REVIEW article
Front. Mol. Neurosci.
Sec. Neuroplasticity and Development
Volume 18 - 2025 | doi: 10.3389/fnmol.2025.1665802
This article is part of the Research TopicMolecular neuroscience of cognitive resilienceView all 5 articles
The Transcriptional and Cellular Landscape of Cognitive Resilience to Alzheimer's Disease
Provisionally accepted
- 1Harvard College, Cambridge, United States
- 2Massachusetts Institute of Technology The Picower Institute for Learning and Memory, Cambridge, United States
- 3Boston Children's Hospital Research Administration, Boston, United States
- 4Broad Institute, Cambridge, United States
- 5The Scripps Research Institute, San Diego, United States
- 6University of California San Diego, La Jolla, United States
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It is estimated that 5-40% of patients with pathological features of Alzheimer's disease (AD) maintain normal cognitive health throughout their lifetimes, a phenomenon known as cognitive resilience. Studies have identified many factors that contribute to a patient's capacity for resilience, with those that modulate gene expression being the most dynamic, adaptable, and potentially addressable as targets for future drug development. In patients cognitively resilient to AD and AD-related dementias (ADRD), transcriptional changes within specific cell types serve to preserve the processes most critical to cognitive function within each cell, exerting protective effects on other cell types as well via non-cell autonomous effects. Key themes in preserved cognitive function include maintenance of synaptic stability and function, dampening neuronal hyperexcitability, reducing misfolded protein accumulation, increasing myelination, and countering neuroinflammation. With future research on the most upstream and impactful transcriptional drivers, there lies immense potential for both therapeutics to address AD and a greater fundamental understanding of AD and the brain.
Keywords: Cognitive resilience, Alzheimer's disease, transcription factor, MEF2C, Nrf2, REST (RE-1 silencing transcription factor)
Received: 14 Jul 2025; Accepted: 14 Oct 2025.
Copyright: © 2025 Khera, Raju and Lipton. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Ravikiran M Raju, ravikiran.raju@childrens.harvard.edu
Stuart A. Lipton, slipton@scripps.edu
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