Cortisol awakening response and Val66Met BDNF polymorphism interact to shape verbal fluency in aging

Neural plasticity is central for cognitive functioning. Across the lifespan, age-related changes in neural plasticity are particularly evident in higher-order cognitive abilities. Among these, verbal fluency (VF) is considered a sensitive marker of cognitive aging, as it reflects the efficient function of both language and executive control systems. VF is commonly differentiated into two subdomains: phonemic verbal fluency (PVF), which depends on executive functions and prefrontal cortex activity, and semantic verbal fluency (SVF), which relies more strongly on lexical-semantic networks and associative retrieval processes. Neural plasticity is influenced by both neurotrophic and neuroendocrine mechanisms. Thus, on the one hand, the Brain-Derived Neurotrophic Factor (BDNF) Val66Met polymorphism modulates synaptic plasticity, with the Met allele being associated with reduced BDNF secretion and greater cognitive vulnerability. On the other hand, the Cortisol Awakening Response (CAR) has been linked to prefrontal efficiency and executive control. This study examined the interaction between CAR and the BDNF Val66Met polymorphism in relation to PVF and SVF in healthy older adults. Results showed a significant moderating effect of the BDNF Val66Met polymorphism in the CAR-PVF relationship: greater CAR was associated with better performance only in Val-homozygous participants. No significant associations were found for SVF. These findings highlight how cognitive aging is shaped by a complex interplay between genetic and hormonal factors controlling endocrine and neurotrophin functions.