Magagnoli Joseph, Ambati Meenakshi, Cummings Tammy H, Nguyen Joseph, Thomas Claire C, Ambati Vidya L, Sutton S Scott, Gelfand Bradley D, Ambati Jayakrishna
Dorn Research Institute, Columbia VA Health Care System, Columbia, South Carolina, USA.
Department of Clinical Pharmacy and Outcomes Sciences, College of Pharmacy, University of South Carolina, Columbia, South Carolina, USA.
Alzheimers Dement. 2025 May;21(5):e70180. doi: 10.1002/alz.70180.
Inflammasome activation is implicated in Alzheimer's disease (AD). We previously demonstrated that nucleoside reverse transcriptase inhibitors (NRTIs), drugs approved to treat human immunodeficiency virus (HIV) and hepatitis B, also inhibit inflammasome activation.
We evaluated the association between NRTI exposure and subsequent development of AD in the United States Veterans Health Administration over a 24-year period and in the MarketScan database over a 14-year period using propensity score-matched multivariate Cox hazards regression and Kaplan-Meier analyses.
We report that in humans, NRTI exposure was associated with a significantly lower incidence of AD in two of the largest health insurance databases in the United States. In contrast, exposure to non-NRTIs, protease inhibitors (PIs), and integrase strand transfer inhibitors (INSTIs) was not associated with reducing AD incidence.
These findings support the concept that inflammasome inhibition could benefit AD and provide a rationale for prospective clinical testing of inflammasome inhibitors such as NRTIs in AD.
Exposure to NRTIs, a class of anti-retroviral drugs that also block inflammasome activation, was associated with a reduction in the risk of developing AD. The reduction in risk was observed in two large, diverse health insurance databases after correcting for numerous comorbidities known to be associated with AD. Other anti-HIV therapies such as non-NRTIs, protease inhibitors, and integrase strand transferase inhibitors were not associated with a reduction in the risk of developing AD. Our work provides a rationale for randomized clinical trials of inflammasome inhibitors in AD.
炎症小体激活与阿尔茨海默病（AD）有关。我们之前证明，核苷逆转录酶抑制剂（NRTIs），即已被批准用于治疗人类免疫缺陷病毒（HIV）和乙型肝炎的药物，也能抑制炎症小体激活。
我们使用倾向评分匹配的多变量Cox风险回归和Kaplan-Meier分析，评估了美国退伍军人健康管理局24年期间以及MarketScan数据库14年期间NRTI暴露与AD后续发病之间的关联。
我们报告称，在美国两个最大的健康保险数据库中，人类NRTI暴露与AD发病率显著降低相关。相比之下，非NRTIs、蛋白酶抑制剂（PIs）和整合酶链转移抑制剂（INSTIs）的暴露与降低AD发病率无关。
这些发现支持了炎症小体抑制可能有益于AD的概念，并为在AD中对NRTIs等炎症小体抑制剂进行前瞻性临床试验提供了理论依据。
暴露于NRTIs（一类也能阻断炎症小体激活的抗逆转录病毒药物）与患AD风险的降低相关。在两个大型、多样的健康保险数据库中，在校正了众多已知与AD相关的合并症后观察到风险降低。其他抗HIV疗法，如非NRTIs、蛋白酶抑制剂和整合酶链转移酶抑制剂，与患AD风险降低无关。我们的工作为在AD中进行炎症小体抑制剂的随机临床试验提供了理论依据。
