Background <p>The choroid plexus (CP) plays a critical role in maintaining central nervous system (CNS) homeostasis, producing cerebrospinal fluid, and regulating the entry of specific substances into the CNS from blood. CP dysfunction has been implicated in various neurological and psychiatric disorders, including Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis.</p> Methods <p>This study investigates the relationship between CP structural integrity and cognitive decline in normative aging, using structural and advanced magnetic resonance imaging techniques, including CP volume, diffusion tensor imaging indices (mean diffusivity, MD, and fractional anisotropy, FA) and relaxometry metrics (longitudinal, T₁, and transverse, T₂, relaxation times).</p> Results <p>Our results show that lower CP microstructural integrity, as reflected by higher T₁, T₂, and MD values, or lower FA values, is associated with lower cognitive performance in processing speed and fluency. Notably, CP microstructural measures demonstrated greater sensitivity to cognitive decline than macrostructural measures, i.e. CP volume. Longitudinal analysis revealed that individuals with lower CP structural integrity exhibit steeper cognitive decline over time. Furthermore, structural equation modeling revealed that a latent construct representing CP integrity predicts faster overall cognitive decline, with an effect size comparable to that of age.</p> Conclusions <p>These findings highlight the importance of CP integrity in maintaining cognitive health and suggest that a holistic approach to assessing CP integrity could serve as a sensitive biomarker for early detection of cognitive decline. Further research is needed to elucidate the mechanisms underlying the relationship between CP structural integrity and clinical decline and to explore the potential therapeutic implications of targeting CP function to prevent or treat age-related cognitive deficits.</p>