Follow PsyPost on Google News
New research published in Alzheimer’s Research & Therapy suggests that small shifts in how the brain processes information could serve as early warning signs of Alzheimer’s disease, even in people who still appear cognitively healthy. In a group of older African American adults with no signs of dementia, the study found that higher levels of a blood-based biomarker were linked to both reduced flexibility in how memory-related brain regions work together and lower scores on a task measuring generalization—the ability to apply what one has learned to new situations. These results point to the potential of combining non-invasive brain imaging, cognitive testing, and blood tests to detect Alzheimer’s risk before traditional memory tests pick up a problem.
Alzheimer’s disease is a progressive condition that causes brain cells to die, gradually impairing memory and thinking. It is believed to start long before noticeable symptoms appear, with the accumulation of abnormal proteins like amyloid-beta plaques and tau tangles in areas of the brain such as the medial temporal lobe, which supports memory. These changes eventually lead to structural damage, functional disruptions, and cognitive decline.
Older African American adults face a disproportionately high risk of developing Alzheimer’s, yet they remain underrepresented in research and clinical trials. This underrepresentation stems in part from limited access to healthcare and the perception that some research tools—like brain scans that require radioactive tracers—are too invasive. Blood-based tests are far less burdensome and offer an appealing alternative for identifying individuals at risk.
“Alzheimer’s disease is a progressive neurodegenerative disorder that begins affecting the brain years—if not decades—before clinical symptoms emerge,” said study author Miray Budak, a postdoctoral associate at the Aging & Brain Health Alliance at Rutgers University–Newark.
“We are particularly interested in identifying early neural and blood-based biomarkers that could help detect Alzheimer’s in its preclinical stage, especially in African American individuals, who are at higher risk for the disease yet remain underrepresented in research. By combining novel cognitive assessments, neuroimaging, and blood biomarkers, our study provides a more comprehensive understanding of early Alzheimer ’s-related changes, which could inform prevention efforts and improve early detection.”
To better understand the early signs of Alzheimer’s in this underrepresented group, the researchers studied 148 African American adults over age 60 who showed no signs of dementia based on standard screenings. All participants had normal scores on the Mini-Mental State Examination and had not been diagnosed with a neurodegenerative condition. The researchers assessed each person’s memory using a traditional verbal recall task and evaluated their generalization ability using a specially designed video-based game.
Participants also gave blood samples that were analyzed for three Alzheimer’s-related biomarkers: p-tau231, p-tau181, and the ratio of two forms of amyloid-beta (Aβ42 and Aβ40). Within two weeks of testing, they underwent an MRI scan to examine how flexibly their medial temporal lobe networks changed over time.
To measure generalization, the researchers used a computerized game called the Rutgers Acquired Equivalence Task. In this game, participants learn a series of face-to-fish pairings across several stages and are later asked to apply what they’ve learned to new, untrained pairings. This kind of flexible thinking, or generalization, is often supported by the medial temporal lobe.
In contrast, long-term memory was measured using a more traditional tool, the Rey Auditory Verbal Learning Test, where participants are asked to recall a list of words after a delay. Resting-state brain scans were analyzed to measure dynamic network flexibility in the medial temporal lobe—a marker of how well that region adapts over time and supports learning.
The researchers found that participants who performed better on the generalization task had greater flexibility in their medial temporal lobe networks. This suggests that a brain that can shift and reorganize connections may better support flexible thinking. In contrast, performance on the verbal recall task did not show a link to network flexibility, highlighting the possibility that these tasks measure different cognitive processes.
Next, the team explored how blood biomarkers were related to these cognitive and brain measures. Higher levels of plasma p-tau231—a protein fragment associated with tau tangles in the brain—were strongly linked to worse generalization performance and reduced network flexibility in the medial temporal lobe. A second tau marker, p-tau181, was also associated with lower generalization scores, though the effect was weaker and not related to network flexibility.
“One of the most striking findings was that generalization performance, a relatively simple cognitive ability assessed via a video-based task, was linked to both medial temporal lobe network flexibility and plasma p-tau231 levels,” Budak told PsyPost. “This suggests that everyday cognitive processes, such as applying learned information to new situations, could be subtly impacted in individuals at risk for Alzheimer’s even before clinical symptoms develop. It also highlights the potential of using computerized cognitive tasks for early screening.”
None of the blood biomarkers were linked to performance on the verbal memory task, nor did levels of amyloid-beta (as measured by the Aβ42/Aβ40 ratio) predict any of the cognitive or brain measures.
Together, these findings suggest that tau-related changes, particularly involving p-tau231, may interfere with how flexibly the memory system functions and how well people can apply past learning in new contexts—long before memory loss becomes obvious. These results build on earlier work showing that generalization ability declines with age and may be particularly sensitive to early Alzheimer’s-related changes in the brain.
“The key takeaway is that subtle changes in brain function and cognition can be detected long before noticeable memory problems emerge,” Budak explained. “We found that higher levels of plasma p-tau231—an emerging blood biomarker for Alzheimer’s—are associated with reduced medial temporal lobe network flexibility and difficulties in cognitive generalization (applying the learned information on new situations), even in cognitively healthy older adults.”
“This means that non-invasive tools, such as video-based cognitive tasks and MRI-based network measures, could complement blood-based biomarkers in identifying individuals at risk for Alzheimer’s much earlier than traditional cognitive tests.”
But as with all research, there are some limitations. While the study focused on a group at high risk, it did not follow participants over time, so it remains unclear whether the observed differences in brain function and cognition will lead to future memory decline. Longitudinal studies will be needed to determine how early these changes appear and whether they predict who eventually develops Alzheimer’s.
“One important consideration is that our study focused exclusively on cognitively unimpaired older African Americans,” Budak noted. “While this is a strength in terms of addressing disparities in Alzheimer’s research, future studies should examine whether these findings generalize to other racial and ethnic groups. Additionally, although we observed significant associations, this was a cross-sectional study, so we cannot yet determine causality.”
“Our long-term goal is to refine and integrate multi-modal biomarkers—spanning cognitive, neuroimaging, and blood-based measures—to improve early detection and intervention strategies for Alzheimer’s disease, particularly in at-risk populations. We aim to investigate how genetics and other blood-based biomarkers influence MTL network flexibility and cognitive function in preclinical Alzheimer’s. By understanding these early neural changes, we can develop more effective and accessible screening tools to guide personalized interventions.”
The study adds to a growing body of research showing that subtle disruptions in how the brain processes and adapts information—especially in the medial temporal lobe—may be one of the earliest signs of Alzheimer’s.
“Our study underscores the importance of early detection and highlights the potential of non-invasive screening methods, including cognitive assessments that do not rely on traditional memory tests,” Budak said. “As Alzheimer’s research progresses, integrating blood biomarkers with cognitive and imaging-based tools may provide a more accurate and comprehensive picture of who is at risk and when interventions should begin.”
The study, “Elevated plasma p-tau231 is associated with reduced generalization and medial temporal lobe dynamic network flexibility among healthy older African Americans,” was authored by Miray Budak, Bernadette A. Fausto, Zuzanna Osiecka, Mustafa Sheikh, Robert Perna, Nicholas Ashton, Kaj Blennow, Henrik Zetterberg, Patricia Fitzgerald-Bocarsly, and Mark A. Gluck.