Recent research has focused on the mechanisms underlying Alzheimer's disease (AD) and potential therapeutic strategies. A key study identified that signaling through the cholecystokinin B receptor (CCKBR) via Gs and Gq pathways is beneficial for AD treatment, contrasting with the detrimental effects of Gi signaling. Clinically, patients with more severe AD exhibited lower CCKBR-Gq activity, suggesting a potential target for intervention (ref: Wang doi.org/10.1016/j.cell.2025.10.034/). Additionally, the therapeutic antibody Lecanemab was shown to activate microglial functions that facilitate amyloid-beta (Aβ) clearance, significantly reducing Aβ pathology in a human microglia xenograft model, highlighting the importance of immune mechanisms in AD (ref: Albertini doi.org/10.1038/s41593-025-02125-8/). Furthermore, research on the apolipoprotein E (APOE) gene revealed that switching from the risk allele APOE4 to the protective APOE2 allele in mice improved metabolic signatures and cognitive outcomes, emphasizing the genetic factors influencing AD pathology (ref: Golden doi.org/10.1038/s41593-025-02094-y/). These findings collectively underscore the multifaceted nature of AD and the potential for targeted therapies that modulate both genetic and immune pathways. In addition to pharmacological approaches, lifestyle factors such as physical activity have been identified as modifiable risk factors for AD. A study demonstrated that higher physical activity levels were associated with slower cognitive decline in cognitively unimpaired older adults with elevated amyloid levels, suggesting that lifestyle interventions could play a crucial role in AD prevention (ref: Yau doi.org/10.1038/s41591-025-03955-6/). This relationship was independent of baseline amyloid burden, indicating that physical activity may exert protective effects regardless of existing pathology. Overall, the integration of genetic, immunological, and lifestyle factors presents a comprehensive view of AD research, paving the way for innovative therapeutic strategies.

The exploration of neurodegeneration and biomarkers has gained momentum, particularly in understanding the molecular underpinnings of diseases like Alzheimer's and other neurodegenerative disorders. A significant advancement is the development of pan-expansion microscopy, which allows for the visualization of specific proteins within the ultrastructural context of brain tissue. This technique combines fluorescent staining with electron microscopy-like resolution, providing insights into the molecular anatomy and connectivity of the brain (ref: M'Saad doi.org/10.1038/s41587-025-02905-4/). Such imaging technologies are crucial for elucidating the spatial distribution of biomarkers associated with neurodegeneration, thereby enhancing our understanding of disease mechanisms. In addition to imaging advancements, blood-based biomarkers have emerged as promising tools for diagnosing and monitoring neurodegenerative diseases. A study highlighted the potential of plasma TDP-43 as a biomarker for advanced limbic-predominant age-related TDP-43 encephalopathy neuropathologic change, demonstrating significant correlations with brain TDP-43 burden in Alzheimer's disease subgroups (ref: Wang doi.org/10.1186/s13024-025-00910-4/). Furthermore, research on plasma p-tau217 has shown its efficacy in distinguishing between cognitively stable individuals with Down syndrome and those with Alzheimer's dementia, indicating its potential utility in high-risk populations (ref: Huber doi.org/10.1038/s41467-025-65882-x/). These findings underscore the importance of identifying reliable biomarkers that can facilitate early diagnosis and track disease progression across various neurodegenerative conditions.

Neuroinflammation plays a pivotal role in the pathogenesis of neurodegenerative diseases, and recent studies have shed light on the complex interactions between immune responses and neuronal health. One study demonstrated that activated microglia can induce astrocyte reactivity in Alzheimer's disease, suggesting that microglial activation is closely linked to the progression of neuroinflammation and neurodegeneration (ref: Ferrari-Souza doi.org/10.1038/s41593-025-02103-0/). This relationship highlights the potential for targeting microglial activation as a therapeutic strategy to mitigate neuroinflammatory damage in AD. Moreover, the enteric nervous system has been identified as a critical regulator of intestinal immune responses, with vasoactive intestinal peptide (VIP)-positive enteric neurons playing a role in maintaining barrier homeostasis (ref: Jakob doi.org/10.1038/s41590-025-02325-1/). This finding suggests that neuroimmune interactions extend beyond the central nervous system and may influence systemic inflammation and neurodegeneration. Additionally, the burden of neurological disorders in the US has been quantified, revealing that disorders affecting the nervous system significantly impact millions of individuals, emphasizing the need for effective interventions to address neuroinflammation and its consequences (ref: Ney doi.org/10.1001/jamaneurol.2025.4470/). Collectively, these studies underscore the intricate interplay between neuroinflammation and neurodegenerative processes, paving the way for novel therapeutic approaches targeting immune mechanisms.

Research into amyotrophic lateral sclerosis (ALS) has revealed critical insights into the molecular mechanisms underlying the disease, particularly focusing on the role of TDP-43 in neuronal hyperexcitability. A study demonstrated that TDP-43-dependent mis-splicing of the KCNQ2 gene, which encodes a potassium channel, contributes to intrinsic neuronal hyperexcitability observed in ALS and frontotemporal dementia (ref: Joseph doi.org/10.1038/s41593-025-02096-w/). This finding highlights the importance of RNA processing in ALS pathology and suggests that targeting splicing mechanisms may offer therapeutic avenues. In addition to splicing abnormalities, the accumulation of misfolded proteins poses a significant challenge in ALS treatment. A targeted BioPROTAC degrader was developed to selectively target misfolded variants of the SOD1 protein, a known contributor to familial ALS (ref: Chisholm doi.org/10.1038/s41467-025-65481-w/). This innovative approach demonstrates the potential of proteolysis-targeting chimeras in addressing the dynamic nature of misfolded proteins in neurodegenerative diseases. Furthermore, large-scale drug screening using patient-derived induced pluripotent stem cells (iPSCs) has identified potential combinatorial therapies for sporadic ALS, emphasizing the utility of iPSC technology in modeling disease and discovering new treatments (ref: Bye doi.org/10.1038/s41593-025-02118-7/). These advancements collectively enhance our understanding of ALS and open new avenues for therapeutic intervention.

