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01.
arXiv (CS.LG) 2026-06-24

RE4: Transformation-aware Imitation of Object Interactions Using Manipulation Modes

arXiv:2606.24403v1 Announce Type: cross Abstract: Object interaction tasks have been a focus of advances in imitation learning. End-to-end methods, dominated by diffusion and flow-based variants have shown leaps in performance while sacrificing interpretability. Object-centric and pose-informed variants have had a role in learning from demonstration in manipulation tasks. In this paper, we revisit a few modern imitation learning benchmarks for object interactions, with the aim of composing a framework that repurposes principled theories of manipulation, preserving both performance and interpretability. For image observations, lightweight training is proposed for model-free pose estimation of the target object, using self-supervision over the demonstration data available for imitation learning. This information is then used to inform a manipulation mode-aware retrieval of a demonstration, a mode-aware transformation, a replan step that connects to the retrieval point while preserving mode constraints, and finally rolling out the transformed demonstration. These compose four key steps of the proposed RE4 framework, evaluated over state-based and image-based benchmarks in Push-T and Robomimic. An adversarial benchmark that evaluates sparse data regions of image-based Push-T showcases the robustness, further bolstered by indications from low-data regime experiments. The current work shows promise in using simple interpretable building blocks to learn manipulation skills.

02.
arXiv (quant-ph) 2026-06-16

Physically Motivated Ansatz for Open Fermionic Systems on Quantum Computer

arXiv:2606.16823v1 Announce Type: new Abstract: Determining non-equilibrium steady states (NESS) of open fermionic systems is a fundamental problem akin to finding ground states of closed systems. To address this, variational quantum algorithms can be used to solve the Lindblad master equation, much like the Schrödinger equation, yet ansatz design for NESS remains challenging. Existing approaches rely mostly on hardware-efficient ansätze (HEA), which suffer from the barren plateau problem. Here, we introduce a physically motivated ansatz named NE-UCC. Numerical simulations demonstrate that NE-UCC reliably converges to the steady state even in strongly correlated regimes far from equilibrium, reducing the infidelity by up to ten orders of magnitude compared to HEA. Furthermore, NE-UCC facilitates the exploration of excited eigenmodes with specific symmetries.

04.
arXiv (CS.CL) 2026-06-16

Virtual Speech Therapist: A Clinician-in-the-Loop AI Speech Therapy Agent for Personalized and Supervised Therapy

This paper develops Virtual Speech Therapist (VST), an intelligent agent-based platform that streamlines stuttering assessment and delivers customized therapy planning through automated and adaptive AI-driven workflows. VST integrates state-of-the-art deep learning-based stuttering classification, and multi-agent large language model (LLM) reasoning to support evidence-based clinical decision-making. The VST begins with the acquisition and feature extraction of patient speech samples, followed by robust classification of stuttering types. Building on these outputs, VST initiates an agentic reasoning process in which specialized LLM agents autonomously generate, critique, and iteratively refine individualized therapy plans. A dedicated critic agent evaluates all generated therapy plans to ensure clinical safety, methodological soundness, and alignment with peer-reviewed evidence and established professional guidelines. The resulting output is a comprehensive, patient-specific therapy draft intended for clinician review. Incorporating clinician feedback, the system then produces a finalized therapy plan suitable for patient delivery, thereby maintaining a clinician-in-the-loop paradigm. Experimental evaluation by expert speech therapists confirms that VST consistently generates high-quality, evidence-based therapy recommendations. These findings demonstrate the system's potential to augment clinical workflows, reduce clinician burden, and improve therapeutic outcomes for individuals with speech impairments. An interactive user interface for the proposed system is available online at: https://vocametrix.com/ai/stuttering-therapy-planning-agent , facilitating real-time stuttering assessment and personalized therapy planning.

