Moving beyond memory metrics for early identification of Alzheimer’s risk

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Forgetting is not always easy. If you have ever tried to erase that annoying earworm from your mind or stop thinking about whether you locked the door after leaving the house, you know how disruptive it can be to think about something irrelevant to the task at hand. While much work in cognitive neuroscience focuses on how the human brain remembers and retains information, some cognitive neuroscientists have instead turned to forgetting – working to track exactly how we forget a piece of information and what it means for patients suffering from neurocognitive disorders. “It may sound surprising that people can control what and how they forget,” says Marie Banich of the University of Colorado, Boulder, who is chairing a session about new research on forgetting at the Cognitive Neuroscience Society (CNS) annual meeting today in San Francisco. “But control over working memory is critical for switching between and re-prioritizing tasks. So in many ways, it is not surprising that we have control over the ability to remove information from the focus of our thoughts.” In new work that Banich and others are presenting, researchers have identified distinct mechanisms by which people remove information from their working memory and have also found that forgetting requires much effort. “We’ve found that intentionally forgetting no-longer-relevant information from the mind is beneficial, but it doesn’t happen automatically,” says Sara Festini of the University of Tampa, who will also be presenting new work at the CNS conference. The hope is that the body of work can lead not only toward better understanding attention and focus but also toward clinical targets for helping patients suffering from disorders ranging from depression and schizophrenia to PTSD and ADHD. Tracking the Loss of a Thought Banich became interested in understanding forgetting after losing someone to suicide. The experience got her thinking about the dangers of intrusive thoughts for people suffering from depression and related disorders. “The content that gets stuck in mind varies across different disorders,” Banich explains. For example people with schizophrenia may be consumed with paranoid thoughts, while those who have obsessive compulsive disorder might be worried about germs, and someone with anxiety may get stuck thinking about bad things that might happen in the future. “But it's the same process,” she says. “The thoughts are going round and round, becoming the focus of attention and difficult to remove.” Complicating the treatment of these disorders is the fact that so many rely on self-reporting of symptoms, and even if a patient reports improvement, they may still be negatively ruminating. That challenge led Banich, a trained cognitive neuroscientist, down a path to answer the question: How can we know whether somebody has really stopped thinking about something? Step by step, Banich and her colleagues have been learning how to track what happens when someone tries to purge a thought from their mind. Their latest work builds upon their past peer-reviewed work that documented three neurologically distinct ways people remove information from their working memory: replacing the thought with something else, suppressing that thought, or clearing their mind of all thoughts. This seemingly simple framework has taken many years of work, with the help of fMRI imaging, machine learning, and other technological and experimental advancements. It started, Banich said, with the realization in the middle of one night that “we can actually use neuroimaging to verify that somebody stopped thinking about something.” Asking participants to think about information in different categories (e.g. faces, places, fruit) while in the fMRI scanner, Banich and her team first trained a computer on the resulting neural patterns for the categories and examples from each. They then asked study participants to forget information in different categories, verifying whether it was removed by tracking whether the brain pattern was still present. They also identified the neural pattern of brain activation associated with each of the three mechanisms of forgetting – whether they replaced the thought of a face like Emma Watson, with an object, like the Golden Gate Bridge, suppressed the memory of Emma Watson, or cleared all thoughts. Through this work, they have identified four brain networks that distinctly activate whether the memory is maintained or purged through one of the three mechanisms: the somatomotor network, the visual network, the default mode network, and the frontoparietal control network. Their work suggests that when the brain suppresses a thought or clears thoughts entirely, the frontoparietal control network likely plays a prominent and distinct role. In identifying these specific brain networks, the research offers a path forward for investigating potential differences among individuals in how they forget. “Can we get some metric of people who might have difficulty controlling their thoughts?” Banich asks. “Maybe the frontoparietal network in people who are having difficulty controlling their thoughts can't differentiate between those mechanisms, or in them they are all muddled together?” In future work, Banich and her colleagues will also be looking at whether they can use biofeedback while participants are in the fMRI scanner to see if that can aid individuals in controlling the mechanism for removing unwanted information. Putting in the Effort to Forget An important part of this work has been looking at “proactive interference,” which can happen when the brain is trying to learn something new that overlaps in category with something already in mind – like trying to learn Emma Stone’s face instead of Emma Watson’s. The takeaway from Banich’s work has been that, in part due to proactive interference, suppressing a thought is more efficient than replacing it. Indeed in work by Sara Festini and colleagues being presented in San Francisco, researchers found that one benefit of voluntarily forgetting a piece of information is that it reduces proactive interference – making it easier for someone to learn something new. “Proactive interference occurs, for example, when you accidentally walk to where you parked your car yesterday instead of where you parked your car today,” Festini says. “We’ve shown that by voluntarily removing information from working memory, it makes the information less susceptible to detrimental forms of memory interference, like false memories and proactive interference.” In Festini’s studies, the researchers, following an established paradigm, direct their participants to forget through explicit instructions that include a “forget cue.” These cues, she says, are not just a contrivance of the lab. In real life, a forget cue may come implicitly when gathering drive-thru orders: if someone changes their order, they might say “Oh, never mind! I don’t want that anymore.” Or in class, an instructor might tell their students to disregard a prior statement, if it was inaccurate or no longer relevant. Evidence from Festini’s lab suggests not only that these forget cues work but that they promote goal-directed removal of information from working memory in a process that is “different—and more beneficial than—simply curtailing processing of information,” she says. “We also have evidence that other attention-demanding tasks can disrupt the efficiency of directed forgetting within working memory.” That makes the process of forgetting effortful and distinct from just discontinuing the processing of the information, echoing some of Banich’s work. In other studies, Festini and her colleagues have found that directed forgetting in older adults is impaired compared to in younger adults, but that explicit forget cues can still help mitigate interference in working memory for both younger and older adults. Although Festini’s team’s research has not specifically examined clinical applications, it suggests that voluntarily removing information from working memory may be more difficult for individuals with major depressive disorder or ADHD, for example. Banich has also speculated about how the body of work could help contribute to understanding and treatment of PTSD, noting that people with PTSD tend to overgeneralize memories (e.g. when a backfiring vehicle may trigger a memory of an explosion). Because the process of forgetting appears to be effortful and best when specifically targeted, those with PTSD could potentially have challenges identifying and then suppressing the specific memory. “There is a paradoxical effect that if you're told to stop thinking about something, you actually have to identify and think about it to suppress it,” she says. Currently, Festini is undertaking a new study on how and when people remove information from working memory that is designated as less valuable or less important, without providing specific “forget” instructions. “I’m curious to understand what the tipping point is to motivate someone to engage in effortful removal of information from working memory,” she says, “since there are clear benefits to the removal of less valuable information, but this removal process is attentionally demanding.” – The symposium “'Stop Thinking About It!': Cognitive and Neural Mechanisms of the Removal and Inhibition of Information in Memory” is taking place at 1:30pmPT on Sunday, March 26, as part of the CNS 2023 annual meeting from March 25-28, 2023 in San Francisco. CNS is committed to the development of mind and brain research aimed at investigating the psychological, computational, and neuroscientific bases of cognition. Since its founding in 1994, the Society has been dedicated to bringing its 2,000 members worldwide the latest research to facilitate public, professional, and scientific discourse.

