Alzheimer & Parkinson

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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Alzheimer disease (AD) is defined biologically by the presence of amyloid-β (Aβ) plaques and tau neurofibrillary tangles in the brain; however, these pathologies do not affect all brain regions equally. Typical AD usually presents with memory impairment, whereas atypical forms of AD, including posterior cortical atrophy, logopenic variant primary progressive aphasia, behavioural and dysexecutive AD, and corticobasal syndrome, manifest with prominent non-memory symptoms. Aβ biomarkers usually...

Although women live longer, they paradoxically face heightened susceptibility to cognitive and systemic decline emerging in midlife-an underexplored transition from resilience to vulnerability. Here, we investigate biological processes associated with this female-biased vulnerability and their molecular regulation. Senescence-associated features were preferentially elevated in middle-aged females in human brain and spleen tissues, with similar changes in mice. In female mice, epigenetic...

Microglia, the brain's resident immune cells, rely on histone modifications and chromatin remodeling to sculpt their identity across the trajectory from development through aging. Recent studies have identified enhancer rewiring and metabolic-epigenetic coupling-exemplified by histone lactylation-as central drivers of microglial plasticity. Disruption of this regulatory balance drives the transition from homeostatic microglia toward disease-associated microglia (DAM) in Alzheimer's and...

APOE gene variants encoding the apolipoprotein E (ApoE) protein are strong genetic modifiers of risk of Alzheimer's disease (AD) with the APOE ε4 allele (APOE4) associated with substantially increased disease risk, APOE ε2 allele (APOE2) associated with decreased risk and APOE ε3 allele (APOE3) considered neutral. Recently the Christchurch variant of APOE3 (APOE3CH) has been shown to protect people from familial AD. Despite this strong evidence for APOE mediating AD risk, the exact biological...

Alzheimer's disease (AD) involves complex neuroimmune dysregulation, and the role of immune checkpoint pathways in regulating neuro-glial interactions and intrinsic glial homeostasis remains unclear. In AD, glial expression of programmed cell death protein 1 (PD-1) and its ligand (PD-L1) is elevated in mouse models and human patients, suggesting involvement of immune checkpoint signaling in glial function. To define the role of this pathway in the AD brain, we locally modulated PD-1/PD-L1...

Toward development of an autologous, induced pluripotent stem cell (iPSC)-based cell therapy for Parkinson's disease (PD), we demonstrate successful, reproducible genomic and transcriptomic qualification of patient-derived dopaminergic neuron precursor cells (DANPCs) across multiple donors. Our analysis includes whole-genome sequencing data from fibroblasts, iPSCs, and DANPCs and the development of NeuriTest, an RNAseq-based bioinformatic analysis of DANPCs designed to predict cell quality based...

The role of physical fitness in cognitive reserve and brain maintenance remains unclear. We investigated the associations of muscular and aerobic fitness (VO(2)max) with markers of brain health and cognition in 353 cognitively unimpaired older adults (mean age = 72.77 ± 7.95 years; 177 females). Muscular fitness comprised handgrip strength, appendicular skeletal muscle mass, and Timed-Up-and-Go performance. Blood biomarkers of Alzheimer's pathology (Aβ(1-42)/Aβ(1-40), p-tau(217), GFAP) and...