05.
arXiv (CS.AI) 2026-06-17

Lean4Agent: Formal Modeling and Verification for Agent Workflow and Trajectory

arXiv:2606.06523v2 Announce Type: replace Abstract: Equipping Large Language Models (LLMs) to execute reliable multi-step workflows has become a central challenge in artificial intelligence. Despite recent advances in LLMs' agentic capabilities, most agent systems still lack formal methods for specifying, verifying, and debugging their workflow and execution trajectories. This challenge mirrors a long-standing problem in mathematics, where the ambiguity of natural languages (NLs) motivates the development of formal languages (FLs). Inspired by this paradigm, we propose **Lean4Agent**, to the best of our knowledge, the first framework that uses Lean4, a dependent-type FL to model and verify agent behavior. **Lean4Agent** launches **FormalAgentLib**, an extensible Lean4 library for formally modeling and verifying agent workflows' semantic consistency under explicit assumptions, and enabling localization of execution-time failures revealed by trajectories. Building on **FormalAgentLib**, we further develop **LeanEvolve**, which applies results in **FormalAgentLib** to revise workflows to enhance its capability. Extensive experiments on a hard problem subset of SWE-Bench-Verified and a subset of ELAIP-Bench across 5 leading LLMs indicate that the verification-passing workflows outperform the failing ones by an average of **11.94%**, and **LeanEvolve** further improves SWE performance by **7.47%** on average. Furthermore, **Lean4Agent** establishes a foundation for a new field of using expressive dependent-type FL to formally model and verify agent behavior.

06.
arXiv (math.PR) 2026-06-24

Gradient Mean-Field Dynamics with Measure-Valued States: Well-Posedness, Chaos, and Long-Time Stability

arXiv:2606.24385v1 Announce Type: new Abstract: We study a stochastic mean-field interacting particle system whose state space is $\Y = \Tt^d \times \cP(U)$, where the first component represents a spatial variable and the second one is a probability measure over a compact metric space $U$. The dynamics are driven by locally Lipschitz drift operators: the spatial component evolves according to a Brownian diffusion, while the measure-valued component is perturbed by a projected cylindrical noise acting in the Arens–Eells space. We first establish existence and uniqueness of strong solutions for both the $N$-particle system and the associated nonlinear McKean–Vlasov equation under locally Lipschitz and linear growth assumptions on the drift coefficients. We then prove propagation of chaos: as $N\to\infty$, the empirical measure converges in expectation in Wasserstein–1 distance towards the unique McKean–Vlasov solution. Further, we investigate exponential convergence of the nonlinear McKean–Vlasov dynamics towards a unique invariant measure.

07.
arXiv (CS.LG) 2026-06-19

Efficient Neural Network Model Selection for Few-Class Application Datasets

arXiv:2606.19712v1 Announce Type: new Abstract: While much effort has focused on developing and benchmarking high-performance neural networks, less attention has been given to how dataset properties, known to practitioners, can guide efficient model selection. Neural models are typically evaluated on datasets with thousands of classes, yet many real-world applications involve fewer than ten. To address this understudied but common setting, we develop a measure of classification difficulty based on data-side properties and show how it enables more efficient model selection for few-class datasets, where traditional approaches are less effective. We term this phenomenon "few-class distinctiveness". Our metric allows comparison of models and datasets 6 to 29$\times$ faster than repeated training and testing. Leveraging this insight, we extend scaled model families below the smallest published models, achieving greater efficiency at similar accuracy, for example models up to 42% smaller than YOLOv5-nano for a mobile robot task. Targeting resource-constrained applications, we demonstrate few-class model selection across mobile robot, drone, and IoT scenarios, highlighting practical gains in efficiency without sacrificing performance.

09.
PLOS Medicine 2026-05-11

Connected or chained by social media? Child and adolescent mental health in a digital era

作者:

by Silja Kosola Social media has evolved from connection to compulsion, disproportionately harming children and adolescents. Addictive designs together with developmental vulnerability fuel mental health risks and highlight the urgent need for stricter age limits and stronger protections. In this Perspective, Silja Kosola outlines how social media disproportionately harms child and adolescent mental health, and argues that while recent policy changes aimed at protecting youth from social media are welcome, stricter age limits and greater accountability of social media companies are needed.