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Say the words “Alzheimer’s disease” and the next word that most readily comes to mind is likely “memory.” Indeed, one of the most devastating effects of Alzheimer’s disease is the toll that it takes on a person’s memory. Long before declines in memory capabilities, however, brain changes happen as early as midlife, in some cases decades earlier than a diagnosis of dementia due to Alzheimer’s. The work of cognitive neuroscientists to identify these midlife changes points the way to new diagnostics and interventions, as presented today at the annual meeting of the Cognitive Neuroscience Society (CNS) in San Francisco.

“The pathological process in Alzheimer’s begins decades before the onset of dementia,” says William Kremen of the University of California, San Diego. “The earlier we can identify people at risk, the better chance we will have of intervening to slow the disease process.”

Kremen’s work showing how a decline in executive function in midlife is predictive of Alzheimer’s disease later in life is just one finding that is being presented at the CNS meeting today in a symposium on cognitive and brain aging. Anja Soldan and Corinne Pettigrew, both of Johns Hopkins University, organized the symposium to showcase research to better understand how to differentiate “normal” cognitive aging from disease-related cognitive aging.

“We now know that many age-related disorders, including Alzheimer’s disease and cerebrovascular disease, have a so-called preclinical phase that precedes the emergence of clinical symptoms by many years,” Soldan says. “This makes it really difficult to say whether age-related cognitive changes reflect ‘normal’ age-related changes, or early disease-related changes. Understanding cognitive aging really requires a lifecourse approach, but that’s very difficult to accomplish.”

New digital health technologies and biomarker work, coupled with large-scale longitudinal studies, however, are shedding more light on the brain changes associated with Alzheimer’s and other neurodegenerative diseases earlier in life.

An Eye Toward Executive Function

Kremen first became interested in understanding the aging brain when conducting studies of cognition in twins. “One afternoon, a couple of colleagues and I were brainstorming about next steps in our research,” he recalls. “We realized that if we studied this twin sample systematically over time, we could have a really interesting and valuable study of cognitive and brain aging. I am now very interested in the tremendous growth of genetics research so that we can better understand what genetic and environmental factors influence normal and pathological cognitive and brain aging.”

