BACKGROUND: TAR DNA binding protein - 43 (TDP-43) nuclear loss is a pathological hallmark of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and related neurodegenerative disorders. While the consequences of TDP-43 dysfunction have been well-characterized, the mechanisms driving TDP-43 mislocalization remain poorly understood. Previous observations of altered localization and function of the adenosine-to-inosine (A-to-I) RNA editing enzyme adenosine deaminase acting on RNA 2 (ADAR2) in ALS/FTD tissue prompted us to investigate whether dysregulated RNA editing contributes to pathological TDP-43 nucleocytoplasmic trafficking. METHODS: TDP-43 cytoplasmic mislocalization was assessed following ADAR2 and TDP-43 co-overexpression in HEK293T cells and a Drosophila model co-overexpressing human TDP-43 and dADAR in motor neurons. We further evaluated TDP-43 mislocalization through both HeLa cell assays and interspecies heterokaryon assays. Next, we assessed TDP-43 binding to A-to-I edited RNA oligomers through electrophoretic mobility shift assays (EMSAs), and investigated inosine-containing RNAs in vivo via TDP-43 RNA immunoprecipitation followed by sequencing (RIP-seq) datasets from human TDP-43-expressing Drosophila. Finally, RNAseq and enhanced cross-linking and immunoprecipitation (eCLIP-seq) were performed in SH-SY5Y cells overexpressing three ADAR2 variants with differing editing activity to identify editing-related transcriptional alterations and RNAs differentially bound to TDP-43. RESULTS: ADAR2 overexpression reduced the nucleocytoplasmic (N:C) ratio of TDP-43 in HEK293T cells in a ADAR2 catalytic activity- and TDP-43 RNA-binding capacity-dependent manner. Drosophila motor neurons overexpressing dADAR also exhibited decreased nuclear TDP-43. Interspecies heterokaryons and permeabilized HeLa cell assays demonstrated that catalytically active ADAR2 and synthetic inosine-containing RNA oligomers, respectively, enhance nuclear export of endogenous TDP-43. EMSAs revealed preferential binding of TDP-43 to inosine-containing RNAs relative to unedited RNAs, and analysis of Drosophila RIP-seq datasets demonstrated enrichment of edited transcripts within TDP-43-bound RNAs. Finally, RNAseq and eCLIP-seq analyses identified editing-dependent alterations in gene expression and TDP-43 RNA-binding profiles in SH-SY5Y cells overexpressing active ADAR2 variants. CONCLUSIONS: Together, our findings identify A-to-I RNA editing as a previously unrecognized regulator of TDP-43 localization and RNA interactions. These results support a model where altered RNA editing modifies TDP-43-RNA interactions, promoting increased nuclear export of TDP-43. Broadly, our work highlights RNA editing dysregulation as a potential contributor to early pathogenic mechanisms underlying TDP-43 proteinopathies.

Frontotemporal Dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS) are linked neurodegenerative diseases characterized by both synaptic dysfunction and TDP-43 pathology. A hexanucleotide repeat expansion (HRE) in the C9ORF72 (C9) gene represents the most common genetic cause of FTD and ALS, yet the synapse-specific mechanisms underlying disease pathogenesis remain poorly understood. Here, we performed integrated multi-omic profiling of synaptosomes enriched from postmortem frontal cortex and patient-derived induced pluripotent stem cell (iPSC)-derived cortical neurons to define molecular alterations associated with C9-FTD-mediated synaptic dysfunction. Proteomic profiling of frontal cortex-derived synaptosomes identified 1,324 differentially abundant proteins (p<0.05) enriched in pathways regulating synaptic vesicle transport and synapse organization, while synaptosomal RNA sequencing revealed 2,835 differentially expressed protein-coding genes. C9-FTD iPSC-cortical neurons exhibited reductions in excitatory and inhibitory postsynaptic markers, accompanied by progressive impairment of neuronal network activity, supporting both structural and functional deficits. iPSC-derived synaptosomes recapitulated key molecular pathways observed in patient brain, revealing convergent dysregulation of synaptic signaling pathways. Comparative analyses revealed divergence between protein and RNA alterations, consistent with the disruption of regulatory processes that link RNA and protein abundance diseased synapses. Consistent with TDP-43 loss-of-function pathology we identified cryptic exon (CE)-containing transcripts within C9-FTD frontal cortex-derived synaptosomes, including KALRN and STMN2, providing evidence that aberrantly spliced RNAs localize to synaptic compartments. Together, these findings define convergent molecular pathways underlying synapse vulnerability in both C9-FTD model systems and identify synaptic localization of CE-containing transcripts as a previously unrecognized feature of TDP-43 proteinopathy.