10.
arXiv (CS.AI) 2026-06-25

Logit Distance Bounds Representational Similarity

arXiv:2602.15438v3 Announce Type: replace-cross Abstract: For a broad family of discriminative models that includes autoregressive language models, identifiability results imply that if two models induce the same conditional distributions, then their internal representations are equal up to an invertible linear transformation. We ask whether an analogous conclusion holds approximately when the distributions are close instead of equal. Building on the observation of Nielsen et al. (2025) that closeness in KL divergence need not imply high linear representational similarity, we study a distributional distance based on logit differences and show that closeness in this distance does yield linear similarity guarantees. Specifically, we define a representational dissimilarity measure based on the models' identifiability class and prove that it is bounded by the logit distance. We further show that, when model probabilities are bounded away from zero, KL divergence upper-bounds logit distance; yet the resulting bound fails to provide nontrivial control in practice. As a consequence, KL-based distillation can match a teacher's predictions while failing to preserve linear representational properties, such as linear-probe recoverability of human-interpretable concepts. In distillation experiments on synthetic and image datasets, logit-distance distillation yields students with higher linear representational similarity and better preservation of the teacher's linearly recoverable concepts.

11.
arXiv (CS.LG) 2026-06-19

Minimal Filling Architectures of Polynomial Neural Networks: Counterexamples, Frontier Search, and Defects

arXiv:2605.09609v2 Announce Type: replace Abstract: We provide counterexamples to the unimodal minimal filling architecture conjecture for polynomial neural networks (PNNs) with power activation functions. Fixing the input and output widths, the conjecture states that any minimal filling architecture has unimodal widths for the hidden layers. We found counterexamples via a frontier search, recursive dimension bounds on neurovarieties, and symbolic computation. Notably, several subarchitectures of our main example exhibit large defect, in contrast with the predominantly small-defect behavior observed in prior literature.

12.
arXiv (CS.CL) 2026-06-12

Rethinking Psychometric Evaluation of LLMs: When and Why Self-Reports Predict Behavior

Anticipating LLM behavioral tendencies from low-cost psychometric probes is critical for safe deployment, but only if self-reports (SR) reliably predict behavior. Recent work documented substantial SR-behavior dissociation in LLMs, but relied on broad personality traits (Big 5) that predict specific behaviors weakly, even in humans. Furthermore, the isolation of conversational sessions combined with weak context matching left open whether LLMs truly lack coherence or whether the conditions needed to detect such coherence were not met. We contrast Big 5 with the Theory of Planned Behavior (TPB), which measures intention targeted to a specific behavior and predicts human behavior substantially better than broad traits. We run experiments across four behavioral tasks and 11 frontier LLMs, while also varying session context and identity induction. We find that SR-behavior coherence exists but is selective. 1) Within a shared conversation, the Theory of Planned Behavior reaches human-level coherence; Big 5 does not. 2) Across separate conversations, coherence survives only for behaviors anchored outside the immediate prompt, such as implicit bias shaped by training, and collapses when behavior is strongly primed by context, as with sycophancy. 3) Persona prompting makes self-reports more consistent across conversations, but does not bring behavior into alignment. These findings suggest that coarse personality frameworks, such as Big 5 may not be the best tools for testing deployment behavior. More task- and behavior-specific instruments are needed, and even these must be evaluated across tasks and contexts.

