Brain shape changes could offer early warning signs of dementia

• Study suggests that brain shape can serve as a reliable indicator of its overall health.
• The researchers say their geometric approach could eventually provide new markers for identifying dementia risk
• The National Institute on Aging helped support the research.

Irvine, Calif., Oct. 1, 2025 - A new study led by University of California, Irvine's Center for the Neurobiology of Learning and Memory researchers found that aging changes the brain's overall shape in measurable ways. Instead of focusing only on the size of specific regions, the team used a new analytic method to see how the brain's form shifts and distorts over time.

The analysis revealed substantial alterations in brain shape, which were closely associated with declines in memory, reasoning and other cognitive functions. This suggests that the shape of the brain can serve as a reliable indicator of its overall health.

The study appears in Nature Communications and received support from the National Institute on Aging, a division of the National Institutes of Health.

"Most studies of brain aging focus on how much tissue is lost in different regions," said Niels Janssen, PhD, senior author and professor at Universidad de La Laguna in Spain and visiting faculty at the CNLM. "What we found is that the overall shape of the brain shifts in systematic ways, and those shifts are closely tied to whether someone shows cognitive impairment."

The team analyzed over 2,600 brain scans spanning adults aged 30 to 97. They discovered that the inferior and anterior parts of the brain expanded outward, while the superior and posterior regions contracted inward. This uneven reshaping was particularly evident in older adults experiencing cognitive decline. For instance, individuals with more pronounced posterior compression exhibited poorer reasoning skills, indicating that these geometric markers directly correlate with brain function. Moreover, the patterns were replicated in two independent datasets, reinforcing the consistency of these shape changes as a hallmark of aging.

One striking implication of the study is the potential impact of shape changes with age on the entorhinal cortex, a small but crucial memory hub located in the medial temporal lobe. The study suggests that these shape changes may physically press the vulnerable region closer to the hard base of the skull. Notably, the entorhinal cortex is one of the first places where tau, a toxic protein linked to Alzheimer's disease, accumulates. The team's findings suggest that mechanical and gravitational forces may help explain why this region is so vulnerable to tissue loss in Alzheimer's disease - a possibility not previously considered as a disease mechanism.

"This could help explain why the entorhinal cortex is ground zero of Alzheimer's pathology," said study co-author Michael Yassa, PhD, director of the CNLM and James L. McGaugh Endowed Chair. "If the aging brain is gradually shifting in a way that squeezes this fragile region against a rigid boundary, it may create the perfect storm for damage to take root. Understanding that process gives us a whole new way to think about the mechanisms of Alzheimer's disease and the possibility of early detection."

The researchers say their geometric approach could eventually provide new markers for identifying dementia risk, potentially years before symptoms emerge and is part of the team's larger effort to understand the mechanisms of risks at the earliest stages of the disease.

"This isn't just about measuring brain shrinkage," added Janssen. "It's about seeing how the brain's architecture responds to aging and how that architecture predicts who is more likely to struggle with memory and thinking."

The work was made possible through a collaboration between UC Irvine and the Universidad de La Laguna in Spain, with co-first authors Yuritza Escalante and Jenna Adams, PhD, leading the analysis.

The study underscores the importance of international partnerships in tackling one of the most pressing challenges in public health.

"We're just beginning to unlock how brain geometry shapes disease," said Yassa. "But this research shows that the answers may be hiding in plain sight - in the shape of the brain itself."

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