Association of nucleoside reverse transcriptase inhibitor use with reduced risk of Alzheimer's disease risk.

introductionInflammasome 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.

methodsWe 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.

resultsWe 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. DISCUSSION: 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. HIGHLIGHTS: 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.