Recent research has significantly advanced our understanding of the mechanisms underlying Alzheimer's disease (AD) and the cellular models used to study it. A pivotal study by Kaji et al. demonstrated that aggregates of Apolipoprotein E (APOE) in microglia can initiate Aβ amyloidosis, a key pathological feature of AD, by influencing lipid metabolism and the JAK/STAT signaling pathway (ref: Kaji doi.org/10.1016/j.immuni.2024.09.014/). This finding suggests a novel model for the onset of amyloid plaque formation, highlighting the role of microglial function in AD pathology. Complementing this, Ortí-Casañ et al. provided a comprehensive transcriptomic atlas that delineates regional differences in cellular vulnerability and resilience in AD, revealing that specific neuronal and glial subtypes exhibit varying degrees of susceptibility to the disease (ref: Ortí-Casañ doi.org/10.1038/s41392-024-02014-9/). This study underscores the complexity of AD, suggesting that targeted interventions may need to consider these regional and cellular differences. Further insights into AD pathology were provided by Gabitto et al., who utilized multiomics and spatial genomics to analyze cell types in the middle temporal gyrus of donors with varying AD pathologies, revealing critical cellular populations that are affected (ref: Gabitto doi.org/10.1038/s41593-024-01774-5/). Additionally, Guo et al. explored the heparin-enriched plasma proteome, identifying significant alterations in heparin binding proteins associated with Aβ and tau pathology, which could serve as potential biomarkers for AD (ref: Guo doi.org/10.1186/s13024-024-00757-1/). Together, these studies highlight the multifaceted nature of AD, emphasizing the need for integrated approaches to understand its complex pathology and develop effective therapies.

Research on Parkinson's disease (PD) has focused on understanding its pathology and exploring potential therapeutic interventions. The PASADENA trial, as reported by Pagano et al., demonstrated that the anti-alpha-synuclein antibody prasinezumab significantly slowed motor progression in early-stage PD patients, with effects sustained over four years (ref: Pagano doi.org/10.1038/s41591-024-03270-6/). This finding is crucial as it suggests that immunotherapy targeting alpha-synuclein may alter the disease trajectory, offering hope for disease-modifying treatments. In a complementary study, Zhu et al. employed single-nucleus transcriptomics and proteomics to profile the prefrontal cortex of late-stage PD patients, identifying distinct transcriptional changes in vulnerable brain cell populations, including an increase in brain-resident T cells, which may contribute to the inflammatory processes observed in PD (ref: Zhu doi.org/10.1126/scitranslmed.abo1997/). Bayati et al. further explored the cellular mechanisms underlying PD by modeling pathology in human dopaminergic neurons exposed to alpha-synuclein fibrils and proinflammatory cytokines, revealing immune-triggered lysosomal dysfunction as a contributing factor to PD pathology (ref: Bayati doi.org/10.1038/s41593-024-01775-4/). This aligns with findings from Son et al., who emphasized the importance of in vivo protein conformation in understanding PD, suggesting that structural changes in proteins precede expression alterations (ref: Son doi.org/10.1038/s41467-024-53582-x/). Collectively, these studies highlight the interplay between immune responses and neurodegeneration in PD, paving the way for innovative therapeutic strategies.

Research into amyotrophic lateral sclerosis (ALS) has focused on understanding its underlying mechanisms and exploring potential therapeutic options. Koch et al. conducted a phase 2 trial assessing the safety and efficacy of fasudil in ALS patients, revealing that while the treatment was generally well-tolerated, there were notable mortality rates in both treatment and placebo groups, indicating the need for further investigation into its efficacy (ref: Koch doi.org/10.1016/S1474-4422(24)00373-9/). Wilkins et al. introduced a novel approach to precision medicine in ALS by utilizing TDP-REG, which exploits cryptic splicing induced by TDP-43 loss of function to drive protein expression in affected tissues, showcasing a potential avenue for targeted therapies (ref: Wilkins doi.org/10.1126/science.adk2539/). Additionally, van den Bos et al. provided insights into cortical hyperexcitability in ALS, demonstrating that dysfunction in cortical interneurons correlates with symptom severity, emphasizing the role of GABAergic circuits in disease progression (ref: van den Bos doi.org/10.1093/brain/). Saez-Atienzar et al. took a genomic approach to identify potential drug repurposing strategies for C9orf72-related ALS, leveraging large-scale genomic data to uncover new therapeutic targets (ref: Saez-Atienzar doi.org/10.1016/j.xgen.2024.100679/). These findings collectively underscore the complexity of ALS and the necessity for multifaceted research approaches to develop effective treatments.

