Abstract Background and objectives Recent animal studies suggest that P2Y12 receptor (P2Y12R) inhibitors, antiplatelet drugs commonly prescribed after stroke, can suppress the activity of the brain’s innate immune system, and potentially affect brain repair processes. Results from preclinical (animal) studies have shown this to be a very real possibility, with animals administered these drugs after stroke or other event which compromises the blood-brain barrier exhibiting worse cognitive outcomes compared with animals not administered these drugs. We conducted an observational target trial emulation study, which was an analogue if an intention-to-treat analysis testing this hypothesis using Swedish National Health and Medical Registers. This study demonstrated cognitive safety in terms of incidence of diagnosis with dementia or mild cognitive disorder. However, the effects of sustained treatment adherence on cognitive outcomes remain unclear. This study will evaluate whether maintaining P2Y12R inhibitor treatment for at least one year affects subsequent dementia risk, and will examine whether this relationship is mediated through prevention of recurrent cardiovascular events. Methods We will conduct a target trial emulation with per-protocol analysis using Swedish National Health and Medical Register data. We will include individuals with incident ischemic stroke who received P2Y12R inhibitors within three months post-stroke. Treatment exposure will be defined as maintaining P2Y12R inhibitor use for at least one year. We will employ multistate modelling to account for potential transitions through intermediate states (recurrent stroke, acute cardiovascular syndromes) to the primary outcome (dementia/mild cognitive disorder) or competing risk (death). Clone-censor-weight techniques will be applied to address time-varying confounding and selection bias. We will estimate both direct effects of sustained P2Y12R inhibitor use on dementia risk and indirect effects mediated through prevention of recurrent vascular events. Expected outcomes This study will quantify the effect of sustained P2Y12R inhibitor treatment (≥1 year) on post-stroke dementia risk, while accounting for transitions through intermediate cardiovascular events. We will determine the proportion of the total treatment effect that is mediated through prevention of recurrent vascular events versus potential direct neuroprotective mechanisms. Additionally, we will calculate absolute risk differences for dementia between sustained users and non-users, accounting for competing mortality risk. Significance This approach will extend our previous intention-to-treat analysis by evaluating the cognitive effects of sustained P2Y12R inhibitor use and disentangling potential causal pathways. This research addresses a critical knowledge gap regarding commonly prescribed post-stroke medications that have concerning preclinical evidence of potential cognitive harm. With stroke survivors at high risk for dementia, understanding whether these drugs affect cognitive outcomes has significant public health implications. Our innovative methodological approach combines causal inference with multi-state modelling to overcome biases inherent in observational studies, while providing direct clinical insights that could inform treatment guidelines. By addressing these questions, our research has potential to impact the care of millions of stroke patients worldwide.