A class of drugs commonly used to treat human immunodeficiency virus and hepatitis B infections could reduce the risk of developing Alzheimer's disease, according to a new study. The research, which analyzed data from over 270,000 individuals across 2 major U.S. health insurance databases, found that exposure to nucleoside reverse transcriptase inhibitors may be associated with a lower incidence of Alzheimer's disease.
Investigators from the University of Virginia and University of South Carolina discovered that each additional year of nucleoside reverse transcriptase inhibitor (NRTI) exposure was associated with a 4% reduced risk of Alzheimer's disease (AD) in the Veterans Health Administration (VA) database and a 10.3% reduced risk in the MarketScan database.
"NRTI exposure was associated with a significantly lower incidence of AD in two of the largest health insurance databases in the United States," the study authors wrote. "In contrast, exposure to non-NRTIs, protease inhibitors (PI), and integrase strand transfer inhibitors (INSTI) was not associated with reducing AD incidence," they added.
The protective effect persisted after the investigators controlled for numerous demographic factors and comorbidities known to increase AD risk. When using propensity score matching to minimize potential selection bias, the association remained significant, with a 6% reduced risk per year of NRTI use in the VA database and a 13% reduced risk per year in the MarketScan database.
The findings build on previous research showing that NRTIs inhibit inflammasome activation independent of their antiretroviral activity. Inflammasome activation, particularly of the NLRP3 inflammasome, has been implicated in the pathogenesis of AD.
"A critical effector in the pathogenesis of AD is the NLRP3 inflammasome, a multimeric protein complex that responds to aberrant [amyloid beta] and tau aggregation by launching a potent inflammatory response characterized by caspase-1 activation, interleukin-1 [beta] release, and neuronal cell death," the study authors explained.
VA data spanning 24 years (2000 to 2024) and MarketScan data over 14 years (2006 to 2020) was used. In the VA sample, 72,193 patients met the study criteria, while the MarketScan database included 199,005 eligible patients. Both data sets showed consistent protective associations between NRTI exposure and AD development.
Post-hoc analyses revealed that the protective effect was present in both HIV-positive patients without hepatitis B and in hepatitis B–positive patients without HIV, strengthening the generalizability of the findings.
To account for the possibility that patients receiving NRTIs might die prior to developing AD, the investigators conducted a competing risk analysis. Even after adjusting for mortality risk, NRTI exposure remained associated with a 32% reduced risk of developing AD in the unmatched population and a 37% reduced risk in the propensity-matched population.
The study provides epidemiologic support for the concept that inflammasome inhibition could benefit patients with AD. The investigators noted that two NRTIs have recently been tested in clinical trials for AD: lamivudine (ClinicalTrials.gov identifier NCT04552795), which has completed a pilot study showing reduction in neurodegeneration and neuroinflammation biomarkers, and emtricitabine (NCT04500847), which is ongoing.
K-9, an NRTI derivative that lacks reverse transcriptase inhibition but retains inflammasome inhibition ability, as a promising candidate for future AD treatment that might avoid toxicity concerns associated with traditional NRTIs.
"Our work provides a rationale for randomized clinical trials of inflammasome inhibitors in AD," the study authors concluded, suggesting that NRTI derivatives with improved safety profiles might be particularly suitable for chronic administration in patients with AD.
Disclosures can be found in the published study.
Source: Alzheimer's and Dementia