Aging is an unavoidable part of life, but gaps still remain in the understanding of age-associated molecular changes within the brain. We generated single-nucleus multiome ATAC plus gene expression profiles in 357 human brain samples from European and African admixed ancestry individuals ranging from 15 to 100 years old. The final dataset consisted of paired transcriptomic and epigenomic profiles for over 1.5 million cells. These were classified into seven major cell types using canonical marker genes, and each type was analyzed for features associated with aging. Open chromatin regions were correlated with transcription factor expression to identify age-associated regulatory networks, and co-accessibility identified linked peaks and genes, revealing a catalog of putative cis-regulatory elements by cell type. These multiomic data serve as a resource to characterize transcriptional regulation by cell type and generate hypotheses about how these distinct profiles both influence and are influenced by aging and disease.

Background:Plasma brain-derived pTau217 (BD-pTau217) may provide a Alzheimer's disease-specific plasma tau measure than total pTau217, but its prognostic value is unclear. We compared BD-pTau217 and total plasma pTau217 for predicting clinical and amyloid PET progression in cognitively unimpaired (CU) ADNI participants. Methods:Plasma NULISAseq biomarkers were measured in 1,427 ADNI participants, including 529 CU individuals. Amyloid PET progression was assessed in baseline CU amyloid-negative participants (Centiloid ≥24.1) with longitudinal PET imaging; clinical progression was assessed in all baseline CU participants. Associations were evaluated using Cox models and time-dependent AUC. Results:BD-pTau217 did not clearly outperform total pTau217 for predicting progression to mild cognitive impairment or dementia. However, among baseline amyloid-negative participants (N=175), BD-pTau217 better predicted amyloid PET positivity at 2.5 years (tdAUC 0.82 vs 0.69; HR=10.54, p=0.00015) and 4 years (tdAUC 0.77 vs 0.64; HR=7.03, p=0.00055). Conclusion:BD-pTau217 improved prediction of near-term amyloid PET progression, with less clear advantage for clinical progression.

We demonstrate how Large Language Models (LLMs) accelerate biomedical data harmonization through automated Common Data Element (CDE) generation. We processed 31 datasets including clinical taxonomies and research data dictionaries through OpenAI's Generative Pre-trained Transformer - 4 (API Model gpt-4-0613), generating comprehensive metadata for each element using a template-based system. Subject-matter experts validated outputs, finding 94% of generated metadata fields required no revision overall, with an unweighted accuracy of 83.8%, unweighted, for semi-structured sources. Dramatically faster than manual approaches. Our system uses ElasticSearch with weighted field matching to identify semantic equivalences between variables, avoiding duplicate CDEs while building a standardized repository. Testing with Alzheimer's Disease Neuroimaging Initiative (ADNI) and Global Parkinson's Genetic Program (GP2) datasets showed 32.4% of previously unseen headers successfully mapped to our CDEs, with interoperability scores averaging 53.8/100 based on matching, completeness, and compliance metrics. This approach automates the most tedious aspects of data integration, reducing barriers to cross-study collaboration in biomedical research.

