Psychological Resilience in Adolescence as a function of Genetic Risk for Major Depressive Disorder and Alzheimer’s Disease

Abstract Major Depressive Disorder (MDD) and Alzheimer’s Disease (AD) are two pathologies linked to prior stress exposure and altered neurodevelopmental trajectories. As a putative antecedent to AD, MDD could be key to understanding the neurobiological changes that precede the clinical onset of AD by decades. To test this hypothesis, we used longitudinal data from the Adolescent Brain and Cognitive Development study (N total = 980, 470 females) and investigated overlapping connectomic, transcriptomic, and chemoarchitectural correlates of adjustment to stressors (i.e., resilience) among adolescents at genetic risk for AD and MDD, respectively. The potential for perinatal adversity to directly and/or indirectly, via accelerated biological ageing, foster resilience (i.e., “inoculation” effects) was also probed. We identified two distinguishable neurodevelopmental profiles predictive of resilience among MDD-vulnerable adolescents. One profile, expressed among the fastest developing youth, overlapped with areas of greater dopamine receptor density and reflected the maturational refinement of the inhibitory control architecture. The second profile distinguished resilient MDD-prone youth from psychologically vulnerable adolescents genetically predisposed towards AD. This profile, associated with elevated GABA, relative to glutamate, receptor density, captured the longitudinal refinement and increasing context specificity of incentive-related brain activations. Its transcriptomic signature implied that poorer resilience among AD-prone youth may be associated with greater expression of MDD-relevant genes. Our findings are compatible with the proposed role of MDD as a precursor to AD and underscore the pivotal contribution of incentive processing to this relationship. They further speak to the key neuromodulatory role of DA-gonadal hormone interactions in fostering resilience in adolescence. Significance Statement Environmental stressors can substantially alter brain maturation and incur lifelong costs. Using longitudinal data, we characterise two developmental profiles correlated with positive adjustment to environmental challenges (i.e., resilience) among adolescents at genetic risk for two stress-related conditions, Alzheimer’s Disease (AD) and Major Depressive Disorder (MDD), respectively. One dopamine-related profile typified the fastest developing MDD-prone adolescents and reflected the neural maturation of the inhibitory control architecture. The second profile, neurochemically linked to excitation/inhibition balance, indicated the developmental refinement of motivational pathways, distinguishing resilient MDD-prone from psychologically vulnerable AD-prone teens. Its transcriptomic signature supported the posited role of MDD as an antecedent to AD. Our results unveil candidate neurobiological mechanisms supporting lifespan resilience against both psychiatric and neurological conditions linked to stress exposure.