Research on Huntington's disease (HD) has increasingly focused on the role of somatic CAG repeat expansions and their association with neurodegeneration biomarkers. A study involving 57 HD gene expanded individuals demonstrated that somatic CAG repeat expansions in blood correlate with neurodegenerative biomarkers, occurring approximately 23 years prior to the expected clinical motor diagnosis. Notably, no significant decline in clinical, cognitive, or neuropsychiatric function was observed over a 4.5-year period compared to controls, suggesting that while biomarkers may indicate neurodegeneration, clinical symptoms may not manifest until much later (ref: Scahill doi.org/10.1038/s41591-024-03424-6/). Additionally, the exploration of proteomic changes in cerebrospinal fluid (CSF) has revealed alterations detectable up to 30 years before symptom onset in autosomal dominant Alzheimer's disease, underscoring the importance of early diagnosis in neurodegenerative diseases (ref: Ross doi.org/10.1038/s41392-024-02109-3/). Furthermore, innovative therapeutic approaches utilizing RNA-targeting CRISPR/CasRx systems have shown promise in reducing HTT mRNA levels across various models, including humanized mouse models, thereby alleviating disease symptoms (ref: Lin doi.org/10.1186/s13024-024-00794-w/).

Alzheimer's disease (AD) research has revealed critical insights into the pathology and potential therapeutic interventions. A study using the 5xFAD mouse model indicated that the parental origin of the transgene significantly influences amyloid-β plaque burden, highlighting the necessity for rigorous reporting of genetic backgrounds in AD research (ref: Sasmita doi.org/10.1016/j.neuron.2024.12.025/). Moreover, the ApoE3 R136S variant has been shown to bind to Tau, inhibiting its propagation and reducing neurodegeneration in mice, suggesting a protective role against AD symptoms (ref: Chen doi.org/10.1016/j.neuron.2024.12.015/). In contrast, a study examining the relationship between depressive symptoms and amyloid pathology found no association in cognitively normal individuals, while a lower likelihood of amyloid pathology was observed in those with mild cognitive impairment, indicating a complex interplay between mood disorders and neurodegenerative processes (ref: Wiels doi.org/10.1001/jamapsychiatry.2024.4305/).

Research into Parkinson's disease (PD) has increasingly emphasized the role of sex and gender in disease onset and progression. A review of observational studies highlighted inconsistencies regarding the impact of menopause and hormone replacement therapy on PD, suggesting that these factors may influence disease characteristics differently in men and women (ref: Castro-Aldrete doi.org/10.1038/s41591-024-03363-2/). Additionally, studies on α-synuclein pathology have revealed that deposits in the kidneys may contribute to PD, with findings indicating a progression of pathology from peripheral organs to the central nervous system (ref: Yuan doi.org/10.1038/s41593-024-01866-2/). Furthermore, the use of glucagon-like peptide 1 receptor agonists has been associated with reduced risks of various neurocognitive disorders, although they also present risks for gastrointestinal and renal complications (ref: Xie doi.org/10.1038/s41591-024-03412-w/).

Neuroinflammation has emerged as a critical factor in the pathogenesis of neurodegenerative diseases. A study identified that demyelination-derived lysophosphatidylserine promotes microglial dysfunction, contributing to Alzheimer's disease pathology, thereby suggesting that targeting microglial activation could be a viable therapeutic strategy (ref: Zhou doi.org/10.1038/s41423-024-01235-w/). Additionally, the modulation of the glymphatic system through visual circuit activation has shown promise in alleviating memory impairment in mouse models of AD, indicating potential non-invasive therapeutic avenues (ref: Wu doi.org/10.1038/s41467-024-55678-w/). Moreover, ischemic conditioning has been linked to enhanced recovery from stroke, promoting transneuronal survival through mechanisms involving CD36-mediated efferocytosis, which may have implications for neuroprotection strategies in neurodegenerative contexts (ref: Ju doi.org/10.1161/CIRCRESAHA.124.325428/).

Genetic and epigenetic factors play a significant role in neurodegenerative diseases, as evidenced by a trans-ancestry genome-wide study that identified 697 associations with major depression, implicating various neural cell types and potential pharmacotherapies (ref: doi.org/10.1016/j.cell.2024.12.002/). This highlights the complexity of genetic contributions to neurodegenerative conditions. Additionally, a genomic reanalysis of a pan-European rare-disease resource led to new diagnoses in 8.4% of previously undiagnosed cases, emphasizing the importance of collaborative efforts in genetic research (ref: Laurie doi.org/10.1038/s41591-024-03420-w/). Furthermore, the interaction of α-synuclein fibrils with HIV-1 has been shown to enhance viral infection in human immune cells, suggesting that neurodegenerative processes may intersect with infectious disease mechanisms (ref: Olari doi.org/10.1038/s41467-025-56099-z/).

The projected burden of dementia is a growing concern, with estimates indicating an increase from approximately 514,000 new cases in 2020 to nearly 1 million by 2060 in the U.S. This underscores the urgent need for public health strategies aimed at prevention and early intervention (ref: Fang doi.org/10.1038/s41591-024-03340-9/). Additionally, a randomized clinical trial comparing health system, community-based, and usual dementia care revealed nuanced differences in outcomes, suggesting that integrated care models may enhance support for individuals with dementia and their caregivers (ref: Reuben doi.org/10.1001/jama.2024.25056/). The findings also highlight the importance of addressing comorbidities in dementia care, as individuals with intermittent explosive disorder exhibited extensive psychiatric and neurological comorbidities, emphasizing the need for comprehensive treatment approaches (ref: Zhang-James doi.org/10.1001/jamapsychiatry.2024.4465/).

The identification of biomarkers for neurodegenerative diseases has gained momentum, with studies revealing significant associations between somatic CAG repeat expansions in Huntington's disease and neurodegeneration biomarkers, detectable decades before clinical symptoms manifest (ref: Scahill doi.org/10.1038/s41591-024-03424-6/). Additionally, the detection of preclinical CSF proteomic changes in autosomal dominant Alzheimer's disease highlights the potential for early diagnosis and intervention (ref: Ross doi.org/10.1038/s41392-024-02109-3/). Furthermore, the relationship between depressive symptoms and amyloid pathology has shown complex associations, with findings indicating that depressive symptoms may correlate differently with amyloid pathology depending on cognitive status (ref: Wiels doi.org/10.1001/jamapsychiatry.2024.4305/). These insights underscore the importance of integrating biomarker research into clinical practice for improved diagnostic accuracy.

Innovative therapeutic strategies are being explored to address neurodegenerative diseases. In vivo base editing techniques have been developed to extend the lifespan of humanized mouse models of prion disease, demonstrating the potential for genetic interventions in neurodegeneration (ref: An doi.org/10.1038/s41591-024-03466-w/). Additionally, the application of RNA-targeting CRISPR/CasRx systems has shown efficacy in reducing HTT mRNA levels in Huntington's disease models, providing a promising avenue for therapeutic development (ref: Lin doi.org/10.1186/s13024-024-00794-w/). Furthermore, the upregulation of astrocyte HDAC7 has been implicated in inducing Alzheimer-like tau pathologies, suggesting that targeting epigenetic regulators may enhance therapeutic outcomes (ref: Ye doi.org/10.1186/s13024-025-00796-2/). These studies collectively highlight the potential for novel interventions aimed at modifying disease progression in neurodegenerative disorders.