from collapsing.
Such compensatory mechanisms clearly exist. “Cognitive reserve,” which increases with years of education and learning, refers to back-up brain circuitry that can buffer the effects of losing neurons and synapses to Alzheimer’s. Because learning promotes denser circuitry and more synapses, if the original circuit is lost to Alzheimer’s then the brain can activate the back-ups. Brains with greater cognitive reserve can therefore lose more synapses and neurons to Alzheimer’s pathology without showing it: same amount of amyloid, less cognitive decline.
“These are people who have a demonstrable burden of disease [as measured by the extent of brain pathology] but less than the expected consequences,” said Thomas Grabowski, an Alzheimer’s expert at the University of Washington School of Medicine. “Amyloid isn’t as toxic to some people as it is to others.”
There is clear physical evidence for the power of cognitive reserve to counteract the toxic effects of amyloid. In people with the same degree of Alzheimer’s, those with more years of education had more tau tangles and more amyloid than people with less education. Put another way, the same level of brain pathology has worse consequences for people with less cognitive reserve. And in the first study of Alzheimer’s and the brain’s white matter (the axons that carry signals from one neuron to the next), scientists in Germany found that the more amyloid that elderly but cognitively healthy people had in their brains, the stronger and more extensive their white matter, they report in a manuscript being submitted to a journal. In other words, for a given amount of amyloid, avoiding Alzheimer’s (again, none of the people had the disease) is possible with more extensive and better functioning white matter.
Compensatory mechanisms such as cognitive reserve (another one is cardiovascular health) don’t affect the actual process of Alzheimer’s, as measured by vanishing neurons and synapses. And cognitive reserve can’t be put into a pill. But the other kind of resilience — exterminating the termites, not just erecting new ceiling beams — just might affect Alzheimer’s pathology itself, and both academic labs and companies are trying to bottle it.
Last year, for instance, scientists described the case of a Colombian woman in her 70s who is the living embodiment of Alzheimer’s resilience. She has two copies of a gene that causes sky-high levels of amyloid and, in everyone else known to science, Alzheimer’s disease before age 60. Yet she didn’t develop cognitive impairment until three decades after everyone else with the mutation, and even then it was mild. And she has very little neuron-killing tau, which is supposed to follow amyloid like night follows day.
But what the woman did have is a double dose of an ultra-rare variant of a gene called APOE3. After several biochemical steps, this variant keeps tau from spreading through the brain. The woman had very little neuronal loss.
So it wasn’t that her brain developed a workaround to amyloid and tau. Instead, its APOE3 tamed tau. (As for amyloid plaques, they’re probably not particularly toxic to synapses, as long thought.) She wasn’t erecting new beams to replace the ones eaten by termites; she was exterminating the termites.
The woman’s extreme resilience is now the basis for research on possible Alzheimer’s therapies, said neuropsychologist Yakeel Quiroz-Gaviria of Mass. General, who led the study. “We’re currently working on that,” she said. So far, she and her team have produced a monoclonal antibody against 14 of APOE’s amino acids, sidelining them in a way that mimics the resilient woman’s APOE3 mutation.
There may well be more resilience genes.
In the largest-ever study of the DNA basis of Alzheimer’s resilience, Vanderbilt’s Hohman and his colleagues looked for genetic factors that let some people avoid memory loss and other symptoms of Alzheimer’s even though they have the brain signatures of the disease. They focused on 5,108 people (including those in ADNI) who had better cognitive performance than they should have, given how much amyloid was in their brain.
Many of the resilience genes fall into the “compensatory” category, include those related to cardiovascular health. (Better heart health preserves brain health, which keeps the brain from suffering additional blows on top of the damage from Alzheimer’s.) But one is involved in DNA repair: In resilient people, this gene is expressed at higher levels. The study, posted this month to the preprint site bioRxiv, needs data from about 10,000 more people to provide assurance that that finding is real, Hohman said. If it is, DNA repair might be a molecular contributor to resilience and one of several “novel pathways for therapeutic targets,” he and his colleagues suggest.
“You can have abundant plaques and tangles without having Alzheimer’s disease. The challenge is to figure out how.”
Neurologist Rudy Tanzi
Turning novel pathways into drugs is already underway.
After finding that a gene called CD33 comes in a form that seems to protect people from Alzheimer’s, Tanzi and his colleagues spent years trying to figure out how. Basically, they reported in 2013, this variant can’t carry out CD33’s usual function: turning the immune cells that patrol the brain, called microglia, into assassins.
Microglia ordinarily clear out amyloid, dead cells, and other brain debris. But in the presence of amyloid and tau, they go on the warpath. “They stop being housekeepers and start being killers,” Tanzi said, producing neuroinflammation that “kills 10 times more neurons than plaques and tangles do.” Brains can withstand amyloid plaques and tau tangles, he believes, but not the buzzsaw of neuroinflammation.
This week, researchers unveiled a study quantifying how controlling inflammation might confer resilience to Alzheimer’s disease. Neurologist Nancy Donovan of Brigham and Women’s Hospital in Boston and her colleagues compared widows to otherwise similar but still-married women with the same (high) amounts of amyloid in their brains; none had Alzheimer’s. Despite the equal amyloid hit, the still-married women’s cognitive ability declined only one-third as fast as the widows’.
“It was a striking difference to observe among [originally] cognitively unimpaired individuals over only three years,” Donovan said. One possible explanation, she said, is that the psychosocial stress of widowhood triggers neuroinflammation just as stress can trigger inflammation elsewhere in the body. That would turn minimally harmful amyloid plaques and tau tangles into feeding grounds for neuron-killing microglia.
Using clusters of brain cells he calls “Alzheimer’s in a dish,” Tanzi and his colleagues screened existing medications and CD33-specific antibodies to find any that inhibit CD33, in hopes of effectively and safely stopping neuroinflammation. They got several hits. Last month, the biotech company Alector announced that it had dosed the first Alzheimer’s patient in a Phase 1b study of an anti-CD33 monoclonal antibody, which it engineered to mimic the effect of the CD33 mutation and prevent microglia from triggering dangerous neuroinflammation. And AZTherapies, which Tanzi co-founded, is running a Phase 3 trial with 620 Alzheimer’s patients to see if an old asthma drug called cromolyn can convert microglia back to nicely behaved housekeepers, even if they’d spent time as killing machines, as it did in the Alzheimer’s in a dish. Results are expected this year.
Both of the CD33-inspired therapies aim to slow the progression of Alzheimer’s disease in people who already have it. But if they work for that, they might one day be given to healthy people with the beginnings of Alzheimer’s pathology in their brains, preventing the disease altogether.
“We are no longer in the era of just wishing” that the molecular mechanisms of Alzheimer’s resilience can guide the discovery of therapies, said NIA’s Petanceska. “Resilience is now in the mainstream of Alzheimer’s drug discovery, and a high priority.”