Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.

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The effect of life stress on depression is moderated by a repeat length variation in the transcriptional control region of the serotonin transporter gene, which renders carriers of the short variant vulnerable for depression. We investigated the underlying neural mechanisms of these epigenetic processes in individuals with no history of psychopathology by using multimodal magnetic resonance-based imaging (functional, perfusion, and structural), genotyping, and self-reported life stress and rumination. Based on functional MRI and perfusion data, we found support for a model by which life stress interacts with the effect of serotonin transporter genotype on amygdala and hippocampal resting activation, two regions involved in depression and stress. Life stress also differentially affected, as a function of serotonin transporter genotype, functional connectivity of the amygdala and hippocampus with a wide network of other regions, as well as gray matter structural features, and affected individuals' level of rumination. These interactions may constitute a neural mechanism for epigenetic vulnerability toward, or protection against, depression.amygdala ͉ emotion ͉ environment ͉ gene ͉ hippocampus A dverse life events can reveal profound interindividual differences, rousing resilience in some and exposing susceptibility to mood disorders, including depression, in others. Diathesis-stress models have sought to explain these individual differences in terms of genetic predispositions interacting with environmental factors (1). Behavioral genetic studies have supported these models (2), with current work focusing on molecular and neural mechanism that may underlie these associations.Dysfunction of the serotonin (5-hydroxytryptophan, 5-HT) system is implicated in mood disorders, and variation within serotonergic genes has been associated with negative emotional traits such as neuroticism and harm avoidance (3). For example, higher scores in these traits are associated with a common short variant of a repetitive sequence in the transcriptional control region of the 5-HT transporter gene (5-HTT, SERT, SLC6A4), which results in low 5-HT uptake function (4). Two metaanalyses have concluded that presence of the short variant of this repeat (5-HTT-linked polymorphic region, 5-HTTLPR) is associated with higher levels of neuroticism or harm avoidance (5, 6). Although neuroticism itself is a risk factor for depression (7), the link between 5-HTTLPR genotype and depression has been more tenuous, suggesting that 5-HTTLPR genotype does not have a consistent main effect on depression but instead may be moderated through other variables (8).Caspi et al. (9) conducted a 23-year longitudinal study in a large sample of individuals who were genotyped for the 5-HTTLPR. They found that carriers of the 5-HTTLPR short variant showed more depressive symptoms, diagnosed depression, and suicidality as a function of stressful life events than individuals homozygous for the 5-HTTLPR long variant, thus demonstrating a significant gene-by-environment (...

There is growing interest in non-invasive brain stimulation (NIBS) as a novel treatment option for substance-use disorders (SUDs). Recent momentum stems from a foundation of preclinical neuroscience demonstrating links between neural circuits and drug consuming behavior, as well as recent FDA-approval of NIBS treatments for mental health disorders that share overlapping pathology with SUDs. As with any emerging field, enthusiasm must be tempered by reason; lessons learned from the past should be prudently applied to future therapies. Here, an international ensemble of experts provides an overview of the state of transcranial-electrical (tES) and transcranial-magnetic (TMS) stimulation applied in SUDs. This consensus paper provides a systematic literature review on published data-emphasizing the heterogeneity of methods and outcome measures while suggesting strategies to help bridge knowledge gaps. The goal of this effort is to provide the community with guidelines for best practices in tES/TMS SUD research. We hope this will accelerate the speed at which the community translates basic neuroscience into advanced neuromodulation tools for clinical practice in addiction medicine.