Substance Abuse and Cognitive Decline: The Critical Role of Tau Protein as a Potential Biomarker

Tau protein, essential for neuron stability, becomes toxic when hyperphosphorylated or cleaved, contributing to Alzheimer's disease. Evidence from experimental, clinical, and postmortem studies indicates that chronic substance use alters Tau dynamics in substance-specific ways. Alcohol and opioids promote Tau hyperphosphorylation and fragmentation via kinases like GSK-3β and CDK5 and proteases like caspase-3, leading to neuroinflammation. Stimulants and dissociatives disrupt insulin signaling and increase oxidative stress, exacerbating Tau pathology. Cannabinoids and psychedelics may protect by modulating kinase activity and reducing inflammation; psilocybin and harmine decrease Tau phosphorylation in animal models. Tau emerges as a convergent target in substance-related cognitive disorders, offering a biomarker and therapeutic target.

Study at a glance

Abstract

Tau protein is essential for the structural stability of neurons, particularly through its role in microtubule assembly and axonal transport. However, when abnormally hyperphosphorylated or cleaved, Tau can aggregate into insoluble forms that disrupt neuronal function, contributing to the pathogenesis of neurodegenerative diseases such as Alzheimer’s disease (AD). Emerging evidence suggests that similar Tau-related alterations may occur in individuals with chronic exposure to psychoactive substances. This review compiles experimental, clinical, and postmortem findings that collectively indicate a substance-specific influence on Tau dynamics. Alcohol and opioids, for instance, promote Tau hyperphosphorylation and fragmentation through the activation of kinases such as GSK-3β and CDK5, as well as proteases like caspase-3, leading to neuroinflammation and microglial activation. Stimulants and dissociatives disrupt insulin signaling, increase oxidative stress, and impair endosomal trafficking, all of which can exacerbate Tau pathology. In contrast, cannabinoids and psychedelics may exert protective effects by modulating kinase activity, reducing inflammation, or enhancing neuroplasticity. Psychedelic compounds such as psilocybin and harmine have been demonstrated to decrease Tau phosphorylation and facilitate cognitive restoration in animal models. Although the molecular mechanisms differ across substances, Tau consistently emerges as a convergent target altered in substance-related cognitive disorders. Understanding these pathways may provide not only mechanistic insights into drug-induced neurotoxicity but also identify Tau as a valuable biomarker and potential therapeutic target for the prevention or treatment of cognitive decline associated with substance use.