Alzheimer & Parkinson

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....

CONCLUSION: Probiotics or synbiotics may improve cognitive test performance, but the certainty of evidence is very low because of risk of bias, substantial heterogeneity, and imprecision. Exploratory subgroup analyses did not provide clear evidence that disease category, intervention duration, intervention type, study-level mean age, strain composition, dosage, or cognitive assessment instrument modified the treatment effect. Larger, well-designed randomized trials are needed.

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Alzheimer disease (AD) is defined neuropathologically by the presence of amyloid plaques and neurofibrillary tangles, yet these canonical lesions alone cannot account for its clinical, regional and cellular heterogeneity. AD is a multicellular, spatially organized disease shaped by the interactions of neurons, glia and vascular cells within distinct anatomical microenvironments. Single-cell and single-nucleus RNA sequencing have made it possible to dissect the transcriptional signatures of...

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Tauopathies, such as Alzheimer's disease, are neurodegenerative disorders characterized by the accumulation and propagation of toxic extracellular forms of the microtubule-associated protein tau across brain regions. Microglia, the resident macrophages of the brain, are known for clearing and degrading toxic proteins. However, emerging evidence suggests that microglia also enhance tau spreading. To dissect the molecular mechanisms underlying microglial responses to extracellular tau, we use...

Spatial multi-omic technologies measure multiple molecular layers within intact tissues. Two central challenges are vertical integration, which combines different molecular modalities, and horizontal integration, which aligns cell types across studies. Here we show domain invariant representation through adaptive calibration (DIRAC), a geometric deep learning model that unifies these tasks in a generalized domain adaptation framework. DIRAC learns task-discriminative features that are...

Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and dementia with Lewy bodies have long been viewed through the lens of protein aggregation. Emerging evidence, however, highlights lipid transfer, load, metabolism, and cellular homeostasis as upstream drivers of pathology. This perspective integrates established neurobiological, genetic, and mechanistic evidence of lipid dysfunction and outlines how these pathways can guide patient stratification, biomarker discovery,...

CONCLUSIONS: This preliminary single-center cross-sectional study revealed significant differences in brain structure and function between PD-WO and PD-nWO patients. These findings provide a better understanding of the neural mechanisms behind the WO phenomenon in PD and suggest potential therapeutic targets.

Pharmacotherapies for obesity and type 2 diabetes are increasingly being evaluated for their effects on cognition and brain health. Evidence from preclinical models, observational cohorts, and clinical trials has intensified interest, but findings remain mixed. A central challenge is to determine whether potential cognitive effects arise from direct actions on neural circuits, indirect consequences of improved cardiometabolic health, or both. This Review examines the evidence across...

While the accumulation of Aβ peptides, derived by proteolytic cleavage from the amyloid precursor protein APP, constitutes a hallmark of Alzheimer's disease, the question of whether endogenous, physiological APP processing serves an essential role for normal brain function(s) has remained elusive. Here, we modified the mouse APP locus to delete the endogenous α- and β-secretase sites (APP residues S592-G621) while preserving the transmembrane topology and the APP C-terminus. These novel knockin...