13.
arXiv (CS.AI) 2026-06-16

DynaDebate: Breaking Homogeneity in Multi-Agent Debate with Dynamic Path Generation

arXiv:2601.05746v2 Announce Type: replace Abstract: Recent years have witnessed the rapid development of Large Language Model-based Multi-Agent Systems (MAS), which excel at collaborative decision-making and complex problem-solving. Researchers have further investigated Multi-Agent Debate (MAD) frameworks, which enhance the reasoning and collaboration capabilities of MAS through information exchange and debate among multiple agents. However, existing approaches often rely on unguided initialization, causing agents to adopt identical reasoning paths that lead to the same errors. As a result, effective debate among agents is hindered, and the final outcome frequently degenerates into simple majority voting. To solve the above problem, we introduce Dynamic Multi-Agent Debate (DynaDebate), which enhances the effectiveness of multi-agent debate through three key mechanisms: (1) Dynamic Path Generation and Allocation, which employs a dedicated Path Generation Agent to generate diverse and logical solution paths with adaptive redundancy; (2) Process-Centric Debate, which shifts the focus from surface-level outcome voting to rigorous step-by-step logic critique to ensure process correctness; (3) A Trigger-Based Verification Agent, which is activated upon disagreement and uses external tools to objectively resolve deadlocks. Experiments show that DynaDebate achieves superior or highly competitive performance across the majority of benchmarks\footnote{The code is at https://github.com/nwpuLee2021/brianstorm.}.

14.
arXiv (math.PR) 2026-06-15

Secondary terms for first moments of Selmer groups of twists of elliptic curves over global function fields

作者:

arXiv:2606.14274v1 Announce Type: cross Abstract: Let $E$ be a non-isotrivial elliptic curve over a global function field $\mathbb{F}_q(t)$ of characteristic coprime to $2$ and $3$. Under some explicit conditions, we determine the secondary terms for the first moments of prime Selmer groups of cyclic prime twist families of $E$ over $\mathbb{F}_q(t)$.

15.
arXiv (CS.CV) 2026-06-17

Recover Semantics First, Generate Better: Improved Latent Modeling for 3D MRI Reconstruction and Cross-Contrast Synthesis

Multi-contrast magnetic resonance imaging (MRI) provides complementary information for clinical diagnosis. However, acquiring all MRI sequences is often time-consuming and costly. Recent generative models perform cross-contrast synthesis to address this issue by inferring absent contrasts from the available ones. Nevertheless, synthesizing 3D MRI presents significant challenges. Due to the massive volume sizes, operating directly in the pixel space is computationally prohibitive; therefore, a common approach is to first compress the 3D volumes into a latent space and subsequently train generative models in that space. We observe that existing compression architectures face several critical issues: they under-preserve long-range anatomical coherence, discard clinically meaningful semantics, and rely on optimization objectives that lead to over-smoothed reconstructions. Ultimately, these shortcomings compromise the performance of subsequent generative models. In this work, we propose a semantics-first latent modeling framework for 3D MRI reconstruction and cross-contrast synthesis. Specifically, we introduce a Latent Harmonization Encoder (LHE) to capture global anatomical dependencies, ensuring coherent volumetric representations. To mitigate semantic degradation during latent compression, we further design a Semantic Recovery Block (SRB) that injects high-level priors from a self-supervised semantic teacher, enhancing contrast-aware separability in the latent space. Additionally, we propose an Anatomy-aware Frequency Loss (AFL) to adaptively preserve diagnostically relevant high-frequency structures. Extensive experiments on two public multi-contrast MRI datasets demonstrate consistent improvements in reconstruction fidelity and cross-contrast synthesis quality. Our code is available at https://github.com/script-Yang/RSF.

