Research on Huntington's Disease (HD) has increasingly focused on the role of genetic modifiers, particularly mismatch-repair (MMR) genes. A study demonstrated that knockout of specific MMR genes, such as Msh3 and Pms1, significantly rescues early-onset phenotypes in striatal medium-spiny neurons and late-onset phenotypes in cortical neurons in HD mice with 140 CAG repeats, indicating a strong link between MMR gene function and neuronal pathogenesis (ref: Wang doi.org/10.1016/j.cell.2025.01.031/). This highlights the potential for targeting MMR pathways in therapeutic strategies. Additionally, the exploration of transcriptomic signatures in genetic behavioral variant frontotemporal degeneration (bvFTD) revealed significant overlaps with genes associated with cortical atrophy, suggesting that common pathways may underlie neurodegenerative processes across different diseases (ref: Shen doi.org/10.1186/s13024-025-00806-3/). Furthermore, the loss of MEF2C function due to enhancer mutations was shown to lead to mitochondrial dysfunction and motor deficits, emphasizing the importance of genetic and epigenetic factors in neurodegeneration (ref: Yousefian-Jazi doi.org/10.1186/s13024-024-00792-y/).

Alzheimer's Disease (AD) research has identified critical biomarkers and mechanisms underlying disease progression. A notable study highlighted phospho-tau serine-262 and serine-356 as potential biomarkers for pre-tangle soluble tau assemblies, which could help in identifying patients who might benefit from therapies targeting tau pathology (ref: Islam doi.org/10.1038/s41591-024-03400-0/). Another significant finding was the role of the NLRP3 inflammasome in promoting AD progression through glutaminolysis and microglial phagocytosis, linking neuroinflammation to amyloid-beta deposition (ref: McManus doi.org/10.1016/j.immuni.2025.01.007/). The MorPhiC Consortium aims to create a comprehensive catalog of molecular phenotypes associated with null alleles of human genes, which could enhance our understanding of AD pathology (ref: Adli doi.org/10.1038/s41586-024-08243-w/). Additionally, a national cohort study revealed that air pollution significantly impacts mortality and hospital readmission rates among Medicare beneficiaries with AD, indicating environmental factors' role in disease outcomes (ref: Dong doi.org/10.1016/S2542-5196(25)00001-4/).

In Parkinson's Disease (PD) research, the potential of exenatide as a disease-modifying treatment was evaluated in a phase 3 trial, showing that it could slow disease progression with a comparable safety profile to placebo (ref: Vijiaratnam doi.org/10.1016/S0140-6736(24)02808-3/). Pre-clinical studies on human induced pluripotent stem cell-derived midbrain dopaminergic cells demonstrated promising safety and efficacy for autologous cell therapy in PD, emphasizing the need for standardized regulatory criteria for clinical translation (ref: Jeon doi.org/10.1016/j.stem.2025.01.006/). Furthermore, research into the structural basis of tri-heteromeric NMDA receptors revealed unique pharmacological characteristics that could inform future therapeutic strategies (ref: Kang doi.org/10.1016/j.neuron.2025.01.013/). Additionally, findings from the A53T PD rat model indicated that increased beta oscillations correlate with motor deficits, suggesting their potential as biomarkers for disease progression (ref: Hofman doi.org/10.1093/brain/).

Neuroinflammation plays a pivotal role in neurodegenerative diseases, as evidenced by the identification of distinct microglial aggregates in Alzheimer's Disease (AD) that contribute to disease progression. These aggregates, including plaque-associated microglia and coffin-like microglia, were characterized using advanced neuropathological techniques, revealing their involvement in engulfing neurons and associating with tau pathology (ref: Fixemer doi.org/10.1007/s00401-025-02857-8/). Additionally, a novel approach utilizing optimal transport analysis in spatial transcriptomics has been developed to infer cell trajectories, enhancing our understanding of cellular differentiation in the context of neuroinflammation (ref: Shen doi.org/10.1016/j.cels.2025.101194/). The versatility of boronic acids in creating functional molecules also points to their potential applications in neuroinflammatory contexts, although their specific roles in neurodegeneration remain to be fully elucidated (ref: António doi.org/10.1021/acs.accounts.4c00691/).

