Alzheimer & Parkinson

Misfolded alpha-Synuclein (α-Syn) accumulation is the defining molecular pathology of Parkinson's disease (PD), yet blood-based assays remain challenged by the high background of peripheral α-Syn originating mainly from red blood cells. Neuronal extracellular vesicles (EVs) circulating in blood offer a biologically enriched source of brain-derived α-Syn proteoforms, but their ultralow abundance has hindered reliable detection. Here, we introduce an organic electrochemical transistor-based...

Biological aging clocks offer estimations of aging and dementia, yet scalability is limited. We introduce a large-scale, cross-national speech clock derived from 2928 individuals across five Latin American countries, spanning healthy controls (HCs), mild cognitive impairment (MCI), Alzheimer's disease (AD), and non-language/language-dominant frontotemporal dementia (nldFTD/ldFTD). Multimodal acoustic and linguistic features were trained with supervised models to estimate chronological age,...

Examination of genetic risk factors associated with neurodegenerative diseases has provided important mechanistic insights into the pathophysiology of these disorders, and it has implicated defects in lysosomal function as a key component of the neurodegenerative process. The lysosome has a primary role in mediating degradation of both intracellular contents and endocytosed material from the extracellular space. Aggregation of misfolded proteins is a pathological mechanism that is observed...

Meningeal lymphatic vessels drain brain fluid and waste into the cervical lymph nodes, but how removing these nodes during surgery affects brain health is unknown. Retrospective analysis of cancer patients who underwent neck lymphadenectomy without chemo-radiation therapy found that up to 25% developed mild-to-severe cognitive impairment, and neuroimaging showed accelerated temporal horn enlargement after bilateral surgery. To determine mechanistically how cervical lymphadenectomy contributes to...

Atherosclerosis, recognized as a prototypical age-associated vascular disease, is driven by macrophage foam cell formation. Individuals with Parkinson's disease (PD) exhibit an elevated risk for stroke. While α-synuclein (α-Syn) is known for its neuronal role in PD, its presence in the circulation and potential vascular effects remain unexplored. Here, we identify α-Syn as a previously unrecognized circulating factor that promotes atherosclerosis. α-Syn was detected in human atherosclerotic...

Tau, a neuronal microtubule-associated protein (MAP), organizes the axonal cytoskeleton, and regulates intracellular transport. Tau hyperphosphorylation is linked to neurodegeneration in tauopathies, including Alzheimer's disease. Tau binds microtubules cooperatively to form cohesive envelopes, which are thought to control access to the microtubule lattice and regulate the activity of motor proteins and other MAPs. However, how disease-related perturbations affect tau dynamics and its function...

Bcl-2-associated athanogene 3 (BAG3) is a mediator of chaperone-assisted selective autophagy, and in the brain, is most highly expressed in astrocytes. However, its role in astrocytes remains poorly defined. Given the genetic and pathological links of BAG3 to proteostasis and neurodegenerative diseases, we investigated how BAG3 contributes to astrocyte function and Alzheimer's disease (AD). To define its function and relevance, we used single-nucleus RNA sequencing to confirm BAG3 enrichment in...

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder, and dysfunction of triggering receptor expressed on myeloid cells 2 (TREM2) in microglia increases AD risk. TREM2 activation promotes protective microglial functions and mitigates AD pathology. Although TREM2-activating antibodies show therapeutic potential, the mechanisms underlying TREM2-mediated rescue effects remain unclear. Here, we show that two TREM2-activating single-domain antibodies (sdAbs), 10C11 and 10E12,...

Caspase-3, a cysteine-aspartic protease canonically known for its role in apoptotic cell death, has been implicated in several non-apoptotic functions, particularly in microglia, the brain-resident macrophages. These novel functions appear to depend on distinct levels of caspase-3 activation; however, the role of basal caspase-3 activity remains unclear. Here, we show that basal caspase-3 regulates RNA splicing in microglia, and its deficiency in a Parkinson´s disease (PD) model leads to...