BACKGROUND:Most Alzheimer's disease (AD) cases show mixed pathology, with α-synuclein (αSyn) aggregates present in a substantial proportion. The cerebrospinal fluid (CSF) α-synuclein seed amplification assay (αS-SAA) enables in vivo detection of pathogenic αSyn aggregates, but its clinical significance remains unclear. METHODS:We prospectively evaluated 108 individuals with mild cognitive impairment or mild dementia due to suspected AD undergoing lumbar puncture for anti-amyloid therapy (ATT) eligibility. CSF AD biomarkers and αS-SAA were analyzed alongside cognitive, olfactory, and rapid eye movement sleep behavior disorder (RBD) assessments. RESULTS:Of 65 participants with biomarker-confirmed AD, 21 (32.3%) were αS-SAA positive. Positivity was linked to older age at testing and self-reported olfactory impairment (P = 0.004), but not other demographic or cognitive features. Within the αS-SAA-positive group, RBD presence correlated with faster seeding kinetics. CONCLUSIONS:αS-SAA positivity is common in early AD and associated with olfactory dysfunction. Longitudinal follow-up is required to test if assay status predicts response to ATTs.

The Persistence of SARS-CoV-2 in tissues has been proposed as a driver of prolonged symptoms in long COVID. Pulmonary rehabilitation with exercise training is a well-established intervention for improving symptoms, functional capacity, and inflammation in chronic cardiorespiratory diseases. To investigate whether long COVID is associated with persistent viral or immune-related signals, we analyzed the long RNA profile of circulating extracellular vesicles (EVs) to determine the presence of virus-related transcripts and assess changes in response to exercise training. Fourteen adults with long COVID participated in this single-center pilot clinical trial and completed a 10-week aerobic exercise training program (twenty 1.5 h sessions). Serum-derived EV RNA profiles were analyzed via sequencing at rest (T0) and peak cardiopulmonary exercise testing (T1), before (V2) and after (V24) exercise training. Differentially expressed genes (DEGs) were identified (q < 0.05), and pathway activation analysis was performed. Serum EVs carried diverse RNA species, including protein-coding RNAs, long non-coding RNAs, short non-coding RNAs, and pseudogenes, with no virus-related RNAs detected. No significant DEGs were identified at rest between pre- and post-training, nor in response to acute exercise at pre-training. However, following training, 53 DEGs were found at peak exercise (V24T1) compared to rest (V24T0), including three upregulated genes (ANK3, FTO, FCN1) and 50 downregulated genes (TOP 5: MYL9, NRGN, H2AC6, MAP3K7CL, B2M). These genes were primarily involved in inflammation and metabolism. Pathway analysis revealed significant regulation of 100 pathways at post-training compared to pre training, predominantly inactivated, including pathways involved in inflammation (STAT3 signaling) and metabolism (O-linked glycosylation). Acute exercise and exercise training modulated EV-associated gene expression in long COVID, primarily through transcriptional downregulation. Suppression of inflammation- and immune-related genes post-training highlights potential molecular mechanisms underlying symptom improvement and identifies candidate biomarkers of recovery biology in long COVID. Importantly, while exercise training did not substantially alter EV RNA content at rest, it enhanced the body’s ability to mount a dynamic EV-mediated molecular response during exertion, reflecting improved physiological adaptability. Clinical trial registration number: NCT05398692.

Warfighters face significant risk of mild traumatic brain injury (mTBI) during operations and training. We performed a double-blind, randomized, placebo-controlled trial to: (1) determine head strike (HS) incidence, during US Army Basic Airborne Course's Improved Swing Landing Trainer (ISLT) training, (2) test protective efficacy of ketone monoester (KME) supplementation, and (3) assess blood-based mTBI biomarker signatures. We enrolled 354 active-duty male and female service members randomized 1:1 to placebo (PLA) or KME; n = 318 completed ISLT and assessments (PLA = 157, 142 M/15F; KME = 161, 144 M/18F). N = 112 (35.2%; 35.7% in PLA, 34.8% in KME) experienced HS, defined as whiplash or helmet-to-ground impact. Assessments included the Automated Neuropsychological Assessment Metric (ANAM-4), SWAY balance testing, and plasma biomarkers. One ANAM-4 measure (Simple Reaction Time-Repeat; p = 0.024) and one SWAY measure (Single Leg Right; p = 0.014) demonstrated significant HS × Time × Treatment interactions, with performance decrements in HS + PLA not observed in HS + KME. Several HS × Time interactions were observed for ANAM-4 and SWAY variables, indicating HS-induced cognitive and balance decline. No relevant blood-based biomarker patterns were associated with HS or KME. Predictive modeling identified variables associated with HS risk with moderate accuracy. In conclusion, ISLT resulted in ~32% head injury incidence and KME supplementation showed limited protection of cognitive and balance without corresponding biomarker changes.

