Metabolic inflexibility in Alzheimer's disease. Schematic illustrating the biphasic trajectory of metabolic activity relative to canonical Alzheimer's disease (AD) biomarkers. In the presymptomatic p...

Microglia influence amyloid-β effects on astrocyte reactivity in the living brain of individuals with Alzheimer’s disease. This phenomenon further contributes to cognitive impairment via tau phosphory...

Yang et al. show that moments of failed attention we experience after sleep deprivation reflect brief ‘sleep-like’ episodes in the brain, corresponding to a brain- and body-wide event with altered bra...

Brain clearance mechanisms are challenging to visualize in humans. Using magnetic resonance imaging, the authors noninvasively mapped cerebrospinal fluid motion across the brain, showing region-specif...

Disrupting the astrocyte-neuronal dynamic in mice destabilizes their memory of fear conditioning.

Overview of our approach for extreme value statistics. First, we fit a normative model to imaging phenotypes, before employing a ‘peaks-over-threshold’ approach widely used in meteorology and finance...

The brain constantly generates predictions based on one’s knowledge of the world, as captured in memory. When these predictions are in error, our knowledge base must be revised to remain relevant. Her...

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.

Background: Unsupervised cognitive assessments are becoming commonly used in studies of aging and neurodegenerative diseases. Because assessments are completed in everyday environments and without a p...

Rationale One of the earliest changes associated with Alzheimer’s disease (AD) is the loss of catecholaminergic terminals in the cortex and hippocampus originating from the Locus Coeruleus (LC). This ...

Generate design matrices, contrasts, and scripts to set up FSL randomise analyses. - jmumford/randomise-prep