Alzheimer & Parkinson

Hypothesis generation in biomedicine is constrained by human cognitive limitations in synthesizing insights from fragmented biomedical knowledge and multimodal data sources. Here we introduce XunZi, an AI biologist that integrates logical reasoning and multimodal data fusion to autonomously generate de novo therapeutic target hypotheses with testable mechanisms. XunZi has been trained on 24.4 million publications and 613.6 TB of multisource data spanning 21,008 human genes and 5,850 diseases,...

Metabolic dysfunction is a defining but poorly understood feature of Alzheimer's disease. Du et al. show that a brain-penetrant GLP-1 receptor agonist rewires astrocyte-neuron metabolic coupling through lactate-driven histone lactylation, linking astrocytic glycolysis to neuronal lipid homeostasis and positioning metabolite signaling as a therapeutic axis in neurodegeneration.

Alzheimer's disease (AD), as the leading cause of dementia, poses an increasingly severe socioeconomic burden in the context of global ageing. Traditionally defined by amyloid-β and tau pathology, it's increasingly recognized as a systems disorder in which impaired glucose metabolism, mitochondrial dysfunction, and neuroinflammation interact across neural cell types and disease stages. However, the interaction among these three mechanisms, their role in promoting the classical pathology of AD,...

Metabotropic glutamate receptor subtype 5 (mGlu5) is an important regulator of excitatory neurotransmission and remains a therapeutic target for neuropsychiatric and neurological disorders, including substance use disorders, depression, Fragile X syndrome, Parkinson's disease-related dyskinesia, and other movement disorders. However, the clinical development of mGlu5 negative allosteric modulators (NAMs) has been limited by translational challenges, inconsistent efficacy, and safety concerns,...

Postural and locomotor dysfunction represent axial symptoms of Parkinson's disease (PD), which remain poorly treated by medication and deep brain stimulation. Whilst non-invasive neuromodulation of the vestibular system via the vestibular nucleus complex (VNC) offers a novel therapeutic avenue, the underlying circuits are still poorly characterized. Here we show that the mouse VNC feeds extensive Vglut2-defined projections into striato-thalamo-subthalamic and caudal medulla motor hubs and...

Various cellular stressors inhibit translation initiation and promote ribosome disassembly, thereby transiently inducing stress granules (SGs), dynamic ribonucleoprotein condensates that contain mRNAs and RNA-binding proteins. Although SG assembly is usually reversible, dysregulated SG dynamics can trigger the formation of persistent ubiquitin-positive protein inclusions. There is increasing evidence that this conversion of SGs into insoluble aggregates represents a central pathogenic mechanism...

Epigenetic aging clocks based on DNA methylation patterns across the genome have emerged as a potential biomarker for risk of age-related diseases, like Alzheimer's disease (AD), and environmental and social stressors. However, methylation clocks have not been comprehensively validated in genetically diverse individuals. Here, we evaluate a set of first-, second-, and third-generation methylation clocks in 621 AD patients and matched controls from African American, Hispanic, and White cohorts....

Lysosomal dysfunction is causally linked to neurodegeneration in many lysosomal storage disorders and is associated with various age-related neurodegenerative diseases. Here, we investigated the question of underlying mechanisms using a mouse model of mucopolysaccharidosis type IIIA caused by deficiency of the lysosomal hydrolase SGSH. Systematic imaging and transcriptomic and epigenetic studies revealed microglia to be the most profoundly impacted cell type in brains of Sgsh-deficient mice....

Brain aging, the strongest risk factor for Alzheimer's disease (AD), varies across cortical regions. Global brain age (GBA), an imaging-derived measure of neuroanatomic decline, reduces structural aging to a single summary value. This can potentially obscure regional patterns of cognitive vulnerability preceding AD. This study introduces a deep-learning architecture trained on the [Formula: see text]-weighted MRIs of 14,748 cognitively normal (CN) participants from multiple sites to estimate...

