Alzheimer & Parkinson

Epidemiological studies link kidney function to Parkinson's disease risk, but the genetic basis of this relationship remains unclear. Here, we leverage genome-wide association data for Parkinson's disease and five UK Biobank-derived kidney-related traits in individuals of European ancestry, combining genetic correlation, pleiotropy mapping, colocalization and enrichment across sex-combined and sex-stratified analyses. Genome-wide genetic correlations with Parkinson's are modest, with only a...

Although brain cholesterol dysregulation is implicated in Parkinson's disease (PD), targeting cholesterol synthesis has shown limited efficacy. Here we identify ATP-binding cassette transporter A1 (ABCA1) as a critical regulator of cholesterol homeostasis in PD. We show that ABCA1 expression is elevated in the substantia nigra of postmortem PD brains and in a PD mouse model, with regional analyses revealing preferential alterations in nigral and striatal circuits. Mechanistically, astrocytic...

Blood biomarkers are transforming Alzheimer's disease diagnostics by enabling a scalable, minimally invasive assessment of pathology. Food and Drug Administration clearances and European market certifications of different plasma tests mark a shift toward biological diagnosis in routine care. However, clinical implementation is not guided by diagnostic accuracy alone but will depend on improved patient-centered and pathway-level outcomes, including diagnostic confidence, the appropriate use of...

Genetic evidence implicates immune dysfunction in Alzheimer's disease (AD), yet the neuroimmune mechanisms operating in human tissue remain poorly defined. Here, we establish a modular human forebrain organoid platform that systematically integrates human induced pluripotent stem cell-derived microglia and CD8^(+) T cells to reconstitute multicellular AD pathology. This system enables functional interrogation of both innate and adaptive immune components in a human-relevant context. Using this...

Multiple lysosomal stresses activate Parkinson's-linked LRRK2 kinase, and these involve the so-called "CASM" pathway to help recruit LRRK2 to lysosome surfaces. Clegg et al. (https://doi.org/10.1083/jcb.202511137) show that LRRK2, activated upon lysosome swelling caused by PIKfyve inhibition, instead relies solely on Rab GTPase binding for lysosome localization and activation.

Increased activity of leucine-rich repeat kinase 2 (LRRK2) confers Parkinson's disease risk. LRRK2 dynamically localizes to lysosomal membranes in response to various stresses, yet the mechanisms by which distinct lysosomal perturbations are communicated to LRRK2 remain unclear. Here, we show that inhibition of the lysosomal lipid kinase PIKfyve promotes LRRK2 recruitment and signaling through a pathway that requires the lysosomal chloride/proton antiporter ClC-7. ClC-7 in turn controls the...

Immune-neuron interactions play a critical role in neuroinflammatory and neurodegenerative diseases, such as Alzheimer's disease (AD), but how CD8⁺ T cells contribute to brain pathology remains poorly understood. Amyloid-β (Aβ), a hallmark of AD, is known to trigger neuronal stress and inflammation. Here, we established a human cortical organoid (hCO) model to investigate CD8⁺ T cell responses to Aβ-induced neurodegenerative stress. Aβ exposure increased neuronal expression of CX3CL1...

α-synuclein (αS), amyloid-β (Aβ), and Tau aggregates are hallmarks of many neurodegenerative diseases, yet the prevalence and nature of their nanoscopic co-assemblies remain poorly understood. Here, we adapt a single-molecule pull-down (SiMPull) assay to profile αS, Aβ, and Tau co-assemblies across post-mortem brain tissue homogenates, soluble brain fractions, human serum, cerebrospinal fluid, and saliva. We show that αS-Tau co-assemblies are abundant across all sample matrices, accounting for...

Alzheimer's disease (AD) is characterized by progressive cognitive decline and prominent disturbances in sleep and wakefulness, reflecting dysfunction across distributed neural networks. The zona incerta (ZI) is a highly heterogeneous subthalamic structure whose organization is defined by spatial location, molecular identity, neurochemical phenotype, and circuit connectivity. Recent studies demonstrate that distinct ZI cell populations and projections contribute to memory processing, novelty...

