Changes in brain shape could be early signs of cognitive decline

Getting older doesn’t only thin parts of the brain. It also subtly warps the brain’s overall form. Those geometric shifts, it turns out, track closely with dips in memory, reasoning, and other thinking skills – making shape a promising window into brain health.

In new work led by researchers at the Center for the Neurobiology of Learning and Memory (CNLM), at the University of California, Irvine, scientists mapped how the brain’s form distorts across adulthood and late life, then tied those deformations to cognition.

The study shifts attention from “how much” tissue is lost to “how” the brain’s architecture changes – and why that might matter for diseases like Alzheimer’s.

New angles on brain aging

“Most studies of brain aging focus on how much tissue is lost in different regions,” said senior author Niels Janssen, a professor at Universidad de La Laguna in Spain.

“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.”

Rather than measuring only regional volume, the team applied a geometric analysis to more than 2,600 MRI scans from adults ages 30 to 97. They asked a simple but powerful question: When the brain ages, which parts tend to push outward, and which tend to sink inward?

Shape shifts mirror cognition

A clear pattern emerged. The inferior and anterior portions of the brain tended to bulge outward. The superior and posterior regions tended to compress inward.

That tug-of-war wasn’t random. People with stronger “posterior squeeze,” for example, performed worse on reasoning tasks. The pattern was robust. It replicated in two independent datasets, suggesting a consistent signature of aging rather than noise in a single cohort.

These findings suggest that the way the brain’s envelope deforms appears to mirror how well the brain still thinks.

Brain shape and Alzheimer’s risk

One small region drew special attention: the entorhinal cortex. It sits in the medial temporal lobe and serves as a crucial hub for memory. It is also one of the first sites where tau – a toxic, misfolded protein tied to Alzheimer’s – takes hold.

The shifting shape of the brain may nudge the entorhinal cortex closer to the skull’s rigid base, leaving it more vulnerable.

“This could help explain why the entorhinal cortex is ground zero of Alzheimer’s pathology,” said study co-author Michael Yassa, the director of the CNLM.

“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.”

That idea doesn’t replace molecular causes – it adds physical context. Mechanical and gravitational forces could help set the stage for where degeneration starts and why it spreads the way it does.

Geometric clues to dementia

Because the shape signatures were tied to real-world cognition, the team sees potential for simple, geometric markers that flag dementia risk years before symptoms blossom. That fits a broader push to detect Alzheimer’s at its earliest, most actionable phase.

“This isn’t just about measuring brain shrinkage,” Janssen said. “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.”

If validated in larger and more diverse cohorts, shape metrics could slot alongside familiar measures like hippocampal volume, amyloid and tau PET, or blood-based biomarkers. These combined tools could sharpen risk profiling and help track response to interventions.

Tracking shifts across lifespan

The researchers pooled scans across the adult lifespan and applied a standardized pipeline to capture whole-brain deformation patterns. They then linked those geometric readouts to performance on memory and reasoning tests.

The topography wasn’t uniform. It varied in degree from person to person. But the directions of change – outward in some regions, inward in others – were strikingly consistent, and the strongest deformations lined up with worse cognition.

The replication across two independent datasets strengthens confidence that these deformations reflect a general feature of aging, not an artifact of a single sample or scanner.

Future directions in brain aging

If brain shape carries risk information, it invites new kinds of questions. Can lifestyle changes – sleep, exercise, blood pressure control – slow harmful deformations?

Do certain medications shift the geometry in protective ways? Could head posture, balance issues, or subtle changes in cerebrospinal fluid dynamics amplify mechanical stress on vulnerable regions?

Those are testable ideas. For now, the main takeaway is clarity. The aging brain doesn’t just get smaller. It changes form – and those contours appear to matter.

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

The study was published in Nature Communications with support from the National Institute on Aging.

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