Neurodegenerative diseases are a group of age-related disorders characterized by progressive neuron loss in the central or peripheral nervous system. Their prevalence is rising due to an aging population, and current treatments are mostly symptomatic, with limited impact on disease progression. Recent advances in neurobiology and neurogenetics have improved understanding of their pathogenesis, which involves genetic, environmental, and lifestyle factors. Common mechanisms contribute to neuronal degeneration, but molecular pathways vary between conditions. As understanding of molecular pathophysiology advances, so do therapeutic strategies. Alzheimer's disease (AD) is the most common cause of dementia, characterized by memory loss, behavioral disturbances, and impaired judgment. Key features include amyloid-beta plaques and neurofibrillary tangles. Early diagnosis is crucial for prevention and treatment. The QPLEX™ kit detects biomarkers in blood to identify AD early, offering a non-invasive alternative to spinal fluid or PET scans. New therapeutic approaches for AD include targeting comorbid psychosis, which affects half of AD patients. A viral-mediated gene expression approach in rats showed promise in reversing dopaminergic dysfunction. Simufilam, a novel drug in phase 3 trials, targets filamin A to disrupt abnormal interactions involved in AD pathology. Research on Parkinson's disease (PD) focuses on reducing alpha-synuclein accumulation and enhancing autophagy. ARL6IP5, a novel autophagy regulator, reduces alpha-synuclein aggregation in PD models. Andrographolide shows neuroprotective effects against MPP+ toxicity in SH-SY5Y cells. LAR inhibition protects astrocytes and improves neuronal survival in PD models. ALS is a rapidly progressive disorder with complex pathophysiology. PKCε dysfunction is implicated in ALS, and its activation may offer neuroprotection. Huntington's disease (HD) involves mutant huntingtin aggregation and disrupted calcium signaling. Targeting lysosomal calcium and autophagy may help prevent HD progression. Vitamin E shows neuroprotective effects in experimental models, reducing amyloid-beta and tau pathology. Cellular protein aggregation is a key aspect of neurodegeneration, with various clearance mechanisms and therapeutic strategies being explored. This Special Issue highlights ongoing research into the molecular basis and therapeutic strategies for neurodegenerative diseases, emphasizing the need for early diagnosis and multi-target therapies. The findings underscore the importance of understanding disease mechanisms to develop effective treatments.Neurodegenerative diseases are a group of age-related disorders characterized by progressive neuron loss in the central or peripheral nervous system. Their prevalence is rising due to an aging population, and current treatments are mostly symptomatic, with limited impact on disease progression. Recent advances in neurobiology and neurogenetics have improved understanding of their pathogenesis, which involves genetic, environmental, and lifestyle factors. Common mechanisms contribute to neuronal degeneration, but molecular pathways vary between conditions. As understanding of molecular pathophysiology advances, so do therapeutic strategies. Alzheimer's disease (AD) is the most common cause of dementia, characterized by memory loss, behavioral disturbances, and impaired judgment. Key features include amyloid-beta plaques and neurofibrillary tangles. Early diagnosis is crucial for prevention and treatment. The QPLEX™ kit detects biomarkers in blood to identify AD early, offering a non-invasive alternative to spinal fluid or PET scans. New therapeutic approaches for AD include targeting comorbid psychosis, which affects half of AD patients. A viral-mediated gene expression approach in rats showed promise in reversing dopaminergic dysfunction. Simufilam, a novel drug in phase 3 trials, targets filamin A to disrupt abnormal interactions involved in AD pathology. Research on Parkinson's disease (PD) focuses on reducing alpha-synuclein accumulation and enhancing autophagy. ARL6IP5, a novel autophagy regulator, reduces alpha-synuclein aggregation in PD models. Andrographolide shows neuroprotective effects against MPP+ toxicity in SH-SY5Y cells. LAR inhibition protects astrocytes and improves neuronal survival in PD models. ALS is a rapidly progressive disorder with complex pathophysiology. PKCε dysfunction is implicated in ALS, and its activation may offer neuroprotection. Huntington's disease (HD) involves mutant huntingtin aggregation and disrupted calcium signaling. Targeting lysosomal calcium and autophagy may help prevent HD progression. Vitamin E shows neuroprotective effects in experimental models, reducing amyloid-beta and tau pathology. Cellular protein aggregation is a key aspect of neurodegeneration, with various clearance mechanisms and therapeutic strategies being explored. This Special Issue highlights ongoing research into the molecular basis and therapeutic strategies for neurodegenerative diseases, emphasizing the need for early diagnosis and multi-target therapies. The findings underscore the importance of understanding disease mechanisms to develop effective treatments.