In his latest work with Rongxiang Tang and Daniel Gustavson, Kremen sought to link cognition, brain, and genetics. Looking at genetic data from 1168 individuals and MRI data from 267 individuals ranging in age from 51 to 73 across 12 years, they found that executive function is a important area of study in understanding age-related brain change in those with Alzheimer’s

“In Alzheimer’s disease, the focus is predominantly on memory, but we wanted to highlight the fact that executive function is also important,” he explains. “Executive function is important for many aspects of daily living since it involves planning and anticipation, organization, being able to shift appropriately from one task or topic to another, and inhibiting irrelevant thoughts or stimuli so that a person can focus on the task at hand.

In as-yet unpublished work, Tang and colleagues identified a “modal controllability network” that underlies both executive function in midlife as well as changes in executive function later in life. “Modal controllability refers to the ability of brain regions to facilitate distant and effortful transitions to difficult-to-reach states, which is kind of what executive function is about,” Kremen explains. “Changes in network controllability may be a key mechanism underlying aging-related decline in executive function.”

They also found that poorer executive function was associated with higher genetic risk scores of Alzheimer’ disease, which built on prior work showing that poorer executive function was associated with increased risk of progression to mild cognitive impairment (MCI), which can be a precursor  to Alzheimer’s. Altogether, this and prior work suggest, Kremen says, that “executive function in midlife is predictive of progression” to Alzheimer’s disease.

Kremen and his team want to continue to study the brain and genetic factors associated with Alzheimer’s disease with the same cohort of participants as they continue to age. The goal, he says, is early identification, and he believes the combination of genetics and cognition research shows a promising path forward.

Identifying Biomarkers for Early Detection

Corinne Pettigrew became interested in the aging brain when working with stroke patients in graduate school. She now works to understand cognitive changes and biomarkers in older adults who are at risk for Alzheimer’s disease and other cognitive disorders.

At the CNS meeting, Pettigrew will be presenting results from the BIOCARD Study, a  longitudinal study that began in 1995, enrolling some 350 primarily middle-aged adults. “Because the study is still ongoing, many of these generous volunteers have now been followed for more than 20 years,” Pettigrew says. “Thanks to their dedication, we are in a relatively unique position to examine how midlife risk and protective factors and brain changes impact later life cognitive outcomes, including cognitive impairment and dementia.”

One of the core findings from Pettigrew’s research so far is that some of the brain changes underlying Alzheimer’s disease begin in midlife. “Midlife may therefore be a very important time to intervene, for delaying or preventing the future cognitive decline or symptoms of dementia,” she says.

In a 2020 study published in Neurology, for example, Pettigrew, Soldan, and colleagues reported on the how vascular risk scores (looking at factors such as hypertension, cholesterol levels, diabetes, and smoking, for example) and amyloid-β and tau protein biomarkers (associated with Alzheimer’s disease) from midlife correlated with cognitive change. They found that the vascular risks and Alzheimer’s biomarkers were each independently associated with cognitive decline over approximately 14 years.

“Our biomarker findings suggest that Azheimer’s disease-related brain changes are evident in midlife or earlier, particularly among individuals at greatest risk of progressing to mild cognitive impairment or dementia,” Pettigrew says. Although effective treatments do not yet exist for dementia, it is becoming increasingly clear, Pettigrew says, that protecting brain and vascular health throughout and lifespan, including by staying cognitively and physically active, are critical for reducing the risk of cognitive decline, even among those at increased genetic risk for dementia.

Indeed, says Soldan: “I think this symposium very nicely illustrates the fact that cognitive aging trajectories are influenced by a large number of factors and that there might be things we can do – such as physical activity and managing vascular risks, like blood pressure and cholesterol – to stay on a more positive trajectory.”

Soldan sees an exciting future for the integration of digital technology into the study of brain and cognitive aging. “This includes various smart devices that people can wear at home while they go about their normal life that allows researchers to learn about their sleep-wake cycles, physical activity levels, heart rate, blood pressure, etc., which are related to brain and cognitive health,” she says. “This may allow us to reach a wider and more diverse population.”

She is also excited by the progress being made in developing blood-based biomarkers for Alzheimer’s disease and other conditions. “In the not so far future, this might allow us to detect early Alzheimer’s disease during routine clinical care, which could help with developing more effective interventions for cognitive decline.

The symposium “Cognitive and Brain Aging: New Insights from Biomarkers, Lifestyle Factors, and Genetics” is taking place at 1:30pm PT on Sunday, April 24, as part of the CNS 2022 annual meeting from April 23-26, 2022. CNS is committed to the development of mind and brain research aimed at investigating the psychological, computational, and neuroscientific bases of cognition. Since its founding in 1994, the Society has been dedicated to bringing its 2,000 members worldwide the latest research to facilitate public, professional, and scientific discourse.


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