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Genome-wide analyses identify common variants associated with 11 distinct neuropathology endophenotypes, providing insights into the mechanisms underlying the genetic risk of Alzheimer’s disease and related dementias.

A quantitative fluorescence-activated cell sorting method for generating fully human conformational antibodies against amyloid aggregates associated with neurodegenerative disorders—without the need for immunization—has now been developed. Engineered antibodies obtained using this approach show properties rivaling those of clinical-stage antibodies specific for tau and α-synuclein amyloid aggregates.

Last year's Nobel Prize in Physiology or Medicine was won by Andrew Fire and Craig Mello for their discovery of RNA interference, an evolutionarily conserved cellular pathway that regulates endogenous gene expression. In this Review, Gonzalez and Paulson discuss how RNA interference is being exploited experimentally to suppress the expression of dominantly acting genes that cause incurable neurodegenerative disorders, and highlight the questions that need to be answered before human clinical trials of this technology can commence.

A network of dual-gate silicon p–i–n photodiodes, which are compatible with complementary metal–oxide–semiconductor fabrication processes, can perform in-sensor image processing by being electrically programmed into convolutional filters.

Large genome-wide meta-analysis of clinically diagnosed late-onset Alzheimer’s disease (LOAD) from 94,437 individuals identifies new LOAD risk loci and implicates Aβ formation, tau protein binding, immune response and lipid metabolism.

Meta-analysis of genome-wide association studies on Alzheimer’s disease and related dementias identifies new loci and enables generation of a new genetic risk score associated with the risk of future Alzheimer’s disease and dementia.

A system employing liquid-handling robotics and an integrated mobile microscope enables the automated culture, sample collection and in situ microscopy imaging of up to ten fluidically coupled organ chips within a standard tissue-culture incubator.

Using a graphene quantum dot creation and a wavefunction mapping technique, quantum scars are directly visualized for Dirac electrons with a scanning tunnelling microscope.

In vitro blood-brain barrier (BBB) models do not fully recapitulate the in vivo barrier function. Here the authors develop an organ-on-a-chip BBB model using iPS-derived human brain endothelial cells differentiated under hypoxia, primary human pericytes and astrocytes, which maintains in vivo-like BBB barrier and shuttling functions for a week.

Saloner et al. used large-scale cerebrospinal fluid proteomics to uncover molecular signatures in frontotemporal dementia, revealing RNA splicing and synaptic protein candidate markers for genetic and sporadic disease progression.

Nine inherited neurodegenerative disorders are caused by polyglutamine (polyQ) expansions in diverse proteins. A study now suggests that polyQ-mediated depletion of nonhistone chromatin proteins enhances genotoxic stress induced by the disease protein.

Curvature of image sensors that match the focal plane of the lens facilitate focussing but can cause image distortion. Here, an anti-distortion single-lens camera was developed using a curved image sensor with a photo-pixel distribution pattern warped like image warping to correctively reverse distortion.

Cell-based phenotypic assays link in vitro discovery to disease pathology. Here, the authors report a semiconductor-based microplate platform to perform high-throughput, high-dimensional “electrical imaging” for label-free assessment of live cell morphology and function.

Some broadly neutralizing antibodies to HIV-1 recognize glycan-dependent epitopes on gp120. Now X-ray crystallography and EM approaches, along with functional analyses, reveal how one particular antibody (PGT135) recognizes three glycan groups and can accommodate their conformational and chemical diversity.

A mutant repeating DNA sequence produces a toxic RNA molecule that causes the neuromuscular disorder myotonic dystrophy type 1. An ‘antisense’ therapy that targets this RNA in cell nuclei shows promise in mice. See Letter p.111

Among the many neurodegenerative diseases caused by repeat expansions, spinocerebellar ataxia type 8 (SCA8) has been something of a puzzle. Now, a new study shows that the CTG/CAG expansion in ATXN8OS (formerly SCA8) is transcribed in both directions, raising the possibility that two molecular mechanisms contribute to disease.

APOE is the major genetic risk factor for Alzheimer’s disease. In a large number of neuropathologically confirmed cases and controls, the impact of different APOE genotypes on Alzheimer’s dementia risk was greater than previously thought and APOE2 homozygotes had an exceptionally low risk.

An NMR structure reveals that the C terminus of the ubiquitin-conjugating enzyme Ube2w is disordered, leading to specific pairings with disordered substrates; loss of this sequence causes decreased substrate binding and ubiquitin transfer activity.

Sven van der Lee, Julie Williams, Gerard Schellenberg and colleagues identify rare coding variants in PLCG2, ABI3 and TREM2 associated with Alzheimer's disease. These genes are highly expressed in microglia and provide additional evidence that the microglia-mediated immune response contributes to the development of Alzheimer's disease.

Jean-Luc Battini, Giovanni Coppola and colleagues identify XPR1 mutations in several families with primary brain calcification. They further show that these mutations alter phosphate export activity, implicating defective phosphate homeostasis in the etiology of this disease.

Domain-resolved spectroscopy reveals the impact of local atomic registry and crystal symmetry on the exciton properties of individual domains in near-0°-twist-angle MoSe₂/MoSe₂.

Several of the spinocerebellar ataxias (SCAs) result from expansion of polyglutamine (polyQ)-encoding regions in different genes. Here, Orr and colleagues examine the clinical features of the the polyQ SCAs, and suggest that understanding the molecular and physiological mechanisms underlying polyQ SCAs can inform therapeutic strategies for these and other polyQ disorders.

Advances in our understanding of the pathogenic mechanisms of spinocerebellar ataxias (SCAs) have resulted in the development of promising therapeutic strategies for these inherited neurodegenerative disorders. Here, Ashizawa and colleagues review the current progress and future challenges facing clinical trials of new therapies for the SCAs.

The spinocerebellar ataxias (SCAs) are a group of autosomal dominant progressive disorders characterized by loss of balance and coordination and slurred speech. This Primer discusses the epidemiology of SCAs, the complex mechanisms underlying them and how they are diagnosed and managed in the clinic.

The DECIDE-AI checklist, resulting from a multi-stakeholder group of experts in a Delphi process and following the EQUATOR Network’s recommendations, includes key items that should be reported in early-stage clinical studies of AI-based decision support systems, to ensure a responsible and transparent deployment of AI systems in healthcare.

By integrating ongoing bioethical collaboration, neuroscientists can create a positive effect on their research and the knowledge it produces. To this end, we offer our experiences with an interdisciplinary model for the ethical advancement of a promising area of neuroscience — human neural organoid research.

The use of genetic screens to define cellular pathways that regulate neurodegenerative disease proteins has emerged as a powerful strategy to identify potential therapeutic targets for these disorders. Using cross-species genetic screens, Park et al. recently identified RAS-MAPK-MSK1 as a cellular pathway that modulates levels of the polyglutamine-containing protein ATXN1 and its subsequent toxicity in SCA1.