Hexanucleotide repeat expansions (HREs) in C9orf72 are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), yet the age-, sex-, repeat-length-, and circuit-specific influence on the pathology of neurons remains incompletely understood. Here, we established a Drosophila model of C9orf72 -associated dementia by expressing G4C2 repeats in mushroom body neurons (MBNs), a brain region critical for memory, locomotion, and sleep. Expression of 44X G4C2 repeats ((G4C2) 44X ) led to progressive axonal thinning, age-dependent accumulation of Repeat Associated Non-AUG (RAN) translated GR-GFP dipeptide repeat (DPR) puncta, premature nuclear-to-cytoplasmic mislocalization of endogenous TDP-43, increased caspase, reduced lifespan and a loss of presynaptic active zones. Behaviorally, (G4C2) 44X expression caused locomotor hyperactivity, altered spatial working memory, and fragmentation of sleep architecture in an age- and sex-dependent manner, recapitulating core features of FTD. Surprisingly, the shorter (G4C2) 12X repeat, traditionally considered a control, also produced detectable RAN translation and intermediate phenotypes in aging MBNs, suggesting that length- and tissue-associated factors modulate repeat toxicity. We further identified a repeat-length- and age-dependent reduction of the glypican Dally-like protein (Dlp) in (G4C2) 44X consistent with disrupted Wnt-related signaling linked to TDP-43 proteinopathies. Restoring Dlp expression in MBNs mitigated locomotor and working-memory alterations, and loss of presynaptic active zones. In contrast, axonal degeneration, TDP-43 mislocalization, and lifespan were not significantly improved by restoring Dlp, suggesting that multiple mechanisms contribute to G4C2-induced toxicity. Supporting our findings in Drosophila MBNs, a CRISPRi screen in TDP-43 knock-down iNeurons identified GPC6, a human ortholog of Dlp, as a significant contributor to TDP-43 dependent synaptic loss. Together, our findings reveal an aging-sensitive, circuit-specific model of C9orf72 -associated neurodegeneration and highlight roles for DPR accumulation and Dlp/GPC6 dependent synaptic loss in FTD pathomechanisms.

Epstein-Barr virus (EBV) infection is nearly ubiquitous and strongly linked to multiple sclerosis (MS), but how EBV-infected B cells communicate with distal tissues remains unclear. We performed an integrated multiomic characterization of small extracellular vesicles (sEVs) released from spontaneous lymphoblastoid cell lines (SLCLs) derived from healthy donors and patients with MS, transformed ex vivo by endogenous wild-type EBV. Proteomics identified over 6,000 shared proteins enriched in nucleic acid-binding and chromatin-associated factors. EV-associated DNA resolved into two structurally distinct compartments: DNase-sensitive, high-molecular weight DNA associated with the vesicle corona and DNase-resistant, nucleosome-sized (~130-150 bp) DNA. Both compartments were overwhelmingly host-derived and broadly genomically distributed, whereas EBV DNA was minimal. In contrast, viral RNA cargo was dominated by the EBV noncoding RNA EBER1, which was strikingly enriched across all lines and confirmed within individual vesicles by ddPCR and super-resolution microscopy. EBER1 has previously been detected in MS brain tissue, yet its route to the CNS has remained unexplained. Our findings identify sEVs as a plausible vehicle for disseminating this immunostimulatory viral ncRNA beyond sites of latency, pointing to EV-mediated export of EBER1 as a candidate mechanism linking peripheral EBV infection to distal tissue signaling in MS and beyond.