16.
Nature (Science) 2026-06-24

An ECG biomarker for sudden cardiac death discovered with deep learning

Sudden cardiac death is, in theory, preventable with defibrillators. But every year, many patients die without defibrillators because doctors fail to predict their risk1. The only predictive biomarker in wide use, cardiac left ventricular ejection fraction (LVEF), misses most sudden cardiac deaths2, and flags many low-risk patients for futile defibrillators that never fire3,4. Here we apply deep learning to a dataset linking all electrocardiograms (ECGs) in a Swedish region to death certificates. The resulting model isolates a high-risk group (2.2% of the sample) with a 7.0% annual rate of sudden cardiac death, higher than those with reduced LVEF (1.9% of the sample; 4.6% annual rate). Notably, 86.1% of the model’s high-risk patients were not flagged by LVEF. High-risk ECG patients with defibrillators implanted were 54.4% less likely to die than expected, suggesting a mortality benefit. We externally validate the model in a US health system, in which it predicts ventricular arrhythmias that cause sudden death; and a Taiwanese hospital registry, in which it specifically predicts future arrhythmic cardiac arrests. To visualize the waveform morphology ‘discovered’ by the predictive model, we pair it with a generative model of the ECG waveform. Together, they reveal a biomarker that is easily visible and robustly predicts sudden cardiac death, but has not to our knowledge been previously described. Tying the biomarker’s shape to electrophysiological first principles, we form and preliminarily test a new hypothesis on the mechanism of sudden cardiac death. A deep-learning model trained on electrocardiogram (ECG) waveforms identifies an easily visible biomarker that predicts sudden cardiac death more accurately than the current clinical state of the art.

17.
arXiv (CS.AI) 2026-06-19

Global Ease of Living Index: a machine learning framework for longitudinal analysis of major economies

arXiv:2502.06866v3 Announce Type: replace-cross Abstract: The drastic changes in the global economy, geopolitical conditions, and disruptions such as the COVID-19 pandemic have impacted the cost of living and quality of life. It is essential to comprehend the long-term implications of the cost of living and quality of life in major economies. A transparent and comprehensive living index must include multiple dimensions of living conditions. In this study, we present an approach to quantifying the quality of life through the Global Ease of Living Index that combines various socio-economic and infrastructural factors into a single composite score. Our index utilises economic indicators that define living standards, which could help in targeted interventions to improve specific areas. We present a machine learning framework to address missing data for certain economic indicators in specific countries. We then curate and update the data and use a dimensionality reduction approach (Principal Component Analysis and Factor Analysis) to create the Ease of Living Index for major economies since 1970. Our work significantly adds to the literature by offering a practical tool for policymakers to identify areas needing improvement, such as healthcare systems, employment opportunities, and public safety. Our approach with open data and code can be easily reproduced and applied to various contexts, providing transparency and accessibility for ongoing research and policy development in quality-of-life assessment.

18.
arXiv (math.PR) 2026-06-25

An example of Ensemble Kalman Filter with resampling

arXiv:2606.25539v1 Announce Type: cross Abstract: This paper introduces the Exact Ensemble Kalman Filter (ExEnKF), a novel algorithm for state estimation in discrete-time nonlinear filtering problems with linear observations. Unlike traditional Ensemble Kalman Filters (EnKFs), which approximate the filtering distribution using ensembles of Dirac measures, the ExEnKF employs Gaussian measures, enabling more efficient exploration of the state space and potentially alleviating the curse of dimensionality. We prove the algorithm's asymptotic consistency with the optimal filter (Theorem 3.1), establishing a convergence rate of order 1/ $\sqrt$ N for N particles. Numerical experiments on the Lorenz-96 multiscale model demonstrate that the ExEnKF outperforms the standard EnKF under model misspecification and poor initialization, particularly in highly stochastic regimes. The algorithm's robustness is further highlighted by its ability to track hidden components of the true signal, even when observations are generated from a different model (e.g., multiscale vs. single-scale). This work advances the theoretical understanding of ensemble methods in nonlinear filtering and provides a practical alternative to sequential Monte Carlo methods for high-dimensional systems

19.
arXiv (CS.LG) 2026-06-16

OptEMA: Adaptive Exponential Moving Average for Stochastic Optimization with Zero-Noise Optimality

