Lysergic acid diethylamide (LSD) is a potent psychedelic with increasing therapeutic interest, yet qualification of target engagement using in vivo neuroimaging has not yet been performed. Using simultaneous positron emission tomography–magnetic resonance imaging technology, we describe multiple brain actions of LSD in seven healthy volunteers blinded to LSD dose received. Here we show that LSD occupies 5-HT2AR with a high affinity and increases both global cerebral blood flow (CBF) and internal carotid artery flow. LSD also decreases global connectivity, which was negatively associated with changes in CBF. We observe an anticlockwise hysteresis loop between plasma drug levels and subjective effects, suggesting atypical pharmacodynamic mechanisms. We contrast our CBF and global connectivity findings and their relation in a separate cohort of 25 participants administered psilocybin, highlighting key consistencies and differences. By establishing the dose–occupancy relation of LSD in humans, our findings provide insights for the clinical development of psychedelic compounds and demonstrate unique neurophysiological effects that distinguish LSD from psilocybin. Using simultaneous PET–MRI, McCulloch, Larsen and colleagues quantify LSD’s dose–occupancy relationship at the serotonin 2A receptor and reveal hemodynamic effects of LSD that contrast with those of psilocybin.
The genetic changes associated with development of the human cortex are difficult to test functionally, especially in the context of gene regulation. In this issue, Matoba et al. show that variants that shape human cortical structure are hiding inside Alu transposable elements, co-opting their inbuilt machinery to rewire regulatory networks in the developing brain.
Although Alzheimer’s disease (AD) has a polygenic architecture, with numerous associated single-nucleotide polymorphisms (SNPs) identified, the contribution of structural variants (SVs) is unclear. In this study, using long-read (n = 11) and short-read (n = 3,190) sequencing data from the Chinese population, we show that common SVs contribute to AD heritability beyond common SNPs. We identify an expanded CCG repeat in the FAM193B promoter that shows a genome-wide significant association with increased AD risk (odds ratio = 2.20 per 10-repeat increase, P = 5.5 × 10−13). The expanded FAM193B-CCG repeat increases FAM193B expression and mediates the pleiotropic association between brain FAM193B expression and AD risk. Analyses of postmortem human brains and cultured neuronal cells show that elevated neuronal FAM193B expression is associated with DNA damage and cell death-related pathways. These findings establish the common FAM193B-CCG repeat as an AD risk genetic factor and highlight the contribution of common SVs to AD heritability. This study identifies common structural variants contributing to Alzheimer’s disease heritability. An expanded promoter CCG repeat increases FAM193B expression and disease risk, linking its expression to DNA damage and cell death pathways in neurons.
Despite prolific genomic data from individuals with Alzheimer’s disease (AD), translation into treatments has lagged. Here we applied Mendelian randomization to multiple AD genome-wide association studies and functional multiomics datasets to nominate druggable targets, identifying 19 targets for individuals of European ancestry and 7 for African ancestry. This included epoxide hydrolase 2 (EPHX2), for which we identified a protective missense variant (p.Arg287Gln). Experiments in induced pluripotent stem cell-derived neurons and cerebral organoids from patients with AD validated the protective role of p.Arg287Gln via reduced levels of EPHX2 and phosphorylated tau (pTau-181). Pharmacological inhibition of EPHX2 improved cognitive performance in the 5xFAD mouse model of AD. Finally, by leveraging electronic health data from 111,680 patients with mild cognitive impairment, we identified 12 drugs associated with reduced AD incidence, including trazodone (targeting ADRA1A) and baclofen (targeting GABBR1). Thus, integrating multiomics data, functional validation and electronic health data identifies new approaches for treating AD. Hou et al. show a drug target compendium supported by human genetic and real-world patient data for Alzheimer’s disease and validate epoxide hydrolase 2 as a causal Alzheimer’s disease target using CRISPR interference and gene editing experiments in human models.
Memory markedly declines with age, exaggerated in those with Alzheimer’s disease, yet the mechanisms are still not resolved. Here we show that frontal lobe tau pathology in humans is associated with impaired en masse unity and cortical traveling propagation of nonrapid eye movement slow waves, linked to impaired memory retention. We elucidate these findings using positron-emission tomography tau brain imaging, and then replicate and extend them using Alzheimer’s disease pathology markers derived from cerebrospinal fluid in an independent clinical cohort. Thus, tau-associated memory deficits are not wholly direct but indirectly linked to consequential ‘lonely’, nontraveling slow-wave events. Frontal cortical tau pathology in aging humans is associated with reduced slow-wave travel during sleep. This reduced propagation is associated with poorer overnight memory retention, supporting a link between slow-wave travel and age-related memory function.
