Despite decades of research, Alzheimer’s disease (AD) remains without a curative therapy. While amyloid- and tau-centered approaches have dominated the field, failures of monotherapeutic strategies underscore the need for a broader system-level understanding. Here, this review critically revisits the principal hypotheses of AD pathogenesis, including the amyloid cascade, tauopathy, neuroinflammation, cholinergic dysfunction, oxidative and mitochondrial stress, metal dyshomeostasis, autophagy–lysosomal failure, genetic susceptibility, and infectious triggers. This review synthesizes molecular and cellular evidence from human genetics, neuropathology, and experimental models, correcting common misconceptions and emphasizing interactions between pathways. Neuroinflammation is increasingly recognized as a central hub linking amyloid, tau, and vascular factors, while mitochondrial and lysosomal dysfunctions emerge as amplifiers of proteotoxic stress. Genetic studies highlight apolipoprotein-E ε4 (APOE ε4) as the strongest common risk allele, but also implicate genes involved in endosomal trafficking, lipid metabolism, and immune regulation. Taken together, AD is best understood as a multi-hit disorder in which converging processes, rather than a single driver, dictate disease initiation and progression. This narrative review proposes a systems neurobiology framework that integrates these mechanisms and identifies key points of convergence amenable to therapeutic targeting and biomarker development. Finally, this reappraisal aims to inform future research directions and guide the rational design of multi-target interventions.

Centella asiatica (C. asiatica) has attracted significant scientific interest due to its extensive medicinal properties and long-established use in traditional medicine. This review synthesizes recent advances in the technological exploitation of C. asiatica, covering the extraction of bioactive constituents to product development. Modern extraction techniques such as supercritical fluid extraction (SFE) and microwave-assisted extraction (MAE) have substantially improved the yield, selectivity, and preservation of key phytochemicals, particularly triterpenoids, saponins, and flavonoids. These compounds are now routinely characterized using advanced analytical platforms, ensuring product quality, consistency, and standardization. Moreover, the use of innovative formulation technologies and advanced delivery systems has facilitated the development of C. asiatica-based products tailored for various therapeutic areas, including pharmaceuticals, nutraceuticals, and cosmeceuticals targeting neuroprotection, wound healing, skin aging, and stress modulation. Alongside these developments, stringent quality control protocols, toxicological evaluations, and adherence to evolving regulatory standards enhance the safety and efficacy of C. asiatica-derived interventions. This review highlights the integration of traditional knowledge with modern science across the domains of extraction, analysis, formulation, and regulation. It serves as a comprehensive resource for researchers, formulators, and regulatory stakeholders aiming to develop high-quality, evidence-based C. asiatica products with improved bioavailability and therapeutic value.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder marked by neuronal loss, cognitive decline, and pathological hallmarks such as amyloid-beta (Aβ) plaques and tau neurofibrillary tangles. Recent evidence highlights autophagy as a pivotal mechanism in cellular homeostasis, mediating the clearance of misfolded proteins and damaged organelles. However, impaired autophagy contributes significantly to AD pathogenesis by disrupting proteostasis, exacerbating neuroinflammation, and promoting synaptic dysfunction. This review aims to scrutinize the intricate relationship between autophagy dysfunction and AD progression, explaining key pathways including macroautophagy, chaperone-mediated autophagy (CMA), and selective autophagy processes such as mitophagy and aggrephagy. This further extends the discussion beyond the central nervous system, evaluating the role of hepatic autophagy in Aβ clearance and systemic metabolic regulation. An understanding of autophagy’s involvement in AD pathology via various mechanisms could give rise to a novel therapeutic strategy targeting autophagic modulation to mitigate disease progression in the future.

Artificial intelligence (AI) and machine learning (ML), especially deep learning, have profoundly transformed biology by enabling precise interpretation of complex genomic and proteomic data. This review presents a comprehensive overview of cutting-edge AI methodologies spanning from foundational neural networks to advanced transformer architectures and large language models (LLMs). These tools have revolutionized our ability to predict gene function, identify genetic variants, and accurately determine protein structures and interactions, exemplified by landmark milestones such as AlphaFold and DeepBind. We elaborate on the synergistic integration of genomics and protein structure prediction through AI, highlighting recent breakthroughs in generative models capable of designing novel proteins and genomic sequences at unprecedented scale and accuracy. Furthermore, the fusion of multi-omics data using graph neural networks and hybrid AI frameworks has provided nuanced insights into cellular heterogeneity and disease mechanisms, propelling personalized medicine and drug discovery. This review also discusses ongoing challenges including data quality, model interpretability, ethical concerns, and computational demands. By synthesizing current progress and emerging frontiers, we provide insights to guide researchers in harnessing AI’s transformative power across the biological spectrum from genes to functional proteins.

Neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease, multiple sclerosis, and amyotrophic lateral sclerosis share converging mechanisms of neuronal dysfunction, including protein aggregation, oxidative stress, and chronic neuroinflammation. Glial cells, once considered passive supporters, are now recognized as central drivers of these processes, offering both pathogenic triggers and therapeutic opportunities. Yet, despite compelling preclinical evidence, the translation of glial-targeted therapies into clinical success has been limited. This review provides a critical synthesis of current knowledge by examining therapeutic strategies through the lens of their translational challenges and failures. This narrative review highlights how interspecies variability of glial phenotypes, shifting neuroprotective versus neurotoxic states, limited biomarker stratification, and delivery barriers have constrained trials, such as anti-triggering receptor expressed on myeloid cells 2 (anti-TREM2) antibodies in AD and glial cell line-derived neurotrophic factor (GDNF) in PD. By analyzing these obstacles across major neurodegenerative disorders, this review argue that the next stage of glial medicine requires precision approaches that integrate stage-specific phenotyping, biomarker-guided patient selection, and innovative delivery platforms. Understanding not only what has been tried but why translation has stalled is essential to chart a roadmap for effective, disease-modifying glial therapies in the aging brain.

The human microbiota constitute a very complex ecosystem of microorganisms inhabiting both the inside and outside of our bodies, in which health maintenance and disease modification are the main regulatory features. The recent explosion of microbiome research has begun to detail its important role in neurological health, particularly concerning cerebral small vessel disease (CSVD), a disorder associated with cognitive decline and vascular dementia. This narrative review represents state-of-the-art knowledge of the intimate, complex interplay between microbiota and brain health through the gut–brain axis (GBA) and the emerging role of glymphatic system dysfunction (glymphopathy) and circulating cell-derived microparticles (MPs) as mediators of these interactions. We discuss how microbial dysbiosis promotes neuroinflammation, vascular dysfunction, and impaired waste clearance in the brain, which are critical factors in the pathogenesis of CSVD. Further, we discuss lifestyle factors that shape the composition and functionality of the microbiota, focusing on sleep as a modifiable risk factor in neurological disorders. This narrative review presents recent microbiome research from a neuroscientific and vascular perspective to establish future therapeutic avenues in targeting the microbiota to improve brain health and reduce the burden of CSVD.