Many cited studies show associations (e.g., elevated oxidative markers in post-mortem tissue or patient biofluids), but the review often implicitly treats these as evidence of a primary causal role.
This is critically important because if oxidative stress is largely a downstream consequence of other pathological processes (e.g., protein aggregation, mitochondrial genetic defects, or neuroinflammation), then therapeutic strategies primarily targeting ROS may have limited efficacy, as suggested by the disappointing clinical trials of antioxidants noted briefly in Section 2.3.3 and the conclusion.
Key question for the authors: Could you clarify the strength of evidence for oxidative stress as an initiating factor versus a perpetuating or secondary phenomenon in each major disorder discussed (e.g., AD, PD, ALS)? Specifically, what human or model system data demonstrate that directly reducing oxidative stress without affecting the primary cause (e.g., Aβ, mutant huntingtin, SOD1) significantly alters disease onset or progression?