The intersection of metabolic and environmental factors in neurodegeneration has gained attention, particularly concerning the bioaccumulation of microplastics in human brains. This study confirmed the presence of microplastics in various organs, including the brain, raising concerns about their potential health impacts (ref: Nihart doi.org/10.1038/s41591-024-03453-1/). Furthermore, research on air pollution's effects on Alzheimer's Disease mortality and hospital readmissions highlighted the significant public health implications of environmental factors on neurodegenerative diseases (ref: Dong doi.org/10.1016/S2542-5196(25)00001-4/). Additionally, the concept of individual bioenergetic capacity as a resilience factor in Alzheimer's Disease suggests that metabolic differences could influence disease progression, with specific serum profiles correlating with clinical outcomes (ref: Arnold doi.org/10.1038/s41467-025-57032-0/).

Investigations into the molecular mechanisms underlying neurodegenerative diseases have revealed critical insights into the roles of specific circuits and molecular interactions. A study identified a circuit involving the visual cortex and lateral posterior thalamic nucleus that regulates depressive-like behaviors, linking sensory processing to mood disorders (ref: Wu doi.org/10.1038/s41467-024-55600-4/). Additionally, research into energy dynamics within neurons has uncovered that energy availability significantly influences the localization and copy number of molecules, suggesting a fundamental role of energy metabolism in neuronal function (ref: Bergmann doi.org/10.1038/s41467-025-56640-0/). Aspirin's impact on proteasomal degradation and its potential to promote alpha-synuclein clearance through K63 ubiquitination further illustrates the intricate molecular pathways involved in neurodegeneration (ref: Gao doi.org/10.1038/s41467-025-56737-6/). Lastly, a comprehensive genomic and proteomic analysis of dystonia has unveiled significant genetic heterogeneity, emphasizing the need for further exploration of genetic contributions to neurodegenerative disorders (ref: Zech doi.org/10.1093/brain/).

Cognitive decline associated with aging and neurodegenerative diseases has been a focal point of recent research, particularly in the context of Lewy body spectrum disorders. A study demonstrated that degeneration in the hippocampus and basal forebrain significantly impacts cognitive function, with structural changes observed in patients with dementia compared to those with normal cognition (ref: Rau doi.org/10.1093/brain/). Additionally, insights from a methylome-wide association study revealed significant associations between DNA methylation patterns and antidepressant exposure, suggesting that epigenetic factors may influence cognitive outcomes in aging populations (ref: Davyson doi.org/10.1038/s41467-024-55356-x/). Furthermore, the identification of a selective allosteric modulator for SETDB1, a methyltransferase implicated in neurodegeneration, highlights the potential for targeted therapeutic strategies aimed at cognitive decline (ref: Uguen doi.org/10.1038/s41467-025-57005-3/).

Research into amyotrophic lateral sclerosis (ALS) has focused on the cellular and molecular mechanisms driving neurodegeneration. A study demonstrated that graphene quantum dots can attenuate TDP-43 proteinopathy, a hallmark of ALS, by inhibiting amyloid fibril formation and enhancing motor neuron survival in transgenic mouse models (ref: Park doi.org/10.1021/acsnano.4c15283/). Additionally, the role of optineurin in axonal mitochondrial transport was elucidated, revealing that mutations in optineurin lead to neurodegeneration due to impaired mitochondrial delivery in motor neurons (ref: Liu doi.org/10.1038/s41467-025-57135-8/). Furthermore, transcriptomic analyses of genetic behavioral variant frontotemporal degeneration highlighted shared and distinct pathways associated with cortical atrophy, providing insights into the molecular underpinnings of neurodegenerative diseases (ref: Shen doi.org/10.1186/s13024-025-00806-3/).