Cognitive Decline in Chronic Inflammatory Conditions: Exploring Links Between Systemic Inflammation and...

Chronic inflammatory diseases (CIDs), such as rheumatoid arthritis (RA), obesity, type 2 diabetes mellitus (T2DM), systemic lupus erythematosus (SLE), fibromyalgia (FM), and chronic infection, are risk factors for neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD). This review synthesizes evidence from longitudinal cohort studies and clinical trials, highlighting the contrasting evidence to explain the complex association between systemic inflammation and neurodegeneration. These important mechanisms are disruption of the blood-brain barrier, microglial activation, cytokine-related neurotoxicity (e.g., IL-6, TNF-alpha), lysosomal maladaptation, and metabolic imbalance (e.g., insulin resistance, hyperglycemia). Disease-specific correlations present study outcomes that are paradoxical, including that RA has genetic protection against PD but an increased risk of AD, whereas obesity and T2D associations are the same across studies, persistent associations of these terms with worsened cognitive decline. The risk of dementia is worsened by autoimmune diseases, such as SLE and FM, involving neuroinflammation caused by autoantibodies and central sensitization in the latter, respectively. The new markers, such as glial fibrillary acidic protein (GFAP) (neuroinflammation) and neurofilament light (NfL) (axonal injury), have prospects in early detection, but there is a need for validation in future studies. Therapeutic approaches emphasize the need for immunomodulation (e.g., disease-modifying antirheumatic drugs {DMARDs} in RA), glycemic control in T2DM, and lifestyle interventions, with a lack of targeting the non-amyloid pathways. New studies should emphasize longitudinal studies, multiome-based methods, and clinical trials in an attempt to create precision treatment. Considering the inflammatory risk stratification in the prevention of neurodegeneration, this review sheds light on the possibility of early preventative action that may offset the progressive cognitive decline in especially vulnerable groups.