COGNITIVE HETEROGENEITY AND AGING: AN AGE-INDEPENDENT CILIARY GENE PROGRAM TRACKS COGNITIVE RESILIENCE IN MICE

Abstract

Cognitive decline with age is often viewed as inevitable, yet older animals show striking heterogeneity in functional trajectories, with many preserving cognitive integrity despite physiological decline. The biological basis of this resilience remains poorly understood, partly due to insensitive behavioral testing paradigms. Using an automated home-cage platform and hippocampal RNA sequencing, we integrated behavioral phenotyping with transcriptomic profiling to disentangle molecular programs linked to cognitive performance from chronological age. Behavioral data from 906 C57BL/6 mice across 129 standardized studies, trajectory-based modeling, variance-partitioned correlation, and stability-driven gene prioritization identified a transcriptional signature (271 genes) linked to cognitive state independent of age. Preserved cognition was associated with higher expression of genes governing ciliary structure and motility, neurite organization, and synaptic architecture, while impairment was associated with neuroimmune and metabolic-stress programs. A 38-gene cilia structural module score remained associated with resilience after controlling for age (partial rho = -0.81), with consistent effects across leave-one-out resampling. Because the constituent genes were selected on this same outcome, the module-level magnitude is not an unbiased effect-size estimate; recalibration against a null that reapplies the full selection procedure gave an empirical p of 0.026. This divergence emerged among genetically identical mice, indicating non-genetic, discrete hippocampal molecular signatures underlying individual differences. Cell-type attribution against the Allen Brain Cell Atlas localized the module predominantly to ependymal cells, with 27 of 38 genes ependymal-restricted (median detection 90.2% in ependymal cells versus 1.1% in CA1 glutamatergic neurons) and three genes (Dnah9, Dnai4, Kif9) also detected in CA1. The association was not attributable to ependymal tissue content: the module score was unrelated to Foxj1 expression (rho = -0.016) and the partial correlation was unchanged after adjustment for ependymal and choroid plexus marker panels, indicating that the module reflects how strongly the ciliary program is expressed rather than how many ependymal cells each sample contained. These findings support a conceptual shift: cognitive trajectories appear shaped by intrinsic molecular set points rather than by chronological age, with expression of a motile ciliary program at the cerebrospinal fluid interface, rather than the abundance of the cells carrying it, emerging as a candidate correlate of resilience. This approach offers a generalizable strategy for dissecting functional heterogeneity from aging and identifying pathways for hypothesis-driven tests of resilience across the lifespan.