Primary sjögren's syndrome (pSS) is an autoimmune disease characterized by exocrine gland dysfunction and systemic inflammation, with its neurological complications, particularly cognitive dysfunction, receiving increasing attention.  This provides a systematic framework for a deeper understanding of the pathogenesis of cognitive impairment in pSS and offers a theoretical basis for the future development of targeted early interventions.

This article systematically elaborates on the neuroimmunologic mechanisms of cognitive impairment in pSS, and deeply explores the complete pathophysiologic pathway from the initiation of peripheral systemic inflammation, through blood-brain barrier (BBB) dysfunction, to the activation of immune cells and neuroinflammatory cascades in the central nervous system, ultimately leading to neuronal damage and cognitive decline.

 We integrate multimodal research evidence, including neuroimaging findings of abnormal brain connectivity, cerebrospinal fluid biomarker changes, and pathophysiologic discoveries in animal models, revealing the underlying pathophysiologic network of cognitive impairment in pSS. 

Primary Sjögren's syndrome, as a systemic autoimmune disease characterized by dysfunction of exocrine glands, has seen its neuroimmune-mediated cognitive dysfunction become a significant clinical challenge affecting patients' quality of life. Current evidence indicates that peripheral immune activation can lead to CNS damage through multi-level pathological mechanisms. The process involves multifactorial interactions encompassing B-cell-mediated humoral immune dysregulation, compromised BBB integrity, and synaptic plasticity impairment coupled with neuronal dysfunction due to sustained glial cell activation. These pathological mechanisms collectively contribute to the manifestation of characteristic cognitive symptoms, including brain fog. Although immunomodulators such as hydroxychloroquine and rituximab have shown potential in improving cognitive symptoms in some cases[91, 135], there is still a lack of specific treatment options for pSS-related cognitive impairment, and existing therapeutic strategies lack validation through large-scale randomized controlled trials. To address these critical limitations, future investigations should prioritize longitudinal dynamic monitoring studies that integrate single-cell sequencing technologies with multimodal neuroimaging follow-up approaches. At the same time, novel immunomodulatory therapies should be actively explored to mitigate cognitive damage through precise intervention in the neuroimmune cascade. These breakthroughs will not only improve the cognitive prognosis and quality of life for pSS patients but may also provide a therapeutic paradigm for other autoimmune disease-related encephalopathies.