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Tiny, shallow grooves on the surface of the brain may provide new insight into how aging and Alzheimer’s disease affect brain structure and cognitive function. A new study published in The Journal of Neuroscience found that these small indentations, known as tertiary sulci, show more pronounced thinning in older adults and individuals with Alzheimer’s disease than deeper, more prominent brain folds. Importantly, thinning in some of these sulci was closely linked to declines in memory and executive functioning.
Alzheimer’s disease is a neurodegenerative disorder marked by progressive memory loss and cognitive impairment, typically beginning in older adulthood. Researchers have long sought to understand the specific brain changes that underlie this decline. One area of interest is the cerebral cortex, the brain’s outer layer, which has a complex surface pattern made up of ridges (gyri) and grooves (sulci). These features are not just structural; they also relate to brain function and development. While larger sulci have been studied extensively in relation to aging and Alzheimer’s, smaller and more variable sulci have been largely ignored—until now.
The new study focused on these smaller grooves in a brain region known as the posteromedial cortex, or PMC. This area includes parts of the precuneus and the posterior cingulate, and it plays a key role in memory and other cognitive processes. It is also among the first brain regions affected by the buildup of amyloid and tau proteins, which are hallmarks of Alzheimer’s disease.
The research team, led by scientists at the University of California, Berkeley, used high-resolution brain scans to examine the sulci of 216 adults. The sample included 72 younger adults between the ages of 22 and 36, 72 cognitively healthy older adults aged 65 to 90, and 72 older adults with Alzheimer’s disease who were matched in age to the healthy older group. All participants underwent detailed structural brain imaging using magnetic resonance imaging, along with assessments of memory and executive functioning.
Unlike typical studies that rely on automated brain mapping, the researchers manually identified and labeled more than 4,000 sulci across the participants’ brain scans. This process was especially important because the smaller sulci, which the study targeted, often do not appear in average brain templates or automated maps. Each sulcus was labeled by trained experts using specialized software and reference atlases. The team focused on 12 specific sulci in the PMC, some of which were newly identified in recent years and not included in standard anatomical databases.
To measure changes in brain structure, the researchers calculated the thickness and depth of each sulcus. They then compared these measurements across the three participant groups. The data showed clear evidence of cortical thinning with age and disease, with the most dramatic changes found in the smallest and shallowest sulci. For example, two sulci known as the inframarginal sulcus (ifrms) and the ventral subsplenial sulcus (sspls-v) exhibited more pronounced thinning than any of the larger, deeper sulci. These findings were consistent across both hemispheres of the brain, although the right hemisphere showed slightly stronger effects in some comparisons.
Not only did these smaller sulci show greater atrophy, but their structural integrity was also more closely tied to cognitive performance. Using statistical models that could identify the most important predictors of memory and executive function, the researchers found that thinning in a handful of these sulci—particularly in the right hemisphere—was strongly associated with lower scores. These included both the newly described ifrms and sspls-v sulci, as well as some larger, more established grooves. The relationships were specific to cortical thickness; sulcal depth did not predict cognitive performance as strongly.
The results support an idea known as the retrogenesis hypothesis, which suggests that brain areas that develop later in life are also the first to decline in aging and disease. Because tertiary sulci are among the last to emerge during brain development and are found primarily in regions associated with higher-order thinking, they may be especially vulnerable to degeneration. Their involvement in cognition and their structural variability across individuals also make them compelling targets for future research into personalized risk and resilience factors in Alzheimer’s disease.
The study’s authors also note that their individual-level, high-resolution approach stands in contrast to many past studies, which rely on group-level brain averages that can obscure subtle but meaningful differences. By manually labeling sulci in each participant’s brain, the team was able to detect anatomical variations that might otherwise go unnoticed. This focus on individual variability could help explain why cognitive decline progresses differently across people, even among those with similar diagnoses.
The study provides evidence linking tertiary sulcal atrophy to cognitive decline, but there are some limitations. Because the sulci were manually labeled, the process was labor-intensive and limited the sample size compared to large-scale imaging studies. The findings are also based on cross-sectional data, meaning that each participant was studied at a single point in time. Longitudinal research will be needed to confirm how these sulci change over the course of aging and Alzheimer’s progression.
Another open question is why these small sulci are especially vulnerable. Some researchers speculate that their location in brain areas rich in long-range connections makes them more susceptible to degeneration, while others point to their thin cortical structure or their proximity to early sites of protein buildup. Future studies using postmortem data or advanced imaging techniques may help clarify these mechanisms.
The study, “Defining Overlooked Structures Reveals New Associations between the Cortex and Cognition in Aging and Alzheimer’s Disease,” was authored by Samira A. Maboudian, Ethan H. Willbrand, Joseph P. Kelly, William J. Jagust, Kevin S. Weiner and for the Alzheimer’s Disease Neuroimaging Initiative.