作者:

arXiv:2603.09923v4 Announce Type: replace Abstract: Exponential moving averages (EMAs) are a central component of widely used adaptive optimizers such as Adam. However, existing analyses of Adam-style methods often yield suboptimal guarantees in the zero-noise regime, rely on open-loop parameter schedules, or require prior knowledge of smoothness constants. Motivated by these limitations, we introduce OptEMA and analyze two complementary variants: OptEMA-M, which applies an adaptive, decreasing EMA coefficient to the first moment with a fixed second-moment decay, and OptEMA-V, which swaps these roles. At the heart of these variants is a Corrected AdaGrad-Norm coefficient schedule. This formulation renders OptEMA algorithmically closed-loop and Lipschitz-free, meaning its effective stepsizes are trajectory-dependent and require no parameterization via the Lipschitz constant. Under lower-boundedness, unbiasedness, bounded variance, average smoothness, and a bounded stochastic-gradient condition used to control the adaptive normalizers, we prove that both variants achieve the unified noise-adaptive rate $\tilde{\mathcal{O}} \left(T^{-1/2}+\sigma^{1/2}T^{-1/4}\right)$ for the averaged gradient norm. In the zero-noise regime, these bounds automatically reduce to the nearly optimal deterministic rate $\widetilde{\mathcal{O}}(T^{-1/2})$ without manual hyperparameter retuning.

20.
arXiv (CS.CL) 2026-06-18

Which Sections of a Research Paper Best Reveal Its Research Methods? Evidence from Library and Information Science

Research methods are essential carriers of knowledge contribution in academic papers. Automatic multi-label classification of research methods can support knowledge services such as method retrieval, review generation, and research intelligence analysis. While existing studies primarily rely on titles and abstracts, abstracts often provide only limited methodological information, whereas utilizing full-text content faces challenges related to excessive length and information redundancy. Therefore, this paper proposes a segment combination strategy by partitioning the full-text content according to its physical postion. Using an annotated corpus of 1,954 full-text articles from three representative journals in Library and Information Science (JASIST, LISR, and JDoc), we evaluate the classification performance of various segments and their combinations across multiple models. Experimental results indicate that methodological information is distributed unevenly within the full-text content, with the middle-to-late and final segments exhibiting greater discriminative power. Furthermore, integrating bibliographic metadata with cross-segment combination strategies effectively enhances classification performance.

21.
arXiv (CS.LG) 2026-06-11

Range-Aware Bayesian Optimization for Discovering Diverse Designs within Target Property Windows

arXiv:2606.11574v1 Announce Type: new Abstract: In many materials and product design problems, desirable candidates exhibit properties that fall within an acceptable range rather than achieve a single optimum. Recovering multiple, distinct solutions that satisfy such specifications is also practically valuable, as some candidates may be preferred for reasons of cost, processability, or robustness that are difficult to encode directly in an objective function. Here, we develop a range-aware Bayesian optimization (BO) framework in which the acquisition function directly scores the posterior probability that a candidate satisfies a target range. The framework naturally extends to parallel pursuit of multiple distinct specifications over a shared candidate space. Across benchmark tasks, range-aware acquisition consistently recovers larger and more diverse sets of valid designs than standard BO baselines and recent goal-seeking methods. Its utility is further demonstrated in two practically motivated design case studies involving optimizing reaction conditions for polymer synthesis and sequence-defined oligomer discovery for prescribed optical absorption bands, supported by quantum chemical calculations. These results suggest that range-aware BO can provide a practical and sample-efficient foundation for specification-driven design, particularly when design flexibility and solution diversity are important considerations.