Cerebral amyloid angiopathy (CAA) is a cerebrovascular disorder characterized by the deposition of amyloid-β (Aβ) in the walls of leptomeningeal and cortical blood vessels that increases risk of intracerebral hemorrhages and progressive cognitive decline. More than 90

Introduction: The prevalence of hepatic steatosis—a central and early phenotype in multi-system metabolic dysfunction—is increasing in parallel with the obesity pandemic, calling for novel approaches for prevention and treatment. Hypothesis: We hypothesized that the circulating proteome may reflect cell specific mechanisms of hepatic steatosis. Methods: Using multi-modality hepatic imaging and broad circulating proteomics in approximately 5,000 individuals across 3 diverse cohorts (CARDIA, Cameron County Hispanic Cohort, UK Biobank), we identified proteins implicated in the progression of hepatic steatosis. We tested for a relationship with these proteomic markers of hepatic steatosis with metabolic-related clinical outcomes in UK Biobank. We translated these findings from the circulating proteome to several tissue-based datasets including bulk RNA sequencing, single-cell RNA sequencing, and spatial transcriptomics. To further prove the hepatocyte origin of prioritized proteins, we used a humanized “liver-on-a-chip” model. Results: We observed proteins implicated in the progression of hepatic steatosis—such as those related to central carbon and amino acid metabolism, hepatocyte regeneration, inflammation, fibrosis, insulin sensitivity—are largely encoded by genes enriched at the transcriptional level in human liver. Circulating multi-protein signatures of hepatic steatosis were strongly associated with a fatty liver disease phenotype and multi-system metabolic outcomes in >26,000 free-living individuals. Moreover, we observed increased activity of transcripts encoding proteins prioritized in clinical studies spatially in areas of steatosis via spatial transcriptomics in human liver, with several top candidates dynamic during progression of steatosis in human liver. Finally, using a humanized “liver-on-a-chip” model, we induced hepatic steatosis, confirming cell-specific expression of targets implicated across tissue and clinical studies at a transcriptional and proteomic level. Conclusions: These results underscore the utility of a unified approach that combines human studies, multi-omics, and dynamic tissue-on-a-chip experiments to identify a prognostic, functional, dynamic “liquid biopsy” of human liver, with relevance for clinical biomarker discovery and mechanistic research applications.

Blood-based RNA transcriptomics offers a promising avenue for identifying biomarkers of Parkinson’s disease (PD) progression and mechanisms of pathogenesis. Previous work uncovered an age-related increase of neutrophil-enriched gene expression in PD whole blood, which may obscure disease-relevant transcriptomic signals. To better capture PD-associated molecular differences, we analyzed PD whole-blood RNA sequencing data using a differential expression approach that accounts for neutrophil composition. We built a model to estimate neutrophil percentages in 6897 Parkinson’s Progression Markers Initiative and Parkinson’s Disease Biomarkers Program samples from gene expression. By incorporating predicted neutrophil percentages as a covariate, we see significant SNCA downregulation in all PD cohorts, a signal previously obscured by immune cell-related effects. Lowered SNCA expression was observed in individuals with known PD-linked gene mutations (e.g., SNCA, GBA1, LRRK2) and those without known pathogenic variants. These findings suggest that decreased SNCA expression in whole blood may be a defining transcriptomic feature of PD.