The glymphatic system clears cerebral waste, yet strategies to enhance its function remain elusive. Here, we show that 40.68 MHz ultrashort wave (USW) rapidly enhances glymphatic bulk flow in healthy mice within 10 minutes. USW potentiates both glymphatic influx and efflux, concomitant with increased Delta wave neuronal synchronization, as confirmed by local field potentials and electroencephalograms. Chemogenetic silencing confirms that USW-driven glymphatic enhancement depends on neuronal...

Neurodegenerative diseases (NDs) are increasingly recognised in Sub-Saharan Africa (SSA), but the principal scientific challenge is no longer simply to document a presumed hidden burden. It is to determine how much of the observed heterogeneity reflects underlying neurobiology and how much arises from age structure, case ascertainment, culturally sensitive phenotyping and unequal access to neurological diagnosis. This critical narrative review synthesises evidence from 2000 to July 2026 across...

Here, we conduct a large meta-analysis of DNA methylation across multiple cortical brain regions, in relation to increasing burden of Lewy body pathology. Utilizing a dataset of 1205 samples (832 unique donors), we identify 24 false discovery rate significant differentially methylated loci associated with Lewy body pathology, with loci located in UBASH3B and PTAFR, and an intergenic locus passing the genome-wide significance threshold. Ontological enrichment analysis highlights several...

Cognitive reserve theory posits that compensatory mechanisms during aging stave off cognitive decline and lower risk for Alzheimer's disease. Here, in a screen for hippocampal dentate granule cell (DGC) synapse loss-induced factors in mice, we identified a secreted phospholipase, Pla2g2f, whose expression increases in DGCs during aging and is associated with cognitive resilience in humans. Pla2g2f deletion in DGCs exacerbates aging-associated pathophysiological changes, including synapse loss,...

APOE4 is the strongest genetic risk factor for late-onset Alzheimer's disease, yet the cellular mechanisms linking APOE variants to disease risk remain unclear. We previously found that APOE4 expression causes lipid droplet accumulation in oligodendrocytes, reducing myelination, but the underlying mechanisms were unknown. Using a genome-wide CRISPR screen and assay for transposase-accessible chromatin (ATAC) sequencing in human-induced pluripotent stem cell (iPSC)-derived oligodendrocytes, we...

Gamma oscillations are fundamental for cognitive processing, but the cellular and circuit dynamics that generate them remain poorly defined. Establishing a method for simultaneous calcium imaging and electrocorticography recordings in awake mice, we found that spontaneous gamma oscillations are accompanied by dynamic transitions between parvalbumin (PV) interneuron states. Rather than acting as a uniformly synchronized population, PV interneurons showed sequential recruitment, transient...

Single-cell resolution spatial transcriptomics provides a great opportunity to explore the complex cellular contents in different tissues. Here we introduce SpatialZoomer, a spectral graph-based method that applies a set of low-pass filters to efficiently extract spatial molecular features from spatial transcriptomics data at multiple resolutions or scales, including the single cell scale, the niche scale with dozens of closely interacting cells and the domain scale with spatially organized cell...

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Pleiotrophin (PTN) is a heparin-binding growth factor that plays a pivotal role in neurodevelopment, neuroplasticity, and neuroinflammation. PTN signals through a multi-receptor network involving protein tyrosine phosphatase receptor type ζ (PTPRZ1), syndecans (particularly syndecan-3), integrins, nucleolin, and neuropilin-1. Anaplastic lymphoma kinase (ALK) has also been functionally linked to PTN signaling, although whether PTN directly binds and activates it remains debated. This review...

Alzheimer's disease (AD) is a devastating neurodegenerative disorder with no effective cure, characterized by the cerebral parenchymal and vascular accumulation of aggregated amyloid-β (Aβ) and hyperphosphorylated tau. Cerebrovascular and mitochondria dysfunction are early causal events in the progression of AD. Previous studies support that inhibiting carbonic anhydrases (CAs) may prevent mitochondrial and cerebrovascular dysfunction in AD models. Here, we selectively target the mitochondrial...

Microglial dysfunction is increasingly implicated in Alzheimer's disease (AD) pathogenesis, with loss-of-function variants in the microglial receptor TREM2 as major risk factors for late-onset AD. We report VG-3927, an oral, CNS-penetrant small-molecule TREM2 agonist that engages the transmembrane domains of TREM2 and its adaptor DAP12 to promote higher-order receptor complex formation and downstream signaling. VG-3927 and tool compound VG-3909 exhibited (sub)nanomolar potency, cooperated with...