Credit: Ryan Garcia

Super Agers and Centenarians: The Search for Protective Factors

Longitudinal studies of the oldest old could reveal how some people’s brains resist the ravages of time.

At the population level, cognitive function clearly declines with age. But trends in individuals tell a different story. Though some people experience memory decay over time, others maintain the memory capacity of a 50-year-old into their 80s and 90s and beyond. “Cognitive decline is common in aging, but it’s not inevitable,” says Emily Rogalski, a cognitive and clinical neuroscientist at Northwestern University. “Some people are doing extraordinarily well.”

Similarly, the risk of dementia and other diseases increases with age, particularly in the oldest old. But some people seem to march into old age unscathed. Brain autopsy studies of the oldest old have shown that about 40 percent have neurological hallmarks of Alzheimer’s but lack outward signs of dementia, suggesting they have some kind of resilience. Studies of centenarians, people who live to 100 and beyond, have found that about 4 to 10 percent don’t have any of the neuropathological changes that often accumulate with age, suggesting they are resistant to Alzheimer’s and other pathologies.

These observations point to the presence of protective factors that help some people reach old age with their memory and other cognitive functions largely intact. Rogalski and others are studying the oldest old to try to uncover the mechanisms underlying this protection. “Some people can completely ward off the pathology and some deal with it better,” says Stacy Andersen, a behavioral neuroscientist at Boston University School of Medicine and part of the New England Centenarian Study. “There are probably very different underlying mechanisms for those two groups.”

Researchers in the field of aging have identified two different mechanisms of protection: resistance and resilience. People who are resistant avoid the typical pathology that contributes to cognitive decline, while people who are resilient do have age-related pathology, such as the plaques that accompany Alzheimer’s disease, but show no outward signs of dementia. Researchers hope their efforts will inspire new ways to preserve cognitive function in everyone. The potential for resilience is particularly alluring because it could provide a means for people who do have dementia pathology to better maintain cognitive function.

Initial results from these studies point to lifestyle factors that are now well known to improve aging, including sleep, exercise, education and cardiovascular health. But new technologies to measure pathology such as plaques in the living brain are now making it possible to dig deeper for differences in brain structure, function and pathology that contribute to cognitive decline and preservation.

The secrets of ‘super agers’

Rogalski heads the SuperAging study at Northwestern, which seeks to understand why some older people have excellent memories. The study, now running for more than 10 years, focuses on people ages 80 and older who have the memory capacity of 50- or 60-year-olds. “One of the largest challenges in aging is health span not keeping up with life span,” Rogalski says. “Super agers represent a good marriage between the two and will help identify protective factors.”

In the past, studies of successful aging often focused on people who were free of dementia at a certain age or who had good physical and cognitive health. The SuperAging study explicitly decouples memory from overall health. “It’s common for good memory and good health to go together, but it’s not required,” Rogalski says. “By making memory the primary criteria for entry, you can look at the relationship to physical health.”

The study has enrolled 100 people to date, ranging in age from 80 to 107. Super agers have strong episodic memory (memories of past personal events), and their memory performance has remained stable over time. Rogalski notes that they are different from people with extreme autobiographical memory, who know what they were doing on a specific day 30 years ago. Indeed, many participants are surprised to learn of their superior memory. “Super agers don’t necessarily report having amazing memory performance when they were younger or that memory was a strength in their life,” Rogalski says.

Super agers tend to have a thicker anterior cingulate, shown in yellow. Geoff B. Hall

Results to date suggest that super agers’ brains reflect their superior performance. MRI scans show that super agers’ cortical volume and thickness is larger than it is in average agers, and their rate of volume loss is lower. One region in particular, the anterior cingulate, seems to be thicker in super agers. Another longitudinal aging study, the 90+ study at the University of California, Irvine, led by Claudia Kawas and collaborators, has replicated this finding and found that networks connected to the cingulate are thicker as well. Kawas’s team has recently submitted the results for publication.

Many participants in the SuperAging study donate their brains when they die, enabling researchers to look more closely at the parts of the brain and types of cells that may endow super agers with their superior memory. A small autopsy study suggests that super agers have an abundance of von Economo neurons, a recently discovered type of brain cell found in the anterior cingulate and entorhinal cortex of higher-order species that’s thought to be related to social behavior. “Super agers have more than four times the density von Economo neurons compared to their average peers and a greater density than individuals who are younger,” Rogalski says.

