MicroRNA correlates of resilience to Alzheimer's disease identify candidate therapeutic targets for neuroprotection

Many aged individuals accumulate advanced Alzheimers disease (AD) neuropathology without cognitive decline, signifying potent endogenous resilience mechanisms. Mimicking resilience to AD may offer new therapeutic opportunities by emulating endogenous neuroprotection, but the molecular pathways that underpin resilience remain largely unknown. MicroRNAs (miRNAs)--small noncoding RNA molecules that post-transcriptionally regulate gene expression--influence neuronal and glial processes associated with development, aging, and AD neurodegeneration but their role in resilience has not been characterized. We investigated resilience-associated miRNAs and their targeted programs in the dorsolateral prefrontal cortex of post-mortem human brains. We analyzed matched miRNA and messenger RNA (mRNA) expression across resilient, AD, and control subjects from the Religious Order Study and Memory and Aging Project (ROSMAP) cohort. Nine miRNAs were differentially expressed in resilience compared with AD, including previously unreported miR-362-3p and miR-433-3p and new resilience-associated roles for known AD-related miRNAs, including neuronal miR-132-3p and miR-129-5p. By analyzing miRNA activity across AD progression, we found additional cognitive-associated miRNAs (e.g., miR-335-5p and miR-19b) and one plaque-restricted miRNA (miR-199a-5p). Sex-specific miRNA dysregulation was observed: miR-7-5p showed male-specific upregulation in AD versus resilience and suggested sex-specific differences in AD patients. Integrated co-expression and target-enrichment analyses linked resilience-associated miRNAs to pathways that were associated with cognitive decline, including transforming growth factor {beta}, Rho guanosine triphosphatases, and neurotransmitter receptor regulation. We also report restricted co-activity in AD subjects for miR-362-3p with inflammatory pathways, including tumor necrosis factor and Toll-like receptor signaling. These results demonstrate systematic involvement of miRNAs across neuronal and glial programs of AD resilience, cognitive decline, and sex-specific regulation. Our study provides an important resource for discovery of actionable regulatory programs that could lead to new therapies, based on endogenous molecules, that emulate natural resilience to AD. Key pointsO_LINine distinct cortical microRNA (miRNA) signatures correlate with resilience to Alzheimers disease (AD)-related cognitive decline, pointing to endogenous regulatory programs that may help preserve cognitive function. C_LIO_LIAt the miRNA level, resilient brains show minimal or no detectable differences to healthy individuals, despite the profound pathological differences, supporting the idea that resilience reflects preserved molecular homeostasis rather than a separate disease state. C_LIO_LISome miRNA signatures are specific to a certain pathology (e.g., one linked to amyloid-{beta} plaques independently of tau pathology and cognitive decline), helping to disentangle the regulation of these processes. C_LIO_LISex-specific miRNA dysregulation in AD suggests that resilience-linked pathways may be regulated differently in males and females, reinforcing the value of sex-stratified analyses and the potential for differential therapeutic strategies. C_LIO_LIIntegrative miRNA-pathway analysis highlights candidate regulatory networks involved in inflammation, matrisome, and cellular stress responses, providing a framework for resilience-linked therapeutic targets. C_LI