Unveiling the causal link between inflammation and Alzheimer’s disease via integrated Mendelian randomization analysis

<p indent="0mm">With the increasing incidence and mortality rates in China, Alzheimer’s disease (AD) poses a significant challenge to sustainable societal development. Inflammatory progression has been recognized as a pivotal factor in AD pathogenesis; however, the molecular mechanisms driving the transition to AD remain unveiled, leaving the causal relationship between inflammation and AD inadequately elucidated. To address this, this manuscript conducted an integrated Mendelian randomization (MR) analysis. Bidirectional MR analysis revealed that chronic inflammation can unilaterally progress to AD, while multivariable MR further identified chronic obstructive pulmonary disease (COPD) as a specific risk factor for AD. Colocalization and protein-protein interaction studies pinpointed endoplasmic reticulum aminopeptidase 1 as a critical mediator between COPD and AD, leading to the identification of five metal-associated inflammatory factors suitable for clinical detection. Two-step MR analysis based on these inflammatory factors corroborated the high risk of COPD transitioning to AD and highlighted their potential as key markers for evaluating AD susceptibility in COPD patients. These findings offer potential biomarkers and therapeutic targets for the diagnosis and treatment of AD.