Super agers had a similar density of plaques to normal agers. But they tended to have fewer tangles, another type of dementia-related pathology, in the entorhinal cortex and anterior cingulate. (Some evidence suggests tangles are more closely tied to neurodegeneration than amyloid plaques.) “In general, super agers’ memory seems to resist the changes associated with aging,” Rogalski says. “For those without as much pathology, how were they able to resist formation of plaques and tangles?” For super agers who do have pathology, how does their memory stay sharp despite some degeneration?

As researchers do more autopsies, they are looking more closely at the influence of genetic factors on brain structure and pathology. Though both longevity and dementia can run in families, it’s not yet clear whether this is true for super memory in old age. “For some super agers, one sibling performs in the normal control range and the other is in superior range,” Rogalski says.

Super agers do not have an especially low incidence of a variant of the APOE gene called APOE4, which raises the risk of dementia. Nor do they have an abundance of the protective APOE2 variant. Other studies of the oldest old have found that those who carry APOE4 do not seem to be at higher risk of dementia than their peers, another finding that points to the possible presence of protective factors.

In addition to clues from the brain, Rogalski and collaborators are also looking for lifestyle factors that characterize super agers. An abstemious lifestyle isn’t essential to achieving super ager status — some smoke, and no specific diet predominates. But super agers do seem to be especially active in some ways. “These are really engaged individuals,” Rogalski says. “Many are still working, and those who are retired tend to be actively engaged in the community, volunteering or teaching classes, doing something stimulating and keeping the mind fresh.” Though it’s not yet clear if these activities are a cause or effect of super aging, other research suggests mental engagement is important for brain health. According to surveys, super agers also report stronger social connections than cognitively average peers. Rogalski and her team are now exploring this finding in a more unbiased way by collecting sensor data on movement, activity and conversations with others.

“In TV, ads and the news, most portrayal of aging is negative, and our culture spends a lot of time talking about negative consequences of aging,” Rogalski says. “Super agers offer a hopeful message of what can be possible in aging and the science behind it.

A window on pathology

In 1981, more than 1,000 residents of a California retirement community called Leisure World filled out a health survey asking how much coffee and alcohol they drank and how much they smoked and exercised. Two decades later, Kawas and collaborators recognized the possible gold mine of data housed in those questionnaires and reached out to those who were still alive, hoping to find the factors that had led to their long and healthy lives. Thus began the 90+ study, which has since expanded beyond the original 1,600 participants from Leisure World to recruit both cognitively normal and mildly impaired participants.

In addition to extensive lifestyle data, Kawas’ team has amassed one of the biggest brain repositories in the world. They have studied 450 brains to date, from people ranging in age from 90 to 108. About half had dementia, a quarter had mild cognitive impairment, and a quarter were cognitively normal. Autopsy results show that about 60 percent of those who had dementia when they died had plaques and tangles, both signs of Alzheimer’s pathology. But about 40 percent of those who were cognitively normal when they died also had this pathology.

What exactly this means is a point of contention in the field — and an important question for public health. One theory is that the cognitively normal group is somehow resilient, meaning they can weather some level of brain pathology with little or no outward dysfunction. But it’s also possible that these people will develop dementia given enough time. Studies of people with an early-onset, familial form of Alzheimer’s, as well as modeling studies of cross-sectional data, suggest that people accumulate amyloid for an average of 15 years before showing cognitive impairment.

“Many individuals who we think might be resilient might just not have gotten far enough in the disease process,” Kawas says. “Are they normal because they have only had [plaques] for five years, or is it because they are able to withstand it in their brain? I am grappling with it personally. Right now, I’m starting to be a believer.”

Kawas was won over to the idea of resilience in part by a specific case — the surprising autopsy results of a cognitively sharp participant in the 90+ study. “This person was astonishing in terms of scores and thinking ability,” Kawas says. But his autopsy results showed evidence of multiple types of dementia-related pathology, including plaques and tangles, vascular damage and hippocampal sclerosis. “He’s the kind of person who made me believe in the concept of resilience,” she says.

Specialized PET scans can detect signs of amyloid, shown in red and yellow, in the living brain. The brain of a person with Alzheimer's is on the left and the brain of an elderly person with normal memory is on the right. William Klunk/University of Pittsburgh

An answer to the resilience debate may be on the horizon, thanks to the relatively newfound ability to detect plaques and other hallmarks of dementia in the living brain. These pathologies were previously only detectable on autopsy. But almost 20 years ago, researchers developed a way to detect them using PET scans, a development that Kawas calls “one of the most amazing” of her career. In addition to amyloid PET scans, newer techniques, including methods for tracking markers in the cerebrospinal fluid and blood and noninvasive methods for measuring other dementia-related pathologies, such as tau, are giving researchers a new view into what constitutes normal aging.

