Alzheimer & Parkinson

Multimorbidity presents challenges for research and health care. We investigated how immune-proteins influence multiple diseases to identify shared mechanisms and therapeutic opportunities. Using eight large plasma proteome GWAS, we identified cis-acting variants for 151 immune-proteins and applied cis-Mendelian randomization to assess associations with 64 diseases and biomarkers. Protein-disease communities were derived using a knowledge graph integrating multiplicity-corrected associations,...

Transcranial ultrasound stimulation (TUS) is a promising noninvasive technique for modulating deep brain targets and circuits with high spatial precision. For its successful clinical translation, confirmation of target engagement, together with a deeper understanding of the effects of TUS, is essential. To advance these goals, we obtained direct measures of neural activity using electrodes implanted in the subthalamic nucleus (STN) in patients with Parkinson's disease (PD) during TUS of deep and...

Non-neuronal brain cells and systemic immunity play a central role in Alzheimer's disease (AD) and other brain disorders. The immune system, initially protective, becomes dysfunctional as the disease progresses. Here, we discuss next-generation therapeutic approaches aimed at treating the immune system rather than the brain to combat AD and other neurodegenerative diseases.

The assembly of tau into amyloid filaments is associated with more than 20 neurodegenerative diseases, collectively termed tauopathies. Electron cryo-microscopy (cryo-EM) structures of brain-derived tau filaments revealed that specific structures define different diseases, triggering a quest for the development of experimental model systems that replicate the structures of disease. Here, we describe 12 phosphomimetic serine/threonine-to-aspartate mutations in tau, which we term PAD12, that...

Parkinson's disease (PD) is characterized by abnormal beta oscillations (13-30 Hz) within the basal ganglia, which contribute not only to motor symptoms but also to sleep disturbances. In this study, we developed a computational model of the basal ganglia-thalamocortical (BGTC) network that includes the pedunculopontine nucleus (PPN), to investigate the mechanism by which the abnormal oscillations disrupt sleep. The model incorporates key nuclei, neurotransmitter systems, and neural pathways to...

Differential diagnosis of neurodegenerative parkinsonian syndromes is complicated by overlapping clinical features and frequent co-pathology that challenges the interpretation of single-protein biomarkers. We evaluated a multimodal, minimally invasive biomarker strategy integrating dermal α-synuclein and 4-repeat tau seed amplification assays (SAAs) with serum neurofilament light chain. In a prospective cohort of 166 participants (Parkinson's disease, n = 40; multiple system atrophy, n = 29;...

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.