Alzheimer & Parkinson

Although cerebellum is neuropathologically affected in Alzheimer's disease (AD) and AD-related dementia (ADRD), the cell type-specific genomic and epigenomic changes remain poorly understood. Here, we present single-nucleus multiome (RNA-seq and ATAC-seq) analysis of 103,861 nuclei isolated from both the cerebellum and frontal cortex of diseased individuals and cognitively healthy controls. We identify 431,834 significant peak-to-gene linkages across cell subtypes, revealing cis-regulatory...

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The blood-brain barrier (BBB) has been defined primarily by what it excludes, yet the scale and function of physiological blood-to-brain protein transport remain largely unknown. Using bioorthogonal proteomics, we find that the healthy BBB samples 191 plasma proteins and permits 92 into the brain parenchyma. Enriched for carrier and metabolic functions, these proteins home to distinct brain cell types, such as apolipoprotein A1 (APOA1) to astrocytes and alpha-1 antitrypsin (SERPINA1) to...

Alzheimer's disease (AD), the leading cause of dementia, is increasingly recognized as a metabolic disorder characterized by disrupted insulin and insulin-like growth factor-1 signaling in the brain, a concept now referred to as type 3 diabetes. Central to this perspective is the insulin receptor substrate-1/phosphoinositide 3-kinase/protein kinase B/mechanistic target of rapamycin (IRS-1/PI3K/Akt/mTOR) cascade, which acts as the primary convergence point linking systemic insulin resistance to...

Cholinergic dysfunction is a hallmark of Alzheimer's disease and other memory disorders. Yet, the neurophysiological mechanisms linking cholinergic signaling to memory remain poorly understood. In this study, we administered scopolamine, a muscarinic cholinergic antagonist, to neurosurgical patients with intracranial electrodes as they performed an associative recognition memory task. When scopolamine was present at encoding, we observed disruptions to hippocampal slow theta oscillations (2-4...

White matter free water (FW-WM), quantified using diffusion MRI, reflects extracellular water content and microstructural alterations within water matter, but its genetic architecture and clinical relevance remain largely uncharted. We conducted a multi-omics study integrating 42,039 individuals from the UK Biobank and Alzheimer's Disease Neuroimaging Initiative cohorts to characterize tract-specific FW-WM across genetic, phenotypic, and proteomic dimensions. Genome-wide association analyses...

Slow waves during sleep are fundamental for neural homeostasis, metabolic regulation, and waste clearance and are known to be altered in neurodegenerative diseases. Sleep-like slow waves (SLSWs) have been observed in awake, healthy individuals, where they are linked to fluctuations in vigilance and mind-wandering. Whether SLSWs are altered in Parkinson's disease (PD), and whether such alterations contribute to psychiatric or cognitive complications, remains unknown. In a cohort of 84 nondemented...

Lewy body dementia (LBD), encompassing Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB), is defined by widespread α-synuclein (αSyn) aggregation and frequently exhibits coexistent tau and amyloid-β (Aβ) pathologies. However, whether αSyn pathology is sufficient to drive endogenous tau and Aβ aggregation has remained unclear due to a lack of in vivo models that recapitulate the full spectrum of LBD-associated proteinopathies and neurodegeneration. AIMP2, a parkin substrate...

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Extracellular vesicles (EVs) can modify pathological progression in Alzheimer's disease (AD), the most common neurodegenerative disease in older adults, by spreading pathogenic factors. However, the function of mitovesicles (mtVs)-a recently identified subset of EVs-in AD remain unknown. Here we show that release of mtVs is enriched in brain tissue from patients with AD and 5×FAD mice. Administration of 5×FAD mouse brain-derived mtVs (ADmtVs) induced AD-like behavioral and pathological changes...

Previous studies have shown that amyloid-β (Aβ) oligomers are implicated in the pathogenesis of Alzheimer's disease (AD). Aβ oligomers include various molecules with distinct characteristics, such as dimers and trimers; among these, Aβ dimers have been found to possess neurotoxicity. This study found that Aβ dimers can induce microglial proliferation, enhanced phagocytosis, and pro-inflammatory polarization in the mouse brain even before cognitive impairment occurs, and this effect was validated...

Apolipoprotein E (APOE) genotype alters the risk for Alzheimer's disease (AD) but also affects dementia risk in Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Recent evidence suggests that the APOE Christchurch (CC) mutation protects against AD, however, its effects on PD and DLB are unknown. We generated an APOE CC knock-in mouse to understand its effects on amyloid-β (Aβ), tau, and α-synuclein (α-syn) aggregation. APOE CC mice show increased plasma cholesterol and triglyceride...

Intraneuronal accumulation of hyperphosphorylated tau is a pathological hallmark of Alzheimer's disease (AD) and related tauopathies. Although dysregulation of both histone deacetylases (HDACs) and glycogen synthase kinase 3β (GSK-3β) has been implicated in tau pathogenesis, whether and how they functionally interact to drive tau pathology remains unclear. Here, we identify HDAC7 as a critical scaffold that promotes GSK-3β-tau complex formation, leading to GSK-3β activation and tau...

Univariate differential expression analysis dominates single-cell transcriptomic studies of Alzheimer's disease, yet marginal testing alone cannot resolve multivariate disease-associated structure or distinguish clinical from neuropathological signatures. Here we introduce TriSCOPE, a framework integrating multivariate predictive modeling, donor-aware differential expression, and pseudotime inference, applied to six Alzheimer's disease snRNA-seq datasets comprising ~4.2 million nuclei from 627...

Tau propagation is a key driver of Alzheimer's disease (AD), yet selective markers of seeding-competent tau remain elusive. Ubiquitin phosphorylated at Serine-65 (pS65-Ub) is a PINK1-derived cellular stress signal that accumulates in AD with elevated tau pathology, but its relationship to tau seeding is unknown. Here, using postmortem brain tissue from female and male donors, we show that a subset of tau is covalently modified by pS65-Ub in AD brain. The pS65-Ub-associated tau population is...

Neurotoxic intermediates formed during amyloid-β (Aβ) aggregation are thought to drive Alzheimer's disease, yet their rarity and transient nature have obscured their identity and formation pathways in the human brain. Here, we combine super-resolution microscopy and single-molecule functional imaging with kinetic modelling to classify Aβ intermediates according to their membrane-disrupting activity and connect their damaging effects to the aggregation pathways that generate them. Applying this...

Parkinson disease (PD) is a heterogeneous neurodegenerative disorder characterized by variable progression and treatment response. Over the past three decades, genetic discoveries have reshaped our understanding of PD biology, identifying rare monogenic forms, strong genetic risk variants and a large set of common and rare genetic variants variably contributing to PD heritability. These findings led to the identification of key pathways implicated in the neurodegenerative process, including...

Single-cell genomics is transformative for characterizing cellular heterogeneity, but many biological questions require comparing samples rather than individual cells. Typical analyses compare "case" and "control" groups, ignoring sample-level variation within them. Here, we present scSLIDE (single-cell sample-level inference using density estimation), a framework that transforms each sample's single-cell data into a compact profile describing where its cells are distributed in high-dimensional...

Region-specific synapse loss is an early hallmark of Alzheimer's disease, yet the upstream signals that render synapses vulnerable remain unclear. In a mouse model of amyloidosis, we identify an early astrocyte state that emerges in vulnerable brain regions before widespread plaque deposition and overt gliosis. These astrocytes exhibit bulbous-looking perisynaptic processes enriched in p62 and glycogen, impaired autophagic flux and calcium signaling, and diminished astrocyte-synapse coverage....