Some octogenarians have exceptionally sharp memories, even sharper than people who are decades younger. A new analysis of their brains could help explain why.
Researchers autopsied the brains of superagers — individuals over 80 who have exceptional memories — and detailed their findings in a paper published Thursday. They found distinct anatomical differences between superagers and their neurotypical counterparts, including resistance to plaques and tangles associated with Alzheimer’s disease.
“This is a really unique population that we should be studying,” said Sofiya Milman, a geneticist at Albert Einstein College of Medicine who was not involved in the work. “These are the people who may actually hold the key for us to understand what protects people from Alzheimer’s.”
Superagers defy the expectation that cognitive decline is an inevitable part of aging. Previous research has established that their brains have notable characteristics, including slower atrophy of mass. But a better understanding of the genetics and molecular mechanisms that contribute to superagers’ memory capacity could help develop new treatments. The paper, outside experts say, helps pave the way in doing so.
Since 2000, researchers at Northwestern University have recruited 290 superagers; all scored significantly higher than their neurotypical peers on a delayed word recall test. The scientists have analyzed the superagers’ lifestyles and autopsied nearly 80 of their brains.
The paper did not identify behaviors like healthy eating, exercising, or not smoking or drinking as more common among superagers than their neurotypical peers. But it did link memory preservation to certain anatomical and molecular characteristics of the brain and nervous system.
A key finding was that the brains of superagers either resisted or were resilient to the buildup of amyloid plaques and tau tangles. When these get lodged into the hippocampus — the part of the brain involved in memory formation — they can cause amnesia and memory disorders like Alzheimer’s disease, according to Tamar Devora Gefen, a co-author and neuropsychologist at Northwestern’s Feinberg School of Medicine.
The brains of some superagers had a very low density of tau tangles, the paper found. But others had a moderate intensity of such tangles. The authors said this suggests there are at least two pathways to maintaining memory capacity: not developing these tangles at all, or developing them but withstanding their cognitive impacts.
This finding was significant given recent debate in the drug development community about how best to treat Alzheimer’s, according to Nicholas Schork, director of clinical genomics and therapeutics at the Translational Genomics Research Institute, who was also not involved in the work. There are two main approaches for therapeutics that try to slow cognitive decline. The first is correcting pathologies, like tau tangles, which manifest in people with cognitive dysfunction, and the second is preventing them from showing up in the first place.
It’s harder to reverse the course of developed pathologies, Schork said. But the fact that some superagers were able to overcome those pathologies suggests the possibility of treatments for those who have already developed them, he added. “That’s a surprise.”
The paper hypothesized that superagers’ resistance to these plaques and tangles could be due to the size of their entorhinal neurons, which are associated with the memory system of the brain, according to Emily Rogalski, a former Northwestern neurologist who helped lead the work. The researchers found that superagers had larger entorhinal neurons than their neurotypical counterparts.
In the case of superagers who never developed pathologies, these larger neurons could safeguard the pathway for forming new memories against tangle-related degeneration. In the case of superagers who did develop those pathologies, the larger neurons could indicate a heightened ability to form new connections.
“Presumably the larger ones are functioning better, but those are future investigations that will need to be done,” Rogalski said.
Researchers also found that the outermost layer of superagers’ brains generally saw significantly less thinning, which fits with previous research. This suggests less age-related shrinking, loss of fewer neurons, and loss of less white matter, which protects signals sent throughout the brain, according to Stacy Andersen, a behavioral neuroscientist at Boston University who was not involved in the work. The paper also found that superagers had less microglia, which can cause inflammation when present in high levels, Andersen said.
The research has significant implications for drug development, Milman said. “A lot of us are of the opinion that this may actually be the most efficient way to get us to therapeutics, by studying these resilient populations.”
Still, questions remain about how suitable some of the mechanisms and associations outlined in the paper may be to developing therapeutics, according to Schork. One such example is increasing the size of neurons. Though drugs that enhance the creation of neurons and synapses exist, they don’t work by simply making neurons larger, Schork said. More research may need to be done to identify upstream mechanisms that cause an increase in neuron size and could be appropriate for modulation.
Other limitations of the paper include its small sample size and outside factors that could influence the superagers’ molecular characteristics, such as medications an individual may have been taking for a secondary condition, Schork said. But new studies are underway that will help fill some of those gaps, according to Rogalski.
“It’s time to focus on resilience and resistance. What are the protective factors? What is actually protecting people from getting the disease, despite them having certain risk factors?” Milman said. “By studying this population and other populations like it, I think we can get to the answer.”
