An interesting development in Alzheimer's disease.

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

First published: 08 May 2025

INTRODUCTION
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.

METHODS
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.

RESULTS
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.

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.

A critical effector in the pathogenesis of AD is the NLRP3 inflammasome, a multimeric protein complex that responds to aberrant Aβ and tau aggregation by launching a potent inflammatory response characterized by caspase-1 activation, interleukin-1β (IL-1β) release (also IL-18 - ohm20), and neuronal cell death. In turn, NLRP3 activation facilitates further deposition of Aβ plaques and tau fibrils, establishing a positive feedback loop that contributes to the development of AD.
https://alz-journals.onlinelibrary.wiley.com/...alz.70180#

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caspase-1 (via NLRP3/ASC downreg) [-]
IL-1b (via caspase-1 downreg)[-]
IL-18 (via caspase-1 downreg)[-]

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