From Proteinopathies to Systems-Level Diseases: Converging Mechanisms in Neurodegeneration Beyond Protein Aggregation

Across the spectrum of neurodegenerative diseases - including Alzheimer’s disease (AD), Parkinson’s disease (PD), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS) - the misfolding and aggregation of proteins such as amyloid-β, tau, alpha-synuclein, and TDP-43 has long been viewed as the root cause of disease. Yet therapies targeting protein aggregates have offered modest clinical benefit, and protein burden often correlates only loosely with the timing and severity of neuronal loss. Neurodegeneration is increasingly understood as a multifactorial syndrome involving dysfunction across whole biological systems, with mixed pathology now the rule rather than the exception. These observations invite a reframing in which protein aggregation may be as much a consequence as a cause.This Research Topic is organised around a single question: do vascular, immune, circadian or metabolic disturbances precede protein aggregation and neuronal loss, and can they be shown to do so? We are particularly interested in how vascular and blood–brain barrier dysfunction, neuroinflammation, disrupted sleep-wake cycles, mitochondrial and metabolic decline, synaptic vulnerability, peripheral signaling, and cellular senescence may interact. Genetic evidence that immune-related variants influence risk across distinct diseases hints at shared upstream mechanisms, and the frequency of mixed dementia further motivates a systems-level view. We ask that every contribution engage directly with this question. To keep the collection focused rather than a survey of “everything except protein aggregation,” submissions should do at least one of the following:o address the timing of events - whether systemic or immune dysfunction arises before, alongside, or after protein aggregation and neuronal damage;o test whether a mechanism acts as an upstream driver of neurodegeneration, rather than describing it in isolation; and/oro examine the same mechanism across two or more disease models, so a candidate process is evaluated as a potential unifying theme rather than a single-disease observation.The aim is not to set aside pathological proteins, but to situate them within a broader framework, and to open earlier windows for diagnosis and intervention before neuronal loss becomes irreversible.We welcome Original Research, Review, Mini-Review, Systematic Review, Hypothesis and Theory, Perspective, and Methods articles that critically test rather than assume the primacy of proteinopathy. The themes below define the territory of interest; each submission should make clear how it speaks to temporal precedence, upstream causation, or cross-disease generality. Themes include, but are not limited to: neuroinflammation; vascular changes and blood–brain barrier breakdown; circadian disruption; impaired glymphatic clearance; mitochondrial and metabolic dysfunction; synaptic failure; gut–brain axis dysregulation; and cellular senescence. Human cohorts, animal and cellular models, and computational or multi-omic approaches are all welcome.To align with the Neurodegeneration section, studies should provide mechanistic insight, ideally supported by in vivo preclinical models, patient-derived cell-based studies, or robust multi-omic/computational evidence. Vascular/BBB work must link to neurodegenerative mechanisms (not stroke); human cohort studies should be mechanistic or biomarker-driven (not case reports); and interventions must clarify their mechanism of action. Purely cerebrovascular, clinical, or general cell-death studies fall outside the section’s scope.Dr. Preethi Sheshadri serves as a scientific consultant for Biosignatures Tech (India). Topic editors: Preethi Sheshadri, DIEGO ALBANI Source: https://www.frontiersin.org/research-topics/83926/from-proteinopathies-to-systems-level-diseases-converging-mechanisms-in-neurodegeneration-beyond-protein-aggregation