Extracellular vesicles (EVs), membrane-encapsulated nanoparticles shed from all cells, are tightly involved in critical cellular functions. Moreover, EVs have recently emerged as exciting therapeutic modalities, delivery vectors, and biomarker sources. However, EVs are difficult to characterize, because they are typically small and heterogeneous in size, origin, and molecular content. Recent advances in single EV methods have addressed some of these challenges by providing sensitive tools for assessing individual vesicles; one example is our recently developed Single Extracellular VEsicle Nanoscopy (SEVEN) approach. However, these tools are typically not universally available to the general research community, as they require highly specialized equipment. Here, we show how single EV studies may be democratized via a novel method that employs super-resolution radial fluctuations (SRRF) microscopy and advanced data analysis. SRRF is compatible with a wide range of microscopes and fluorophores. We herein quantified individual EVs by combining affinity isolation (analytical protocol based on SEVEN) with SRRF microscopy and new analysis algorithms supported by machine learning-based EV assessment. Using SEVEN, we first optimized the workflow and validated the data obtained on wide-field and total internal reflection fluorescence microscopes. We further demonstrated that our approach, which we call the SEVEN-Universal Protocol (SEVEN-UP), can robustly assess the number, size, and content of plasma and recombinant EVs. Finally, we used the platform to assess RNA in EVs from conditioned cell culture media. Using SYTO RNASelect dye, we found that 18% of EVs from HEK 293T cells appear to contain RNA; these EVs were significantly larger compared with the general EV population. Altogether, we developed an economical, multiparametric, single EV characterization approach for the research community.

Genetics research in Parkinson's disease has identified over 100 risk loci, yet translating these findings into understanding of disease mechanisms, clinical and pathological heterogeneity, and disease progression remains a challenge. This task requires exploring how genetic risk factors operate over time, interact with environmental factors, and contribute to the diverse ways in which disease manifests. The development of α-synuclein seeding amplification assays (SAAs) offers the opportunity to understand Parkinson's disease pathogenesis and heterogeneity, and drive the development of new disease-modifying and prevention interventions. Emerging biomarker tools, such as α-synuclein SAAs, hold great promise in uncovering the pathological underpinnings of Parkinson's disease and related disorders. Integrating α-synuclein SAAs with genetic data will redefine Parkinson's disease biology and, importantly, identify the temporal sequence of genetic risk, whether that be as a driver of an initiating pathological event or as a response to an initiating stochastic, environmental, or other genetic event. Furthermore, studying genetic and environmental influences in individuals who are asymptomatic but have detectable α-synuclein pathology will provide actionable insights for disease prevention and therapeutic interventions.

Neural stem cell (NSC)-based therapies offer a promising strategy to promote brain repair by delivering neurotrophic factors, supporting cell replacement, and stimulating endogenous neurogenesis following injury. While numerous studies have highlighted the protective and regenerative potential of NSCs and their extracellular vesicles (EVs), progress toward clinical translation remains hindered by limited molecular characterization of NSC lines and their EV cargo. To address this gap, we characterized two therapeutically relevant human fetal NSC lines, LMNSC01 and LMNSC02, both engineered to express the L-MYC gene, along with their corresponding EVs. LMNSC01 cells primarily differentiated into neurones with limited glial populations, whereas LMNSC02 cells gave rise to all three major neural lineages: neural, glial and oligodendrocyte progenitor cells (OPCs). scRNA-seq revealed distinct transcriptional profiles with minimal overlap between the two LMNSC lines. Using single extracellular vesicle nanoscopy, we observed that both lines released predominantly circular EVs, with LMNSC02-EVs exhibiting higher levels of tetraspanins (CD9, CD63, and CD81) and a larger average diameter than LMNSC01-EVs. Proteomic profiling revealed that LMNSC01-EVs are enriched in proteins involved in cell adhesion, migration, junction formation, and neuronal projection development, while LMNSC02-EVs are enriched in factors related to cytoplasmic translation initiation and biosynthesis. These LMNSC-EVs (collected from undifferentiated LMNSCs) demonstrated neuroprotective effects in a brain organoid model of methotrexate-induced toxicity when added to corresponding LMNSC01- or LMNSC02-derived brain organoids. LMNSC01- and LMNSC02-derived EVs restored neuronal and astrocytic populations but failed to rescue OPCs. These findings demonstrate the therapeutic potential of LMNSC-derived EVs to counter chemotherapy-induced neurotoxicity by preserving neurones and astrocytes, while highlighting the need for repeated or complementary interventions to restore oligodendrocyte populations.