22.
arXiv (CS.AI) 2026-06-12

Exploring How Agent Voice Accents Shape Human-AI Collaboration in K-12 Group Learning

arXiv:2606.12805v1 Announce Type: cross Abstract: Collaboration is widely recognized as a cornerstone of 21st-century education, yet teachers still encounter persistent challenges in fostering productive peer interaction. LLM conversational peer agents introduce new possibilities for mediating in-person group work, raising questions about how persona design, particularly their voice characteristics, shapes learners' perceptions, trust, and interactional dynamics. While prior work has examined agent accent effects in one-to-one settings, little is known about how these effects manifest in groups. We conducted a between-subjects mixed-methods study with 33 teachers examining how a GenAI voice agent with different accents (British, Indian, and African American) influenced collaboration and agent perception. Across surveys, group interaction analyses, and artifacts, we find that accent shaped participants' mental models and the roles the agent assumed in group interaction. The British-accented agent was largely treated as a tool and engaged in detached, utility-based ways, whereas Indian- and African American-accented agents were more readily anthropomorphized and integrated as peers. These role expectations influenced trust, engagement, and reliance over time. This work advances understanding of how GenAI's sociolinguistic design features shape group dynamics in CSCL, with implications for designing culturally inclusive AI partners in group learning.

23.
arXiv (quant-ph) 2026-06-17

Projected logical ensembles in surface codes via the random-matrix theory of quantum dots

arXiv:2606.17140v1 Announce Type: new Abstract: Measurements underpin active quantum error correction (QEC) and have been recognized as a source of novel measurement-induced many-body phenomena. Here, we study the statistical properties of post-measurement logical states arising in QEC on topological codes subject to deterministic transversal unitary gates. Upon syndrome extraction followed by maximum-likelihood decoding, a Born-weighted ensemble arises which we dub the "projected logical ensemble" (PLE). Focusing on surface codes subject to uniform single-qubit Pauli-$X$ rotations, we characterize the measurement-induced randomness of the PLE. To this end, we show that for a code with a single logical qubit, the PLE is isomorphic to an ensemble of scattering matrices describing mesoscopic quantum dots obtained from a 2D Majorana network model with suitable boundary conditions. We uncover regimes where these quantum dots are chaotic such that their scattering matrices are well-described by random matrix theory. In these regimes, the PLE approaches a universal ensemble that is maximally random up to symmetry and decoder-induced constraints. The symmetry constraints, set by stabilizer and logical operator weights, realize Altland-Zirnbauer classes D or DIII, which we both illustrate. Our results establish a fundamental connection between emergent universality concepts in mesoscopic physics, quantum many-body systems, and QEC.

24.
Nature Medicine 2026-06-11

Microglia at a key inflection point in Alzheimer’s disease

作者: 未知作者

We analyzed brains from octogenarians and cognitively resilient centenarians to understand why some individuals with substantial Alzheimer’s disease pathology develop dementia whereas others remain cognitively intact. Spatial transcriptomics revealed gene expression changes in discrete tissue domains surrounding amyloid plaques and tau pathology that distinguish early, clinically silent, disease from later stages associated with cognitive decline.

25.
medRxiv (Medicine) 2026-06-22

Genetic modifiers of psychiatric, motor, and cognitive symptoms in Huntington's disease

The Enroll HD natural history platform provides rich longitudinal phenotypes enabling genome wide analyses across diverse clinical domains. Psychiatric symptoms are a major source of morbidity in Huntington's disease (HD), yet the genetic architecture underlying their onset is poorly understood. We analyzed ~18,000 people with HD (PwHD) to define genetic determinants of ages at psychiatric, motor, and cognitive symptom onset, and HD diagnosis. GWAS meta analysis recapitulated 11 established modifiers of motor onset and identified a novel locus spanning RAB3B/ZFYVE9 associated with age at violent/aggressive behavior onset. Exome wide analyses in Enroll HD participants implicated rare variants in FAN1, PMS1, POLD1, and HTT. Several HD modifiers of motor and cognitive symptom onset (MSH3, FAN1, HTT) also influenced psychiatric symptom onset, whereas PMS1 and POLD1 showed significant association with motor symptom onset. Psychiatric polygenic scores predicted psychiatric symptom onset, revealing a hybrid architecture combining psychiatric liability in general population with HD- or repeat expansion disease (RED) specific pathways.