Alzheimer & Parkinson

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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The complexity of Alzheimer's disease (AD) manifests in diverse clinical phenotypes, including cognitive impairment and neuropsychiatric symptoms. However, the etiology of these phenotypes remains elusive. To address this, the PsychAD project generated a population-level single-nucleus RNA sequencing dataset comprising over 6 million nuclei from the prefrontal cortex of >1,000 individual brains, covering a variety of disease phenotypes. Here, leveraging this dataset, we developed a computational...

Parkinson's disease (PD) is characterized by abnormal oscillatory activity and altered interregional coupling within the cortico-subthalamic (M1-STN) circuit. Transcranial magneto-acoustic stimulation (TMAS) combines focused ultrasound with a static magnetic field, but its modeled physical responses and circuit-level effects remain incompletely characterized. We integrated multiphysics simulations with behavioral testing, simultaneous M1-STN local field potential recordings, Golgi-Cox staining,...

Alzheimer's disease is widely conceptualized as a biological continuum initiated by amyloid-β (Aβ) accumulation, followed by tau aggregation and neurodegeneration. Although the ATN framework is commonly used to define disease stages, its static biomarker categories may not fully capture the dynamic pathological transitions that determine the optimal window for anti-Aβ therapies. Here, we introduce a Biological Continuum framework that distinguishes dynamic pathological cascades from static...

Exosomes offer a promising vehicle for noninvasive diagnosis of neurodegenerative diseases by carrying multiple biomarkers across the blood-brain barrier. However, traditional exosome analysis often misses subtle genotype-specific variations because of weak signals from a few exosomes, reliance on markers, and limited understanding of disease signatures. Here, we present a sound way to understand Alzheimer's disease through label-free surface-enhanced Raman scattering (SERS) profiling of...

Mitochondria play a crucial role in cellular energy metabolism. The heart and brain require a continuous and stable energy supply. Energy production strongly depends on proper mitochondrial function. Mitochondrial fusion and fission, known as "plasticity", are vital for maintaining the normal physiological function of cells. Recent studies have shown that impaired mitochondrial dynamics are present in many aging-related diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and...

Parkinson's disease (PD) is characterized by the accumulation of Lewy bodies (LBs) in the brain, predominantly consisting of aggregated and phosphorylated α-synuclein (α-Syn). Consequently, strategies to suppress α-Syn expression offer substantial therapeutic potential for PD. This study explores heteroduplex oligonucleotides (HDOs), an innovative gene-silencing technology utilizing DNA/RNA or DNA/DNA hybrids. We designed two HDOs targeting α-Syn: α-Syn-HDO-1 (DNA/RNA) and α-Syn-HDO-2 (DNA/DNA)....

Menopause is a hallmark process in biological aging that has been implicated in later neurodegenerative risk, but the pathways underlying this connection remain unclear. Here we used blood proteomics data from several cohorts to identify biological changes associated with menopause and its links to brain aging. In n = 80 rigorously staged (STRAW+10) pre-, peri- and postmenopausal women (aged 43-58 years) with serum NULISAseq proteomics, we show that spontaneous menopause is characterized by...

Alzheimer's disease (AD) remains a major unmet medical challenge despite decades of progress in medicines that target tau and amyloid-β (Aβ) pathology. The clinical benefit of monoclonal antibodies (mAbs) against Aβ is limited, with current data showing only slight slowing of cognitive decline despite encouraging biomarker responses and recent regulatory approval of these drugs. Moreover, their wider clinical use is restricted by dose-dependent toxicities such as amyloid-related imaging...

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