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Tau accumulation is associated with disease progression in Alzheimer’s disease. Here the authors use resting state fMRI and tau-PET to demonstrate that baseline connectivity in Alzheimer's disease is associated with tau spreading.

The BIN1 SNP rs744373 is associated with higher CSF tau and phosphorylated tau levels. Here the authors show, using PET imaging, that this SNP is associated with tau accumulation in the brain as well as impaired memory in older individuals without dementia.

In this study the authors identify a possible link between the gene FAM222A and brain atrophy. The protein it encodes is found to accumulate in plaques seen in Alzheimer’s disease, and functional analysis suggests it interacts with amyloid-beta.

Brain-iron elevation is implicated in Alzheimer’s disease (AD), but the impact of the metal on disease outcomes has not been analysed in a longitudinal study. Here, the authors examine the association between the levels of ferritin, an iron storage protein, in the cerebrospinal fluid (CSF) of AD patients and show that CSF ferritin levels predict AD outcomes.

For many neurodevelopmental disorder (NDD) risk genes, the significance for mutational burden is unestablished. Here, the authors sequence 125 candidate NDD genes in over 16,000 NDD cases; case-control mutational burden analysis identifies 48 genes with a significant burden of severe ultra-rare mutations.

This study shows that Epac2, a cAMP-activated Rap-GEF, acts downstream of D1/D5 dopamine receptor signaling to regulate dendritic spines and synaptic transmission. The authors also show that rare mutations of the EPAC2 gene that are associated with autism cause defects in Epac2-mediated spine remodeling.

The Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA) aims to better understand population genetics of the African diaspora. Here, it uses deeply sequenced whole-genomes to describe the impact of admixture and potential disease burden of deleterious variants.

Several studies show that APOE-ε4 coding variants are associated with Alzheimer’s disease (AD) risk. Here, Zhou et al. perform fine-mapping of the APOE region and find AD risk haplotypes with non-coding variants in the PVRL2 and APOC1 regions that are associated with relevant endophenotypes.

Progressive diseases tend to be heterogeneous in their underlying aetiology mechanism, disease manifestation, and disease time course. Here, Young and colleagues devise a computational method to account for both phenotypic heterogeneity and temporal heterogeneity, and demonstrate it using two neurodegenerative disease cohorts.

Duplications of gene segments can allow novel physiological adaptations to evolve. A detailed analysis of the TCAF gene family in primates and archaic humans suggest rapid duplication and diversification in this gene family is associated with cold or dietary adaptations.

Using more than 100 independent iPSC lines derived from patients with Alzheimer’s disease, the authors discovered loci associated with the neuronal production of amyloid β and confirmed their influence using RNA interference.

Personalized medicine requires accurate and ethnicity-optimized reference genome panels. Here, the Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA) evaluates typical variant filters and existing genome databases against newly sequenced African-ancestry populations.

Sun et al. report human lifespan changes in the brain’s functional connectome in 33,250 individuals, which highlights critical growth milestones and distinct maturation patterns and offers a normative reference for development, aging and diseases.

The rich ethnolinguistic and sociocultural differences that exist in India offers a unique opportunity to study human diversity. With the whole genomes of 10,000 healthy and unrelated Indians from 83 populations, the GenomeIndia project captures the genetic diversity of one of the highly underrepresented populations in the global genomics landscape.

The generation of reactive oxygen species (ROS) in photodynamic cancer treatments is limited by low intraturmoural oxygen availability. Here the authors show that irradiation of a silicon phthalocyanine leads to uncaging of a biologically active molecule or to ROS formation in an oxygen-dependent manner.

The tau protein is theorized to spread transneuronally in Alzheimers disease, though this theory remains unproven in humans. Our simulations of epidemic-like protein spreading across human brain networks support this theory, and suggest the spreading dynamics are modified by β-amyloid

Late-onset Alzheimer's disease (LOAD) is a complex multi-factorial disorder. Here, the authors perform a data-driven analysis of LOAD progression, including multimodal brain imaging, plasma and CSF biomarkers, and find vascular dysfunction is among the earliest and strongest altered events.

Combine economic, social and medical data to forecast need and design services to address the growing crisis.

Marshall Horwitz, Charles Mullighan, Kenneth Offit and colleagues report the identification of a recurrent germline PAX5 mutation in families with pre–B cell acute lymphoblastic leukemia. They also identify sporadic cases of this leukemia with the same mutation that arose somatically.

Preimplantation genetic diagnosis (PGD) facilitates conception of a healthy child by couples at risk of having offspring with an inherited debilitating or fatal neurological disorder. PGD has been carried out for various conditions, including spinal muscular atrophy, Huntington disease, fragile X syndrome, and chromosomal and mitochondrial disorders. This article aims to assist neurologists in counselling and treatment of individuals who wish to explore the option of PGD, and advocates the formulation of guidelines for the responsible integration of PGD into preventative neurology.

Socioeconomic inequalities are antecedents for poor mental health outcomes. Mental illness is highly prevalent internationally — impacting 1 in 8 people, with incidence of anxiety and depression skyrocketing during the pandemic. In the USA, one of the world’s wealthiest nations, the economic outlook remains bleak.

Sialic acid acetylesterase (SIAE) is an enzyme that is involved in B-cell activation and is required to maintain immunological tolerance in mice. It is shown here that rare, inherited and functionally defective SIAE variants are associated with a variety of autoimmune diseases in humans. The study provides one of the first examples of the importance of rare genetic variants in complex diseases, such as those involving autoimmunity.

Complementary multi-omics approach, in silico metabolic flux, and neuroimaging analyses link the sphingolipid pathway to Alzheimer’s disease pathogenesis with therapeutic targets validated using behavioral assessments in amyloidogenic APP/PS1 mice.

A novel ALK transcript expressed in a subset of human cancers, arising from a de novo alternative transcription initiation site within the ALK gene, is described; the ALK transcript encodes three protein isoforms that stimulate tumorigenesis in vivo in mouse models; resultant tumours are sensitive to treatments with ALK inhibitors, indicating a possible therapeutic avenue for patients expressing these isoforms.