Alzheimer & Parkinson

Deep learning (DL) has shown success in predicting Alzheimer's disease (AD) diagnosis, yet continuous measures such as cognitive assessment remain critical for richer prognosis, trajectory tracking and clinical trial enrichment. Current neurocognitive batteries are time-consuming, and the few DL models predicting cognition require expensive multimodal neuroimaging and longitudinal data. Although magnetic resonance imaging (MRI) is the most clinically accessible modality, on its own it struggles...

Disease-associated microglial states are thought to contribute to Alzheimer's disease (AD) progression, but characterizing them and their relationships to pathology remains challenging. Here we introduce CODEX-CNS-a multiplexed protein imaging technology with a custom data analysis pipeline for use in human brain samples. We profiled 704,706 cells in samples from the frontal cortex of 8 people with AD and 8 healthy controls and mapped features including blood-brain barrier, meningeal components...

Apolipoprotein E4 (APOE4) is the leading genetic risk factor and an increasingly recognized causal contributor to Alzheimer's disease (AD). AD progresses along a temporal, pathological, and clinical continuum spanning preclinical, prodromal, and dementia stages. Across this continuum, APOE4 exerts detrimental effects at distinct times and in different cell types, underscoring the need for a model defining not only how but also when and in which cells these effects occur. In this review, we...

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Extracellular Vesicles (EVs), the nano-sized extracellular membrane-bound vesicles, facilitate cell-to-cell communication by transporting bioactive molecules like proteins, lipids, and nucleic acids. Their unique cargo, determined by the cell of origin, makes them valuable tools for studying disease pathogenesis and potential drug delivery systems. Research suggests that EVs play a role in the pathogenesis of various diseases, including neurodegenerative and neurodevelopmental disorders. They...

Single-cell multi-omics technologies profile multiple molecular layers in individual cells, but existing methods often struggle to integrate transcriptomic, proteomic, and epigenomic measurements into an interpretable representation while preserving relationships among cells. Here, we present the single-cell multi-omics adversarial graph convolutional autoencoder (scMAGCA), which constructs cell graphs and uses adversarial alignment to learn interpretable shared embeddings that capture cellular...

The APOE locus is the strongest genetic factor for Alzheimer's disease, with ε4 increasing and ε2 decreasing risk, yet the basis of these opposing effects remains unclear. Here we performed a multicohort proteomic analysis across plasma and cerebrospinal fluid in GNPC, BioFINDER-2, ADNI, UK BioBank, and PPMI. APOE-associated protein alterations are detectable before amyloid pathology and remain stable across age and disease progression. APOE2-associated proteins were enriched in pathways related...

Poly(ADP-ribose) (PAR) polymerase 1 (PARP1) has been implicated in DNA damage responses and neuroinflammation in Alzheimer's disease (AD), yet its role in amyloid-beta (Aβ) pathology remains unclear. Here, we show that PARP1 activation drives Aβ pathology and neurodegeneration. Using a sensitive enzyme-linked immunosorbent assay, we observed significantly elevated PAR levels in the cerebrospinal fluid (CSF) of patients with mild cognitive impairment (MCI) and AD compared to controls. In vitro,...

Despite growing catalogs of genetic variation linked to human traits and diseases, the functional impact of most genetic variants remains poorly understood. Alternative splicing, particularly in the human brain, represents a key layer of post-transcriptional regulation that may mediate genetic effects on gene expression and protein diversity. In this study, we systematically map allele-specific alternative splicing (ASAS) events in postmortem brain tissues from the Mount Sinai Brain Bank cohort,...

The accumulation of abnormal tau protein selectively affects distinct brain regions and specific populations of neurons and glial cells in tau-related dementias, such as Alzheimer's disease, Pick's disease and progressive supranuclear palsy. Although the three disorders share the feature of tau protein pathology, the regulatory circuitry of non-coding genetic variants underlying risk-associated cell states remains to be elucidated. Using paired single-nucleus profiling of chromatin accessibility...

ULK1 (Atg1) initiates macroautophagy and mitophagy, which support neuronal growth and survival, yet how this pathway is disrupted in aging and Alzheimer's disease (AD) remains unclear. Here we report reduced ULK1 in serum and cerebrospinal fluid during aging in cognitively unimpaired participants from the COGNORM study (n = 75) and in patients with AD from the NorCog Memory Clinic Cohort (n = 316). In AD mice, ULK1 overexpression stimulates autophagic flux, reduces AD pathology and delays...

Glycoprotein nonmetastatic melanoma B (GPNMB) is critical to cellular uptake of pathological forms of alpha-synuclein (aSyn), the hallmark disease protein in Parkinson's disease (PD). Here, we demonstrate that the non-membrane-anchored, extracellular domain of GPNMB can function in a non-cell-autonomous manner. In the human brain, GPNMB is widely expressed in neurons and microglia. In induced pluripotent stem cell-derived microglia (iMicroglia), GPNMB expression and secretion increase with...

RNA-binding proteins (RBPs) play an essential role in development, normal functioning, and human disease. Staufen1 (STAU1) is an RBP that regulates mRNA degradation and subcellular localization, and is part of the ATXN2 protein complex. Previously, we showed that STAU1 is overabundant in patient fibroblasts and in mouse models of Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and spinocerebellar ataxia type 2 (SCA2), where it is associated with impaired autophagic flux due to...

CONCLUSIONS: In cognitively unimpaired Asian populations, plasma p-tau217 and Aβ42/40 showed good discriminative performance for Aβ PET positivity. Further standardization, external validation, and prospective evaluation are needed.

Accurate measurement of brain vascular pathology is essential for understanding its role in cognitive aging. Here we classified participants using the amyloid-tau-neurodegeneration framework in a multicenter cohort and identified cerebrospinal fluid brain endothelial-derived small extracellular vesicles (c-BEEVs) as a sensitive biomarker, which correlated with vascular risk factors and the severity of small-vessel disease. c-BEEVs showed high diagnostic performance for vascular cognitive...

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Memory decline, particularly in neurodegenerative disorders such as Alzheimer's disease, represents a critical global public health challenge, with projections exceeding 150 million cases by 2050. Current therapeutic options remain limited: while drugs like donepezil and memantine offer symptomatic relief, and newer agents like lecanemab show modest effects on slowing progression, no disease-modifying cures exist. This underscores the urgent need to refine preclinical models bridging discovery...

Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β (Aβ), with soluble oligomers widely recognized as key drivers of neurotoxicity through disruption of synaptic function, mitochondrial integrity, and cellular homeostasis. Targeting Aβ aggregation therefore represents a compelling therapeutic strategy. Here we report a synthetic peptidomimetic foldamer, M4, as a potent modulator of Aβ42 aggregation. Biophysical analyses demonstrate that M4 binds Aβ with high affinity,...

Parkinson disease (PD), the second most common neurodegenerative disorder, is pathologically linked to dysregulated autophagy, a conserved lysosomal degradation pathway. Current conventional PD therapies are often limited by significant side effects, underscoring the demand for alternative treatment strategies. Drug repurposing of FDA-approved compounds represents a promising approach to address this unmet clinical need. Here, by integrating clinical data analysis, we identified an association...

Alzheimer's disease (AD) is associated with impaired connectivity in critical functional networks. This study investigated the effects of 20 Hz transcranial magnetic stimulation (TMS) on brain network mechanisms in 25 patients with AD, including 17 in the TMS group and 8 in the sham group. We analyzed resting-state functional magnetic resonance imaging data, using the amplitude of low-frequency fluctuations (ALFF) and fractional ALFF (fALFF) to quantify neural activity and identify regions of...