Some brains carry the classic marks of Alzheimer’s disease, but their owners never lose memory or thinking skills. A new study from the University of California, San Diego suggests one protein may help explain why.
Researchers focused on asymptomatic Alzheimer’s disease, or ASYMAD, a condition thought to affect about 20 to 30 percent of older adults based on postmortem brain research. These people have the buildup of misfolded amyloid-beta and tau proteins linked to Alzheimer’s, but no harmful mental effects.
“Even when the brain shows clear signs of Alzheimer’s, some people stay mentally sharp,” UCSD medical scientist Sushil Mahata said.
In the new study, Mahata and colleagues used an AI-powered scanning technique on genetic data from thousands of postmortem human brain samples from people who died with and without Alzheimer’s disease. That gave them about 40 genes that together formed what they called a fingerprint of Alzheimer’s.
The team then used that fingerprint to study healthy lab mice and mice bred to develop Alzheimer’s-like brain pathology. The mouse tests showed the fingerprint could tell the groups apart, but also pointed to a protein called chromogranin A, or CgA, as a key driver in the gene network.
When the researchers bred mice that lacked CgA, the animals still developed the biological hallmarks of Alzheimer’s, but not the symptoms.
CgA is involved in brain cell communication and has previously been suspected of influencing Alzheimer’s progression. The researchers said the new findings suggest it may play an important part in asymptomatic Alzheimer’s.
The study also found a difference between male and female mice. Male mice without CgA matched the genetic patterns of Alzheimer’s disease without any memory or learning problems. Female mice without CgA showed even fewer signs of Alzheimer’s-related brain damage.
The reason for that difference is not clear. The researchers said it may be related to sex differences in hormones, immune systems or genetics, and said it is an area for future studies.
“This work establishes a mechanistically grounded framework for studying cognitive resilience in Alzheimer’s disease and provides a scalable platform for interrogating sex-specific protective pathways, identifying early biomarkers of disease trajectory, and enabling mechanism-guided development of preventive therapeutic strategies,” the researchers wrote in their paper.
The team said it is still not known exactly why CgA matters so much. Based on previous work, they think it may act as a “molecular amplifier” of toxic proteins in the brain, and that removing or limiting it could protect against cognitive decline.
The researchers also noted that some study authors are invested in a company researching CgA in relation to Alzheimer’s. Mahata is listed as a founder of CgA Therapeuticals.
Any treatment aimed at regulating CgA is still a long way off, and would need to allow the protein’s normal functions to continue.
“Collectively, these findings support a paradigm in which understanding and harnessing endogenous resilience mechanisms may represent a critical path forward for altering the course of Alzheimer’s disease,” the team wrote.
“We’re beginning to uncover the brain’s built-in defenses,” Mahata said. “And that could fundamentally change how we approach treatment.”
The research was published in Acta Neuropathologica Communications.
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