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The first transgenic mouse models of Alzheimer's disease (AD) developed in the 1990 s were hailed as a major breakthrough. As newer generations of models have emerged over the decades after, they still face growing criticism for translating poorly into clinical outcomes, even if the effects of newer therapeutic compounds, including monoclonal antibodies, align well with those seen in mice. Like any disease model, AD mice have substantial limitations. The real issue is that they are often treated...

Mitochondrial quality control is essential for cellular homeostasis, particularly in neurons, where mitochondrial dysfunction is implicated in the pathogenesis of neurodegenerative diseases. Mitophagy, the selective degradation of damaged or superfluous mitochondria, plays a central role in maintaining mitochondrial integrity and metabolic balance. This review provides a comprehensive overview of the best-characterized PINK1-PRKN/parkin-dependent mitophagy pathway and the expanding repertoire of...

Individual midbrain dopamine (mDA) neurons exhibit complex morphologies, a feature that may underlie their different functions and disease vulnerability. However, the developmental programs and wiring principles underlying this morphological complexity, particularly in terms of axonal and dendritic architecture, remain largely unknown. To address this, we developed and employed a unique intersectional genetic strategy in mice (Gucy2c-iCre:Pitx3-FlpE:Ai65D [GPA]) that enables specific sparse...

Alzheimer's disease is increasingly defined by biomarker evidence of amyloid-β and tau pathology, sharpening questions about whether late-life depression contributes to, or instead reflects, this pathology. We conducted a systematic review and meta-analysis of studies published between 2000 and 2025 that compared amyloid-β biomarkers in adults with and without depression, with depression defined by validated clinical diagnoses or symptom rating scales. Twenty-four studies were included, spanning...

US healthcare systems are struggling to meet the growing demand for neurological care, particularly in Alzheimer's disease and related dementias. Generative artificial intelligence (AI) built on large language models now enables agentic AI systems that can streamline clinical workflows, integrate multimodal data and learn from practicing specialists. We envision an agentic AI system that scales specialist-level care to nonspecialist clinical settings through a continuously learning healthcare...

Decades of structural magnetic resonance imaging (MRI) studies have documented alterations of gray matter morphometry in psychiatric disorders, but the field has failed to identify any consensus disease phenotypes. Here we examine whether current approaches will ever converge on such phenotypes by evaluating the consistency of brain-wide maps of gray matter volume and cortical thickness differences obtained for each of 59 study sites of five psychiatric disorders (schizophrenia, schizoaffective...

Understanding sex-dependent differences in disease risk, manifestation, and treatment response is essential for precision medicine. While funding agencies now mandate consideration of Sex as a Biological Variable (SABV), existing bioinformatics tools lack systematic approaches to characterize sex-related molecular mechanisms. Current practices frequently treat sex as a confounding variable, which may obscure important biological differences such as sex-specific alterations, sex-dimorphic changes...

Dysfunctional mitophagy is proposed as a key component of Alzheimer's disease (AD) pathology, yet direct in vivo evidence and mechanistic insights are still lacking. Here we show that AD model mice expressing a mitophagy reporter (APP/PSEN1/mt-Keima) develop large accumulation of acidic and neutral mitochondria within neuronal processes that form a previously unrecognized pathological structure termed mitochondrial plaques (MPs). The development of MPs is driven by abnormal mitochondrial buildup...

Animals can initiate movements either in response to external cues or from internal drive, yet how the brain flexibly supports both remains unclear. Disorders such as Parkinson's disease disrupt these modes differently, suggesting distinct underlying mechanisms. These differences could arise from specialized circuits or from shared neuronal populations that shift their dynamics across contexts. To distinguish between these possibilities, we performed two-photon calcium imaging in the...

Alzheimer's disease (AD) has a higher prevalence in women than men and is more frequently inherited from mothers than fathers. Yet, while neuroimaging and biomarker studies link maternal family history to stronger AD-related alterations, epidemiological studies suggest that paternal history confers comparable or even greater risk. Here, we leverage the deeply profiled PREVENT-AD cohort to derive three intermediate phenotypes of AD susceptibility. Drawing on nearly 1,000 individual study visits,...