Neuroinflammation and the immune response play critical roles in the pathogenesis of neurodegenerative diseases. Masserdotti et al. developed an innovative in vitro model using 3D iNeuron cultures to study late-onset Alzheimer's disease (LOAD), revealing that specific reprogramming cocktails can reduce DNA damage and enhance immune response-related gene expression, suggesting a potential mechanism for neuroprotection (ref: Masserdotti doi.org/10.1038/s41392-024-01999-7/). This model provides a valuable platform for investigating the interplay between neuroinflammation and neuronal health in LOAD. Ortí-Casañ et al. further contributed to this theme by mapping cellular vulnerability and resilience in AD, identifying distinct molecular architectures across brain regions that may influence immune responses (ref: Ortí-Casañ doi.org/10.1038/s41392-024-02014-9/). Guo et al. highlighted alterations in the heparin-enriched plasma proteome associated with AD, linking heparin binding proteins to Aβ and tau pathology, which could serve as biomarkers for neuroinflammation (ref: Guo doi.org/10.1186/s13024-024-00757-1/). Taylor et al. examined the effects of anti-Aβ immunotherapy, revealing that vascular inflammation and damage are significant adverse events linked to amyloid-related imaging abnormalities, emphasizing the need for careful consideration of immune responses in therapeutic strategies (ref: Taylor doi.org/10.1186/s13024-024-00758-0/). Together, these studies underscore the intricate relationship between neuroinflammation and neurodegeneration, highlighting potential therapeutic targets.

Recent genetic studies have provided significant insights into the molecular underpinnings of neurodegenerative diseases. Shade et al. conducted a genome-wide association study (GWAS) on multiple neuropathology endophenotypes, identifying over 80 genetic loci associated with Alzheimer's disease and related dementias (ref: Shade doi.org/10.1038/s41588-024-01939-9/). This comprehensive analysis underscores the complex genetic architecture of neurodegenerative diseases and highlights potential pathways for future research. García-Marín et al. expanded on this by performing GWAS meta-analyses of brain volumes, revealing 254 independent loci associated with intracranial and subcortical brain structures, which could inform our understanding of the genetic factors influencing neurodegeneration (ref: García-Marín doi.org/10.1038/s41588-024-01951-z/). Additionally, Keeney et al. investigated the role of LRRK2 in oxidative stress within PD models, demonstrating that LRRK2 kinase activity regulates reactive oxygen species production, linking genetic factors to cellular dysfunction (ref: Keeney doi.org/10.1126/scitranslmed.adl3438/). Collectively, these studies highlight the importance of genetic and molecular insights in unraveling the complexities of neurodegenerative diseases, paving the way for targeted therapeutic strategies.

The relationship between neurodegeneration and aging has been a focal point of recent research, with studies exploring the mechanisms that underlie age-related cognitive decline. Rappe et al. conducted longitudinal profiling of mitophagy in the mammalian brain, revealing that sustained mitophagy occurs throughout healthy aging, which may protect against neurodegenerative processes (ref: Rappe doi.org/10.1038/s44318-024-00241-y/). This finding is significant as it suggests that maintaining mitochondrial health could be crucial in preventing age-related neurodegeneration. Xiong et al. investigated the role of the mitochondrial long non-coding RNA lncMtDloop, demonstrating that it regulates mitochondrial transcription and is downregulated in AD, linking mitochondrial dysfunction to cognitive decline (ref: Xiong doi.org/10.1038/s44318-024-00270-7/). Additionally, Ortí-Casañ et al. provided insights into cellular vulnerability in AD, emphasizing the need to understand how aging affects different brain regions and cell types (ref: Ortí-Casañ doi.org/10.1038/s41392-024-02014-9/). Together, these studies highlight the critical interplay between aging and neurodegeneration, suggesting that interventions targeting mitochondrial health and cellular resilience may mitigate cognitive decline.

Innovative therapeutic strategies for neurodegenerative diseases are being explored through various novel approaches. Lofredi et al. reported on the use of deep brain stimulation to investigate striato-pallidal connectivity in dystonia patients, revealing that oscillatory connectivity correlates with symptom severity, which could inform targeted neuromodulation therapies (ref: Lofredi doi.org/10.1038/s41467-024-52814-4/). This study highlights the potential of neuromodulation as a therapeutic avenue for movement disorders. Kilgas et al. examined the role of the long non-coding RNA NEAT1 in maintaining genome integrity, suggesting that targeting RNA-binding proteins could offer new therapeutic strategies for neurodegenerative diseases (ref: Kilgas doi.org/10.1038/s41467-024-52862-w/). Furthermore, Chakraborty et al. explored multimodal gradients of basal forebrain connectivity, providing insights into cholinergic projections that could be leveraged for therapeutic interventions in cognitive decline (ref: Chakraborty doi.org/10.1038/s41467-024-53148-x/). These studies collectively emphasize the importance of innovative approaches in developing effective therapies for neurodegenerative diseases.