Aging ADNP syndrome mice exhibit mutation/sex-dependent disruption of motor behavior and circadian rhythmicity

Circadian disruption is an early and clinically relevant feature of Alzheimer's disease and related neurodegenerative conditions, yet the molecular determinants underlying its emergence remain incompletely understood. Activity-dependent neuroprotective protein (ADNP) is a key regulator of neurodevelopment and neuroprotection, with de novo mutations driving the neurodevelopmental ADNP syndrome tauopathy and with somatic mutations implicated in tauopathy and neurodegeneration in Alzheimer's disease, but its role in circadian system function has not been systematically explored. Here, with Alzheimer's disease being twice as prevalent in women, we performed a comprehensive characterization of circadian locomotor activity, explicitly considering sex as a biological variable in aged mouse models of ADNP disruption, representing two key phenotypes of the syndrome. Using recordings of voluntary wheel-running activity combined with cosinor-based rhythmometry, we quantified parameters of circadian organization, including activity levels, timing, and rhythm integrity. We demonstrate that ADNP haploinsufficiency with late tau deposition was associated with impaired circadian organization in a strongly sex-dependent manner. In Adnp +/− mice, circadian alterations diverged between sexes: males exhibited a pronounced reduction in overall activity levels and rhythmic output, whereas females showed alterations in circadian timing (phase shift), and increased waveform complexity, indicative of fragmented activity patterns. Notably, reduced rhythm robustness was observed in both sexes, pointing to impaired stability of circadian output. In contrast to Adnp +/− mice, mice carrying a heterozygous Adnp p.Tyr718* mutation (with early tauopathy) exhibited marked vulnerability only under a circadian challenge paradigm. This was characterized by a high incidence of arrhythmicity based on cosinor-based zero-amplitude testing, with a particularly severe phenotype in a small exploratory cohort of males, in which all examined Tyr718* mice failed to exhibit detectable circadian rhythmicity. Importantly, the study was conducted in aged mice, a context relevant to age-associated neurodegenerative vulnerability. These findings position ADNP as a contributor to circadian system stability and highlight its associated signaling pathways as candidate targets for future mechanistic and therapeutic investigation.