Neurodegenerative diseases, including Alzheimer’s Disease (AD), Parkinson’s Disease (PD), Lewy Body Disease (LBD), and related dementias, represent a global health challenge, particularly in aging populations. The simultaneous occurrence of neurodegenerative diseases in an aging population suggests a potential link between causative proteins. Such neurodegenerative proteins, including amyloid-β (Aβ), τ-protein (tau), α-synuclein, TAR DNA-binding protein 43 (TDP-43), and Fused in Sarcoma (FUS), share key characteristics of intrinsically disordered proteins (IDPs), which can explain promiscuous physical interactions, cross-seeding, co-occurrence, pathological synergy, and shared upstream and downstream mechanisms. This review synthesizes current evidence on (1) shared biophysical features of neurodegeneration-associated proteins, (2) mechanisms driving mixed neuropathology, (3) therapeutic implications of disorder-driven interactions, and (4) key unresolved questions shaping future research. By framing neurodegeneration as a network of interacting, disorder-driven proteinopathies rather than isolated entities, this perspective highlights the need for integrative, systems-level approaches to better understand disease heterogeneity and to identify novel targets for intervention.

Fever is a common adverse reaction to vaccination, contributing to vaccine hesitancy and reduced uptake. To understand variation in fever risk, we longitudinally profiled fecal microbiota, oral temperature, and serological markers in 171 healthy adults receiving Severe acute respiratory syndrome coronavirus 2 mRNA vaccines. Fever risk correlated with low-grade intestinal inflammation, increased abundance of flagellated Lachnospiraceae bacteria, and increased flagellin expression prevaccine. Microbiomes from fever-high donors triggered stronger inflammation in human intestinal organoids and drove flagellin-dependent vaccine reactions in gnotobiotic mice. Moreover, microbiome flagellin phenotypes and murine vaccine reactions were modifiable by diet. Consistent with this, human fever risk was associated with self-reported diet and metabolic markers. These findings identify the gut microbiome as a driver of vaccine-induced fever, suggesting that microbiome-targeting strategies could modulate immune tone and improve vaccine side effects.

Neurodegenerative diseases, including Alzheimer's Disease (AD), Parkinson's Disease (PD), Lewy Body Disease (LBD), and related dementias, represents a global health challenge, particularly in aging populations. The simultaneous occurrence of neurodegenerative diseases in an aging population suggests a potential link between causative proteins. Such neurodegenerative proteins, including amyloid-β (Aβ), τ-protein (tau), α‑synuclein, TAR DNA-binding protein 43 (TDP-43), and Fused in Sarcoma (FUS), share key characteristics of intrinsically disordered proteins (IDPs), which can explain promiscuous physical interactions, cross-seeding, co-occurrence, pathological synergy, and shared upstream and downstream mechanisms. This review synthesizes current evidence on (1) shared biophysical features of neurodegeneration-associated proteins, (2) mechanisms driving mixed neuropathology, (3) therapeutic implications of disorder-driven interactions, and (4) key unresolved questions shaping future research. By framing neurodegeneration as a network of interacting, disorder-driven proteinopathies rather than isolated entities, this perspective highlights the need for integrative, systems-level approaches to better understand disease heterogeneity and to identify novel targets for intervention.

While the methodological principle “correlation does not imply causation” serves as a crucial safeguard in scientific inquiry, its overly restrictive application can impede legitimate investigative pathways and hinder the proper evaluation of emerging evidence. This phenomenon has been clearly observable in the COVID-19 vaccine safety discussions, where serious adverse events with temporal proximity to vaccination have been frequently rejected without comprehensive examination. This work invites reflection on how the inappropriate application of this methodological principle can obstruct scientific inquiry into adverse event surveillance, potentially affecting scientific credibility. This work applies Kuhnian paradigm theory to analyze how institutionalized frameworks operate simultaneously as mechanisms for knowledge advancement and as barriers to conceptual innovation, particularly in politically contested domains such as vaccine safety evaluation. Additionally, a case report is analyzed using Hill´s criteria for causality, in which an immunohistochemical method was used for the first time to evaluate whether mRNA-based vaccines against SARS-CoV-2 contributed to the cause of death. Results showed that three of the nine criteria demonstrated strong evidence of causality, four were partially fulfilled, and two were not fulfilled. Overall, the report provides approximately 55% causal evidence. This suggests, but does not prove, a causal relationship between the BNT162b2 vaccine and multifocal necrotizing encephalitis. The absence of the nucleocapsid protein does not provide definitive evidence to demonstrate a vaccine origin. An analytical method is described that can distinguish between the wild-type SARS-CoV-2 spike protein and the recombinant spike protein expressed following mRNA vaccination.

The COVID-19 pandemic exposed science’s adaptive strengths and epistemic limits. In fact, in the pandemic, mRNA vaccines are attributed to have saved millions of lives. The maxim “correlation does not imply causation” is an essential safeguard against premature causal inference. However, its use may become epistemically restrictive when the absence of established causality is treated as sufficient reason not to investigate (severe) vaccine adverse events. This article examines the conditions under which a valid cautionary principle may have contributed to premature epistemic closure. Thomas Kuhn’s theory of scientific paradigms is used as one interpretative lens rather than as an empirical explanation of institutional behaviour. We argue that the correlation–causation distinction can shift from a heuristic of caution to an instrument of epistemic conservatism, reinforcing prevailing frameworks and discouraging exploration of anomalies. A published autopsy case report involving multifocal necrotizing encephalitis and myocarditis after BNT162b2 vaccination is examined as an illustrative and hypothesis-generating case, not as representative evidence of systematic institutional conduct. A qualitative approach using Bradford Hill’s criteria provides partial, inconclusive evidence of a causal relationship while also exposing the methodological limits of the tool employed. The results of the analysis showed that one of the nine criteria demonstrated support of causality, seven were partially supported, and one did not support causality. The analysis suggests, but does not prove, a causal relationship between the BNT162b2 vaccine and multifocal necrotizing encephalitis. The absence of the nucleocapsid protein does not provide definitive evidence to demonstrate a vaccine origin. Analytical methods are described which can distinguish between the wild-type SARS-CoV-2 spike protein and the recombinant spike protein expressed following mRNA vaccination. The absence of evidence does not mean evidence of absence and we must keep an open mind to this when reviewing such evidence on causality.