Given enough time, researchers will be able to determine if everyone with plaques will eventually decline or if some people are truly resilient. “Within the next few years, the data will be pouring in,” Kawas says. “The ability to measure this multiple times during life will give all kinds of information.”

The question of whether some people are truly resilient to plaques has taken on new urgency in the wake of the FDA’s controversial approval of the Alzheimer’s drug Aduhelm. The drug reduces amyloid in the brain, a common approach in the development of new treatments to slow or prevent Alzheimer’s. To speed drug trials and to try to treat the earliest phases of the disease, studies often recruit people who have amyloid markers as measured by PET scans but don’t yet show cognitive impairments. “The idea is that if you have amyloid, your risk of developing dementia is much higher. If we remove amyloid with antibodies, can we change the rate at which they develop Alzheimer’s disease?” Kawas says. “But people who talk about resilience say maybe we’re trying to prevent Alzheimer’s in a resilient population — people with positive amyloid scans and normal cognition.”

The original 90+ study population derived from the Leisure World community was largely white and highly educated, so it’s not yet clear how closely the findings will translate to other ethnic and educational groups. Kawas and collaborators Rachel Whitmer and Maria Corrada are exploring that question in a similar study, the LifeAfter90 study, which focuses on a more diverse population.

An earlier look

A central question regarding brain structure and other differences found in super agers and the oldest old is when exactly their special status arises. Are their brains different from the start, or from middle age? Or do their neurological and cognitive trajectories differ mainly in old age? “It’s unclear at this point if high-functioning oldest old have unique biological mechanisms that support high function in late life, or if they have more generally healthy brains in early life, resulting in greater cognitive reserve later in life,” says David Salat, a neuroscientist at Harvard Medical School in Boston. “In that case, they might follow a typical trajectory of cognitive decline, but it would take longer to become noticeably impaired.”

Take the case of super agers’ superior cingulate. “Are you born with a thick cingulate, did you do something early in life to get a thick one then decline like everyone else, or did you decline more slowly?” Kawas says. Kawas suspects that this quality, like many others, is a combination of genetics and environmental factors. “Just like you might be born into a tall family, and nutrition and other things influence how tall you are,” she says.

From a practical perspective, the most important time points to identify are those that are amenable to intervention. A number of groups are exploring how different factors in midlife, including brain structure and behavior, contribute to later-life resilience. “We need to start thinking about interventions in midlife and late life so we are more cognitively resilient,” says Prashanthi Vemuri, a researcher at the Mayo Clinic in Rochester, Minnesota. “Measuring brain changes earlier tells us what happens later.” Vemuri and collaborators are examining how brain connectivity in middle age contributes to later resilience as part of the Mayo Clinic Study of Aging. “The brain is like a large network of busy cities — we can better maintain connections among cities by taking better care of overall health,” she says.

Vascular damage, as shown in the lighter grey blotches of this MRI scan, increases risk of cognitive impairment. Salat lab

Salat is particularly interested in how changes in vascular health over time contribute to cognitive preservation or impairment and risk of dementia. “One of the reasons we are studying life span starting in the 30s is that we want to understand how these life factors contribute to the late-stage brain, how they influence the individual early on and how they progress in one direction or another,” he says. “In some of our work, factors that we think of as late aging, such as blood pressure and hypertension, seem to influence the brain much earlier than we might have expected.”

As part of the Lifespan Human Connectome Project Aging (HCP-A) Study, Salat and collaborators will examine how blood flow to the brain changes with advancing age and how that affects cognitive function. “We think that changes in blood flow are precursors to lesions that occur in later life that promote decline,” he says. A number of studies suggest that people with both vascular damage and other pathology, such as plaques, are much more likely to be cognitively impaired, Salat says.

Salat is interested in vascular health in part because it’s something people can modify with exercise, medication and other interventions. Vascular damage likely accumulates over decades, and reducing it may have a large impact later in life. A healthy vascular system may be an important factor contributing to high function in very old adults.

Another powerful protective factor acts even earlier in life. Kawas notes that the most consistent influence on cognitive function identified in the 90+ study is education. “For those first 20 years, whatever it did, whatever changes in brain or lifestyle it put in place, it continues to be important; it never goes away.”


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