Microglia are immune cells of the brain and act as major antigen presenting cells. Antigen presentation involves the human leukocyte antigen (HLA) complex, which is implicated in genetic risk of multiple neurodegenerative diseases. How HLA affects the function of microglia in the context of neurodegenerative disease remains unclear. Here, we investigated the HLA epitopes and their protein interactome in human induced pluripotent stem cell (iPSC)-derived microglia-like cells (iMGLs) using systematic mass spectrometry (MS)-based immunopeptidomics, whole-cell proteomics, affinity purification, and prediction algorithms. Our results revealed the presence of almost 7,000 peptides presented by HLA class I and II within microglia. We further showed that the immunopeptidome landscapes of iPSCs, iMGLs and interferon-gamma (IFNγ) stimulated iMGLs are all readily distinguishable. Furthermore, HLA interacts with different groups of proteins in iPSCs compared to iMGLs which involve proteins in immune response. Importantly, we detected 25 HLA epitopes derived from 15 genes associated with Alzheimer's and related dementias such as Tau, PLD3 (Alzheimer's disease), TDP-43, FUS (Frontotemporal dementia), and PARK7, VPS35 (Lewy Body dementia). We predicted 31 mutant epitopes derived from these ADRD genes that could be presented with strong interaction to HLA molecules. Along with these epitopes, we observed an enrichment of immune-related interaction proteins in microglia treated with IFNγ. These results provide evidence that aggregated and mutated proteins can interact with HLA alleles and be presented on the cell surface by microglia cells. This study sheds light on the antigen presenting and adaptive immunity mechanism within the central nervous system and its possible effects on neurodegenerative diseases.

Advanced age, genetics, and environmental exposures are leading contributors to the development of neurodegenerative disorders (NDD). In this study, we used data from the UK Biobank (UKB) and the All of Us (AoU) initiative to determine if exposure to specific medications are associated with an increased or decreased risk of NDD, including Alzheimer's (AD), Parkinson's disease (PD), and all-cause dementia (DEM). We investigated the associations between these diseases and prescription drug exposures through an unbiased analysis, assessing both lifetime risk and risk from exposures occurring more than ten years before diagnosis, while also accounting for comorbid conditions. Methods:Cox proportional hazard models were used to evaluate both lifetime and ten-year lag-associated risks of developing a NDD following exposure to specific prescription medications. This analysis followed a two-stage design, incorporating separate discovery and replication cohorts sourced from national-scale biobanks. Findings:We pulled data from over 700,000 health records from individuals of European ancestry to survey a total of 480 prescription medication exposures. After multiple test corrections, we found 241 significant associations between medication exposure and risk of NDDs in our discovery cohort, with 157 of these replicated in an independent dataset. After adjusting for potential comorbidities, 15 medication-NDD associations remained significant, some of which were attenuated after accounting for APOE-ε4 status. Most of these significant pairings were associated with increased risk, however, two antibiotics, one proton pump inhibitor, and one statin had replicated effects inversely associated with disease risk. Interpretation:While correlation does not imply causation and some associations may be driven by medications used to treat prodromal stages of disease, we have utilized large, unbiased datasets to identify and replicate associations between commonly prescribed medications and NDD risk. Additional longitudinal and mechanistic investigations are warranted.

We characterized circulating extracellular vesicles (EVs) in obese and lean humans, identifying transcriptional cargo differentially expressed in obesity (277 unique genes; false discovery rate < 10%). Since circulating EVs may have broad origin, we compared this obesity EV transcriptome with expression from human visceral-adipose-tissue-derived EVs from freshly collected and cultured biopsies from the same obese individuals, observing high concordance. Using a comprehensive set of adipose-specific epigenomic and chromatin conformation assays, we found that the differentially expressed transcripts from the EVs were those regulated in adipose by body mass index-associated SNPs (p < 5 × 10-8) from a large-scale genome-wide association study (GWAS). Using a phenome-wide association study of the regulatory SNPs for the EV-derived transcripts, we identified a substantial enrichment for inflammatory phenotypes, including type 2 diabetes. Collectively, these findings represent the convergence of the GWAS (genetics), epigenomics (transcript regulation), and EV (liquid biopsy) fields, enabling powerful future genomic studies of complex diseases.