Reviews & Analysis

In a study of 17,000 Medicare beneficiaries with mild cognitive impairment or dementia, non-Hispanic white older adults were more likely than Asian, Black or Hispanic older adults to have elevated cortical amyloid, as measured by PET. These findings have important implications for the use of amyloid-targeting therapies.

In this Review, the authors provide an overview of evidence that activity-regulated myelination is required for brain adaptation and learning, and discuss how dysregulation of activity-dependent myelination contributes to neurological disease and could be a new therapeutic target.

Here, the authors discuss the potential effects of social determinants of health on multiple sclerosis risk and outcomes. They suggest that addressing these determinants of health could substantially improve the lives of individuals with multiple sclerosis and call for more research.

Genome-wide association studies have identified loci associated with neurodegenerative disease risk, but many of the implicated genetic variants are noncoding and their functional roles remain unclear. Using massively parallel reporter assays, CRISPR-based validation and genomic annotations, a new study functionally characterizes regulatory risk variants associated with Alzheimer disease and progressive supranuclear palsy.

In this Perspective, the authors discuss the importance of performing well-designed observational studies on Alzheimer disease. They highlight novel approaches to enhance causal inference and discuss ways in which observational data can provide a bridge between preclinical findings and clinical trials.

In this Review, Vezzani et al. discuss how dysregulation of key astrocyte functions — gliotransmission, cell metabolism and immune function — contribute to the development and progression of hyperexcitability in epilepsy and consider strategies to mitigate astrocyte dysfunction.

Following successful clinical trials of a gene therapy for Leber hereditary optic neuropathy, Pitceathly and colleagues discuss progress towards genetic therapies for other primary mitochondrial diseases. They highlight advances in DNA editing technologies and offer their view on obstacles to clinical application.

In this Review, Eichmüller and Knoblich discuss how human brain organoids can recapitulate the unique processes that occur in human brain development and how they can complement classical approaches to revolutionize research into neurological diseases.

Most cases of Alzheimer disease (AD) have a complex aetiology, probably involving multiple genetic and environmental factors. In this Review, the authors discuss how various environmental AD risk factors could induce epigenetic modifications of key AD-associated genes and pathways.

In the first two phase II trials of therapies that target α-synuclein to treat Parkinson disease, the primary endpoints were not met. However, the limitations of these studies need to be addressed in future trials and alternative approaches to targeting α-synuclein should be pursued before α-synuclein is discounted as a target.

Currently, the anti-CD20 monoclonal antibody ocrelizumab is the only approved treatment for primary progressive multiple sclerosis (PPMS). However, a new study suggests that other immunomodulatory disease-modifying therapies that are often used to treat relapsing forms of multiple sclerosis could be effective in people with PPMS who have evidence of active inflammatory disease.

New work building on the results of genome-wide association studies in Alzheimer disease has identified molecular mechanisms that are shared with some psychiatric disorders. The study leveraged ‘omics data and has the realistic potential to elucidate unknown disease mechanisms; however, a lack of information about neuropsychiatric symptoms in the participants with Alzheimer disease limits the conclusions.

In this Review, the authors summarize the interactions of the neurovascular unit with systemic biology after ischaemic stroke, consider how these interactions influence stroke outcome, and discuss how these interactions could be targeted to improve outcomes.

In this Perspective article, the authors outline how studying multiple sclerosis (MS) genetics in ancestrally diverse populations is likely to yield insights that could benefit individuals with MS from all ancestral groups.

In this Perspective, Fiorio et al. discuss the relationship between functional neurological disorder and placebo and nocebo effects, with the aim of providing insights into the pathogenesis of the disorder and identifying potential therapeutic targets.

In this Review, Fong and Inouye explore mechanisms that might be common to both delirium and dementia. They present delirium as a possible modifiable risk factor for dementia and discuss the importance of delirium prevention strategies in reducing this risk.

Numerous studies have attempted to identify pathogenic autoantibodies in people with multiple sclerosis (MS), but their results are conflicting. In this Perspective, the authors explore the available evidence and provide their own opinions on a possible role for autoantibodies in MS.

A phase II trial of the tau antibody semorinemab indicates that it has no clinical benefit in the earliest stages of Alzheimer disease. The repeated finding that antibody-mediated reductions in protein pathology have limited or no clinical benefit indicates that we need to consider more specific or combined therapeutic targets.

In this Review, the authors provide detailed insight into how the gut microbiota influences the immune system, with implications for neuroinflammation, and discuss the accumulating evidence that the gut microbiota is an important factor in multiple sclerosis pathogenesis and a potential therapeutic target.

Cognitive rehabilitation is a promising approach to limit the effect of cognitive impairment on patients with multiple sclerosis, although results so far are conflicting. A new study indicates that structural and functional MRI techniques could provide reliable measures to predict treatment responses and tailor the rehabilitative approach to each patient.