Recent studies have provided valuable insights into the multifaceted nature of Parkinson's disease (PD), particularly concerning its associations with obstructive sleep apnea (OSA) and the implications of early treatment. A study examining US veterans found that OSA is linked to an increased risk of developing PD, with continuous positive airway pressure (CPAP) treatment potentially modifying this risk (ref: Neilson doi.org/10.1001/jamaneurol.2025.4691/). This finding underscores the importance of addressing comorbid conditions in managing PD and highlights the need for further research into the interplay between sleep disorders and neurodegeneration. Additionally, advancements in understanding the structural organization of striatal neurons have been made through dendritome mapping, which profiles the dendritic morphology of medium spiny neurons in the striatum (ref: Park doi.org/10.1038/s41593-025-02085-z/). This approach reveals how aging and disease can alter neuronal architecture, providing insights into the cellular basis of motor deficits in PD. Furthermore, the burden of neurological disorders, including PD, has been quantified, revealing significant impacts on public health and emphasizing the need for effective interventions (ref: Ney doi.org/10.1001/jamaneurol.2025.4470/). Together, these studies contribute to a deeper understanding of PD and its associated risk factors, paving the way for improved management strategies.

The development of innovative models and mechanisms to study neurodegenerative diseases has been a focal point of recent research. A notable advancement is the elucidation of pathway-selective biased agonism at the cholecystokinin B receptor (CCKBR), which has been shown to have therapeutic potential in Alzheimer's disease (AD) by favoring beneficial signaling pathways (ref: Wang doi.org/10.1016/j.cell.2025.10.034/). This finding emphasizes the importance of understanding receptor signaling in the context of neurodegeneration and suggests that targeted modulation of these pathways could lead to novel therapeutic strategies. Moreover, the application of pan-expansion microscopy has allowed researchers to visualize specific molecules within the ultrastructural context of brain tissue, enhancing our understanding of the molecular anatomy of neurodegenerative diseases (ref: M'Saad doi.org/10.1038/s41587-025-02905-4/). This technique provides insights into the spatial distribution of proteins and lipids, facilitating the identification of biomarkers associated with neurodegeneration. Additionally, the identification of distinct brain alterations in cognitive impairment related to post-acute sequelae of COVID-19 has highlighted the need for further investigation into the long-term effects of viral infections on neurodegenerative processes (ref: Seo doi.org/10.1038/s41467-025-65597-z/). Collectively, these studies underscore the importance of innovative modeling approaches and the need for a deeper understanding of the mechanisms underlying neurodegenerative diseases.

Cognitive decline and aging are critical areas of research, particularly in relation to Alzheimer's disease (AD) and its biomarkers. A longitudinal cohort study revealed that the lifetime risk of developing mild cognitive impairment (MCI) significantly increases with the severity of amyloid PET findings, particularly among APOE ε4 carriers (ref: Jack doi.org/10.1016/S1474-4422(25)00350-3/). This study highlights the importance of early identification of individuals at risk for cognitive decline, emphasizing the need for targeted interventions to mitigate progression to dementia. Additionally, blood biomarkers have emerged as promising tools for predicting cognitive decline. A study following dementia-free individuals demonstrated associations between baseline AD blood biomarkers and transitions between normal cognition, MCI, and dementia over a 16-year period (ref: Valletta doi.org/10.1038/s41467-025-66728-2/). These findings suggest that blood-based biomarkers could serve as valuable indicators for monitoring cognitive health in aging populations. Furthermore, research on plasma p-tau217 has shown its potential to differentiate between cognitively stable individuals with Down syndrome and those with AD dementia, indicating its utility in high-risk groups (ref: Huber doi.org/10.1038/s41467-025-65882-x/). Together, these studies underscore the significance of identifying biomarkers and understanding the risk factors associated with cognitive decline in aging populations.

Environmental and lifestyle factors play a crucial role in the risk and progression of neurodegenerative diseases. A study highlighted physical activity as a modifiable risk factor for Alzheimer's disease (AD), demonstrating that higher levels of physical activity were associated with slower cognitive decline in cognitively unimpaired older adults with elevated amyloid levels (ref: Yau doi.org/10.1038/s41591-025-03955-6/). This finding suggests that lifestyle interventions could be effective in mitigating the effects of neurodegeneration, particularly in high-risk populations. In addition to physical activity, the impact of sleep disorders on neurodegenerative diseases has been explored. Research on obstructive sleep apnea (OSA) indicated its association with increased risk of developing Parkinson's disease (PD), with continuous positive airway pressure (CPAP) treatment potentially modifying this risk (ref: Neilson doi.org/10.1001/jamaneurol.2025.4691/). These findings emphasize the importance of addressing comorbid conditions and lifestyle factors in the management of neurodegenerative diseases. Overall, the integration of environmental and lifestyle factors into neurodegenerative disease research highlights the potential for preventive strategies that could improve cognitive health and quality of life.