Navigation in the real world may rely on a multitude of strategies with distinct advantages and disadvantages; however, the characterization of spontaneous strategy use is scarce. We explore data across three groups engaged in virtual navigation: patients with epilepsy undergoing invasive electrophysiological recordings, two groups undergoing fMRI scanning: young adults at genetic risk for Alzheimer's disease (APOE-ε4 carriers), and healthy controls. We establish metrics to quantitatively...

Amyloid aggregates of α-Synuclein are hallmarks of Parkinson's disease (PD) and related neurodegenerative disorders. Literature suggests that mRNA G-quadruplexes (rG4s) bind to α-Synuclein, facilitating its amyloidogenesis. In parallel, α-Synuclein interacts with RNA-binding proteins (RBPs) within cytosolic RNA-protein granules to modulate mRNA stability. However, mechanisms by which α-Synuclein-interacting RBPs regulate its amyloidogenesis remain unexplored. Here, we report that rG4-dependent...

Alzheimer disease begins in the brain many years before symptoms, but early changes are usually studied after death or indirectly through fluid and imaging biomarkers. Here we show that small brain biopsies collected during ventriculoperitoneal shunt surgery can be used to study Alzheimer disease pathology and protein turnover during life. We analysed biopsies from 18 individuals with suspected normal pressure hydrocephalus, alongside matched ventricular and lumbar cerebrospinal fluid and...

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Cerebrovascular disease is a major but poorly understood feature of Alzheimer's disease (AD). The strongest genetic AD risk factor, apolipoprotein E4 (APOE4), is associated with cerebrovascular degeneration, including vascular amyloid deposition and fibrosis. To uncover how APOE4 promotes cerebrovascular pathology, we assembled a single-cell transcriptomic atlas of human brain vasculature. In APOE4 carriers, pericyte abundance was significantly reduced and accompanied by the emergence of a...

Early diagnosis of Alzheimer's disease (AD) and its prodromal stage, mild cognitive impairment (MCI), requires efficient computational frameworks capable of handling high-dimensional and large-scale 18F-FDG-PET data. To address challenges in feature redundancy and computational efficiency, we propose a unified framework integrating an enhanced Grey Wolf Optimizer (CDL-GWO) with approximate nearest neighbor search based on Facebook AI Similarity Search (FAISS). The proposed CDL-GWO incorporates...

Alzheimer's disease (AD) is highly heterogeneous and driven by diverse molecular and cellular mechanisms. Functional genomics investigates these mechanisms from genetic variants to gene expression and regulation. We performed personalized functional genomics analysis on population-scale single-nucleus RNA-seq data, with cross-cohort validation across multiple cohorts comprising over 1900 individual brains, capturing donor-level cell type interactions and gene regulatory networks. Using a...

Advances in single-cell and -nucleus transcriptomics have enabled generation of increasingly large-scale datasets from hundreds of subjects and millions of cells. These studies promise to give unprecedented insight into the cell type specific biology of human disease. Yet performing differential expression analyses across subjects remains difficult due to challenges in statistical modeling of these complex studies and scaling analyses to large datasets. Our open-source R package dreamlet (...

Neurodegenerative and neuropsychiatric diseases impose a considerable societal and public health burden. However, our understanding of the molecular mechanisms underlying these highly complex conditions remains limited^(1,2). Here, to gain deeper insights into the aetiology of different brain diseases, we used specimens from 1,494 unique donors to generate a population-scale single-cell transcriptomic atlas of the human dorsolateral prefrontal cortex, comprising over 6.3 million individual...

Genetic risk variants for common diseases are predominantly located in non-coding regulatory regions and modulate gene expression. Although bulk tissue studies have elucidated shared mechanisms of regulatory and disease-associated genetics, the cellular specificity of these mechanisms remains largely unexplored. Here we present a comprehensive, single-nucleus multi-ancestry atlas of genetic regulation of gene expression in the human prefrontal cortex, comprising 5.6 million nuclei from 1,384...

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