The aggregation of proteins such as TDP-43 and amyloid-beta is a central feature in various neurodegenerative diseases. Recent studies have elucidated the mechanisms underlying these aggregations. For instance, TDP-43 aggregation is shown to require both an increase in concentration within stress granules and oxidative stress, suggesting a dual-trigger model for its pathological aggregation (ref: Yan doi.org/10.1016/j.cell.2025.04.039/). Additionally, the formation of cytoplasmic inclusions of TDP-43 and mutant FUS has been linked to defects in DNA damage response, highlighting the interplay between protein aggregation and cellular repair mechanisms (ref: Modafferi doi.org/10.1038/s41418-025-01530-7/). The role of trinucleotide repeat expansions in diseases like Huntington's and Friedreich's ataxia further emphasizes the genetic underpinnings of neurodegeneration, with base editing techniques showing promise in reducing somatic repeat expansions in patient-derived cells and animal models (ref: Matuszek doi.org/10.1038/s41588-025-02172-8/). Collectively, these findings underscore the complexity of protein aggregation in neurodegenerative diseases and the potential for targeted therapeutic interventions.

Therapeutic strategies for neurodegenerative diseases are rapidly evolving, with several innovative approaches being tested in clinical settings. The TransEuro trial investigated the transplantation of human fetal ventral mesencephalic tissue in Parkinson's disease patients, revealing both clinical benefits and side effects, such as graft-induced dyskinesias, indicating the need for careful patient selection and monitoring (ref: Barker doi.org/10.1038/s41587-025-02567-2/). In the realm of pharmacotherapy, the MIROCALS trial assessed the efficacy of low-dose IL-2 as an adjunct to riluzole in ALS patients, demonstrating a significant impact on disease progression and safety (ref: Bensimon doi.org/10.1016/S0140-6736(25)00262-4/). Furthermore, novel antisense oligonucleotide therapies targeting FUS-ALS have shown promise in reducing FUS protein levels and associated pathology (ref: Shneider doi.org/10.1016/S0140-6736(25)00513-6/). These studies highlight the potential of both cell-based and molecular therapies in addressing the challenges posed by neurodegenerative diseases.

Understanding the genetic and molecular mechanisms underlying neurodegeneration is crucial for developing effective therapies. Recent advances in proteomics have facilitated the construction of comprehensive protein atlases, linking specific proteins to disease processes and aiding in biomarker discovery (ref: Cruchaga doi.org/10.1016/j.cell.2025.04.040/). Whole-genome sequencing studies have identified novel genetic variants associated with Alzheimer's disease, including a previously unreported locus, APCDD1, which may contribute to disease risk (ref: Kim doi.org/10.1038/s41467-025-59949-y/). Additionally, the discovery of mutations in NEK1 that cause ciliary dysfunction presents a new pathogenic mechanism in ALS, emphasizing the importance of cellular structures in neurodegenerative processes (ref: Noh doi.org/10.1186/s13024-025-00848-7/). These findings collectively enhance our understanding of the genetic landscape of neurodegeneration and highlight potential targets for therapeutic intervention.

Microglial dysfunction and neuroinflammation are critical components of neurodegenerative diseases. Recent research has shown that amyloid-beta exposure leads to lipid droplet formation in microglia, impairing their phagocytic function and contributing to Alzheimer's disease pathology (ref: Prakash doi.org/10.1016/j.immuni.2025.04.029/). Moreover, a novel wireless device has been developed to continuously measure brain parenchymal resistance, providing insights into glymphatic function and its role in neurodegeneration (ref: Dagum doi.org/10.1038/s41551-025-01394-9/). Additionally, studies have demonstrated that aging is associated with microglial activation and alterations in myelinated axons, suggesting that targeting microglial function may offer therapeutic avenues for age-related neurodegenerative conditions (ref: Groh doi.org/10.1038/s41593-025-01955-w/). These findings underscore the importance of microglial health in maintaining neuronal integrity and highlight potential strategies for modulating neuroinflammation.

Cognitive decline, particularly in Alzheimer's disease, is a multifaceted issue influenced by various biological factors. Advances in artificial intelligence and aging science have enabled the prediction of Alzheimer's risk years before clinical symptoms manifest, providing a critical window for intervention (ref: Topol doi.org/10.1126/science.ady3217/). Furthermore, cerebrospinal fluid proteome profiling has revealed significant changes in protein levels across the Alzheimer's continuum, aiding in the identification of biomarkers that correlate with disease progression (ref: Weiner doi.org/10.1186/s13024-025-00841-0/). The exploration of peptidylarginine deiminases as potential therapeutic targets also highlights the intricate biochemical pathways involved in Alzheimer's pathology (ref: Dakin doi.org/10.1038/s41467-025-59919-4/). Collectively, these studies emphasize the need for early detection and intervention strategies to mitigate cognitive decline in Alzheimer's disease.

The identification of neuroprotective strategies and biomarkers is essential for advancing treatment options in neurodegenerative diseases. Large-scale plasma proteomic profiling has unveiled numerous proteins associated with Alzheimer's disease, providing a foundation for diagnostic biomarkers and potential therapeutic targets (ref: Heo doi.org/10.1038/s43587-025-00872-8/). Additionally, GLP-1 receptor agonists have demonstrated neuroprotective effects by activating AMPK signaling, which may mitigate Alzheimer's-related phenotypes (ref: Zhang doi.org/10.1038/s43587-025-00869-3/). The discovery of Nageotte nodules in diabetic peripheral neuropathy also highlights the intersection of metabolic disorders and neurodegeneration, suggesting that metabolic health may influence neuroprotective mechanisms (ref: Shiers doi.org/10.1038/s41467-025-59538-z/). These findings underscore the importance of integrating biomarker discovery with therapeutic strategies to enhance neuroprotection.

Innovative models and mechanisms are crucial for understanding neurodegenerative diseases and developing effective therapies. Recent studies have demonstrated that immunotherapy targeting tau fragments can diminish Alzheimer's disease pathology and improve cognitive function in mouse models (ref: Xiang doi.org/10.1186/s13024-025-00854-9/). Additionally, synaptic vesicle-omics has provided insights into the aging process and synucleinopathies, linking age-related changes in synaptic function to neurodegenerative diseases (ref: Gao doi.org/10.1038/s41467-025-59441-7/). Furthermore, the role of DNA methyltransferase 1 in modulating mitochondrial function highlights the intricate relationship between epigenetics and neurodegeneration (ref: Wang doi.org/10.1016/j.molcel.2025.04.019/). These findings illustrate the complexity of neurodegenerative mechanisms and the potential for novel therapeutic approaches.

Environmental and lifestyle factors play a significant role in the risk and progression of neurodegenerative diseases. Recent research has identified a correlation between autism spectrum disorder (ASD) and an increased risk of Parkinson's disease, independent of depression or antidepressant use, suggesting that neurodevelopmental factors may influence neurodegenerative outcomes (ref: Yin doi.org/10.1001/jamaneurol.2025.1284/). Additionally, the New Brunswick neurological syndrome of unknown cause has prompted investigations into potential environmental triggers and their impact on neurological health (ref: Bendahan doi.org/10.1001/jamaneurol.2025.1718/). Furthermore, advancements in gene therapy using AAV variants have shown promise in delivering therapeutic proteins to the brain, potentially mitigating the effects of environmental factors on neurodegeneration (ref: Tecedor doi.org/10.1126/scitranslmed.adr2531/). These studies highlight the importance of considering environmental and lifestyle factors in the context of neurodegenerative disease research.