Not all patients who have Alzheimer’s disease experience a loss of their cognitive abilities, and those who do may experience differing degrees of loss. The biological reasons behind the differences in cognitive function are currently unknown, though researchers recently studied a protein that may play a role early in Alzheimer’s before cognitive decline. Dr. Bruce Yankner, a recipient of both an NIH Director’s Pioneer Award and an NIH Director’s Transformative Research Award, and Dr. Eunjung Alice Lee, an NIH Director’s New Innovator Award recipient, both study changes that occur during aging. The two investigators collaborated on a study of the genetic regulation of Alzheimer’s progression.

The researchers investigated changes in brain cells from aged human patient samples and focused on a protein called RE1-silencing transcription factor, or REST, which controls genetic activity in nerve cells. The research team found that REST was activated in individuals with cellular changes associated with Alzheimer’s who did not yet experience cognitive decline. In the brain cells from patients with Alzheimer’s experiencing dementia, levels of active REST were lower. These findings suggested that REST activity might be important for protecting brain function. In fact, when the researchers removed REST in a mouse model of Alzheimer’s, those mice experienced greater brain cell degeneration and memory loss. In contrast, adding additional REST to brain cells protected the mice from developing cellular symptoms of Alzheimer’s such as accumulation of plaques – a structure characteristic of the disease in humans.  

Overall, the research team’s findings suggest REST is activated in the earliest stages of Alzheimer’s prior to dementia or cognitive decline. In advanced cases with severe cognitive decline, REST appears to be turned off as brain cells accumulate plaques and start to deteriorate. This may mean that activation of REST is an important checkpoint in progression of the disease, which can inform development of new therapies to protect cognitive function in patients with Alzheimer’s.

Reference: Aron L, Qiu C, Ngian ZK, Liang M, Drake D, Choi J, Fernandez MA, Roche P, Bunting EL, Lacey EK, Hamplova SE, Yuan M, Wolfe MS, Bennett DA, Lee EA, Yankner BA. A neurodegeneration checkpoint mediated by REST protects against the onset of Alzheimer's disease. Nat Commun. 2023 Nov 2;14(1):7030. doi: 10.1038/s41467-023-42704-6.