Serotonin transporter polymorphism, memory and hippocampal volume in the elderly: association and interaction with cortisol

Abstract

The s allele variant of the serotonin transporter gene (5-HTT) has recently been observed to moderate the relationship of stress to depression and anxiety. To date no study has considered interactive effects of 5-HTT genotype, stress and hypothalamic-pituitary-adrenal (HPA) function on cognition in healthy, older adults, which may reflect developmental, functional or neurodegenerative effects of the serotonin transporter polymorphism. We investigated whether 5-HTT genotype interacts with cumulative life stress and HPA-axis measures of waking and diurnal cortisol slope to impact cognition in 154 non-depressed, older adults. Structural images of hippocampal volume were acquired on a subsample of 56 participants. The 5-HTT s allele was associated with both significantly lower delayed recall and higher waking cortisol levels. Presence of the s allele interacted with higher waking cortisol to negatively impact memory. We also observed a significant interaction of higher waking cortisol and the s allele on lower hippocampal volume. Smaller hippocampi and higher cortisol were associated with lower delayed recall only in s allele carriers. No impact or interactions of cumulative life stress with 5-HTT or cortisol were observed. This is the first investigation to identify an association of the 5-HTT s allele with poorer memory function in older adults. The interactive effects of the s allele and waking cortisol levels on reduced hippocampal volume and lower memory suggest that the negative effect of the serotonin polymorphism on memory is mediated by the HPA axis. Further, given the significant association of the s allele with higher waking cortisol in our investigation, future studies may be needed to evaluate the impact of the serotonin transporter polymorphism on any neuropsychiatric or behavioral outcome which is influenced by HPA axis function in older adults.

Single Nucleotide Polymorphisms Related to HPA Axis Reactivity

“…Moreover, these subordinate S-allele carriers also showed decreased negative feedback in the 0.25-mg DST. In humans, the S/S genotype was found associated with higher basal morning cortisol levels as compared to l/l genotype in the elderly [59] . Also, effects on basal cortisol levels were observed in a Dutch cohort, with differential effects interacting with risk to develop major depression [60] .…”

HPA Axis Reactivity: A Mechanism Underlying the Associations Among 5-HTTLPR, Stress, and Depression

“…In fact, several lines of evidence now suggest that the serotonin system plays an important role in regulating HPA-axis activity. For example, researchers have now documented involvement of serotonin neurotransmission in both activation and feedback control of the HPA axis (36). More specifically, investigators have demonstrated in animals that serotonin activates the HPA axis by stimulating CRF release, triggering ACTH release, and stimulating corticosteroid secretion (37).…”

Mineralocorticoid Receptor Stimulation Improves Cognitive Function and Decreases Cortisol Secretion in Depressed Patients and Healthy Individuals

“…Memory and executive function are among those domains that are most consistently impaired in depressed patients. Importantly, several groups have found impaired memory and executive function to be associated with elevated cortisol in patients with major depression (Behnken et al, 2013;Gomez et al, 2006;Hinkelmann et al, 2009Hinkelmann et al, , 2013O'Hara et al, 2007) although not all studies concur (Krogh et al, 2012).…”