INTRODUCTION The ε4 allele of the apolipoprotein E (APOE) gene is a risk factor for the development of Alzheimer's disease (AD). APOE4 isoform is associated with increased white matter lesions in hu.....

Asymptomatic Alzheimer’s disease (AsymAD) refers to individuals who, despite exhibiting amyloid-β plaques and tau pathology comparable to Alzheimer’s disease (AD), maintain cognitive performance simil...

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Nature Metabolism, Published online: 04 November 2025; doi:10.1038/s42255-025-01390-yBarnett et al. disentangle the differential contribution of mitochondrial complex I- and complex III-derived ROS to astrocytic function, with CIII-derived ROS being a major driver of neuroinflammatory responses.

Cognitive aging is influenced by sex and sex-specific factors. Indeed, research has shown that parity (pregnancy and parenthood) uniquely alters bioma…

Lactate has been hypothesized to represent an important energy source during brain activation. Here, we explored both lactate production and lactate transport across cell membranes in hippocampal sli...

Aβ induces neuronal hyperconnectivity, which promotes tau spreading from temporal lobe epicenters to connected brain regions in Alzheimer’s disease.

Background A significant proportion of individuals maintain cognition despite extensive Alzheimer’s disease (AD) pathology, known as cognitive resilience. Understanding the molecular mechanisms that protect these individuals could reveal therapeutic targets for AD. Methods This study defines molecular and cellular signatures of cognitive resilience by integrating bulk RNA and single-cell transcriptomic data with genetics across multiple brain regions. We analyzed data from the Religious Order Study and the Rush Memory and Aging Project (ROSMAP), including bulk RNA sequencing (n = 631 individuals) and multiregional single-nucleus RNA sequencing (n = 48 individuals). Subjects were categorized into AD, resilient, and control based on β-amyloid and tau pathology, and cognitive status. We identified and prioritized protected cell populations using whole-genome sequencing-derived genetic variants, transcriptomic profiling, and cellular composition. Results Transcriptomics and polygenic risk analysis position resilience as an intermediate AD state. Only GFAP and KLF4 expression distinguished resilience from controls at tissue level, whereas differential expression of genes involved in nucleic acid metabolism and signaling differentiated AD and resilient brains. At the cellular level, resilience was characterized by broad downregulation of LINGO1 expression and reorganization of chaperone pathways, specifically downregulation of Hsp90 and upregulation of Hsp40, Hsp70, and Hsp110 families in excitatory neurons. MEF2C, ATP8B1, and RELN emerged as key markers of resilient neurons. Excitatory neuronal subtypes in the entorhinal cortex (ATP8B+ and MEF2Chigh) exhibited unique resilience signaling through activation of neurotrophin (BDNF-NTRK2, modulated by LINGO1) and angiopoietin (ANGPT2-TEK) pathways. MEF2C+ inhibitory neurons were over-represented in resilient brains, and the expression of genes associated with rare genetic variants revealed vulnerable somatostatin (SST) cortical interneurons that survive in AD resilience. The maintenance of excitatory-inhibitory balance emerges as a key characteristic of resilience. Conclusions We have defined molecular and cellular hallmarks of cognitive resilience, an intermediate state in the AD continuum. Resilience mechanisms include preserved neuronal function, balanced network activity, and activation of neurotrophic survival signaling. Specific excitatory neuronal populations appear to play a central role in mediating cognitive resilience, while a subset of vulnerable interneurons likely provides compensation against AD-associated hyperexcitability. This study offers a framework to leverage natural protective mechanisms to mitigate neurodegeneration and preserve cognition in AD.

Abstract figure legend Summary of the study where simulated recordings (left) were used to characterise the effect of incomplete detection on mini (mPSC) analysis. Recording noise levels (red) determ...

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Molecular Psychiatry - A study of gene expression in the living human brain

A major challenge in understanding Alzheimer's disease is linking changes that occur across different biological scales. For example, how do changes in individual neurons build into widespread network...

Alzheimer's disease (AD) is not only characterized by amyloid-beta (Aβ) and tau pathology, but also by early and progressive disruptions in metabolism. Neuronal excitability is tightly coupled with me...

Glycogen is the largest energy reserve in the brain, but the specific role of glycogen in supporting neuronal energy metabolism in vivo is not well...

A multi-cell-type drug discovery strategy targeting dysregulated gene networks in neurons and glia identified letrozole and irinotecan as a combination therapy that significantly improved memory and r...

INTRODUCTION Alzheimer's disease (AD) dementia has near full penetrance in adults with Down syndrome (DS) and is strongly linked to late-onset myoclonic epilepsy in Down syndrome (LOMEDS). However, ...

Jackson et al. provide insight into how metabolic adaptations that accompany cell state transitions drive reliance on exogenous nutrient availability, focusing on pyruvate as a key metabolite in central carbon metabolism.

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