HMN 2026: Why some brains with Alzheimer’s stay sharp

Researchers at the University of California San Diego have uncovered new insights into one of Alzheimer’s disease’s most puzzling questions: why some older adults remain mentally sharp despite having hallmark brain changes linked to the disease. This condition—known as asymptomatic Alzheimer’s disease (AsymAD )—has long been observed but poorly understood. Decoding this natural resilience could pave the way for earlier detection and new strategies to prevent memory loss before symptoms begin. The work is published in the journal Acta Neuropathologica Communications.

“Even when the brain shows clear signs of Alzheimer’s, some people stay mentally sharp,” said co-senior author Sushil K. Mahata, Ph.D., adjunct professor of medicine at UC San Diego School of Medicine and research physiologist at the VA San Diego Healthcare System. “We’re beginning to uncover the brain’s built-in defenses—and that could fundamentally change how we approach treatment.”

More than seven million Americans are currently living with Alzheimer’s disease. However, an estimated 20–30% of individuals with Alzheimer’s-related brain pathology remain asymptomatic, maintaining normal cognition despite the presence of amyloid plaques and neurofibrillary tangles in the brain.

To investigate this phenomenon, UC San Diego researchers analyzed gene expression across thousands of human brain samples. Using an advanced artificial intelligence-based framework developed by co-senior author Debashis Sahoo, Ph.D., associate professor of pediatrics and computer science at UC San Diego, the team identified consistent molecular patterns linked to disease progression—and protection—across multiple independent datasets.

Key findings:

• Researchers identified a distinct gene expression “fingerprint” that clearly separates normal aging, symptomatic Alzheimer’s, and asymptomatic Alzheimer’s.
• These molecular signatures were reproducible across multiple human cohorts, strengthening their potential for clinical translation.
• Brains that remained cognitively intact despite Alzheimer’s-related changes showed a protective gene pattern, with lower activity in genes linked to the buildup of tau—a protein that can form damaging tangles in Alzheimer’s disease—and higher activity in cellular stress-response systems
• A protein called Chromogranin A (CgA) emerged as a potential molecular switch that may determine whether Alzheimer’s-like brain changes lead to memory loss.
• In mouse studies, removal of CgA protected against Alzheimer’s-related damage. This protective effect was even stronger in females, who also showed reduced Tau accumulation.

Together, these findings identify CgA-centered stress-response pathways as key drivers of cognitive resilience. The study also introduces a powerful combined computational and experimental framework to accelerate the discovery of preventive therapies for Alzheimer’s disease.

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