The BDNF Val66Met polymorphism involves a valine (Val) to methionine (Met) substitution, with the Met allele implicated in phenotypes (poor memory, depressed mood) and endophenotypes (abnormal hippocampal-prefrontal function) of depression. Given a well-established link between stress and depression, we examined whether early life stress moderates the depressogenic and related cognitive effects of BDNF Val66Met in humans and whether hippocampal loss and autonomic dysregulation mediate these effects.
About 374 healthy subjects from the Brain Resource International Database provided data from cheek swabs (for genotyping), cognitive tests, psychometric questionnaires of mood and personality, tonic and phasic measures of autonomic function (average heart rate and variability during resting conditions and during cognitive- and emotion-related tasks) and magnetic resonance imaging.
Path analysis showed that with increasing stress, BDNF Met status predicts direct effects on hippocampal loss and indirect effects on depressed mood and poor cognition (working memory, executive function/processing speed, verbal memory). These effects were mediated by gray matter atrophy, autonomic dys-regulation (raised average heart rate, reduced heart rate variability) and neuroticism.
The findings suggest that the BDNF Met allele carriers may show an increased risk for structural brain deficits and autonomic dysregulation if exposed to at least three or more stressful early life events. Alterations of this nature may consequently predispose such individuals to emotional and cognitive dysfunctions. These findings may have implications for understanding the pathways to psychiatric disorders of cognition and mood, and may provide some guide to the tailoring of treatment according to the patient's genetic/endophenotypic profile.