Innate immune signaling through the NLRP3 inflammasome has been implicated in the pathogenesis of Alzheimer's disease (AD), the most prevalent form of dementia. We previously demonstrated that nucleoside reverse transcriptase inhibitors (NRTIs), drugs approved to treat HIV and hepatitis B infections, also inhibit inflammasome activation. Here 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. Treatment of aged 5xFAD mice (a mouse model of amyloid-β deposition that expresses five mutations found in familial AD) with Kamuvudine-9 (K-9), an NRTI-derivative with enhanced safety profile, reduced Aβ deposition and reversed their cognitive deficit by improving their spatial memory and learning performance to that of young wild-type mice. These findings support the concept that inflammasome inhibition could benefit AD and provide a rationale for prospective clinical testing of NRTIs or K-9 in AD.

The authors declare the following competing interests: J.A. is a co-founder of DiceRx, iVeena Holdings, iVeena Delivery Systems and Inflammasome Therapeutics, and, unrelated to this work, he has been a consultant for Abbvie/Allergan, Boehringer-Ingelheim, Janssen, Olix Pharmaceuticals, Retinal Solutions, and Saksin LifeSciences. B.D.G. is a co-founder of DiceRx. Sutton has received research grants from Boehringer Ingelheim, Coherus BioSciences, EMD Serono, and Alexion Pharmaceuticals, all for projects unrelated to study. J.A., K.A., S.W., and B.D.G. are named as inventors on matter-related patent applications filed by the University of Virginia or the University of Kentucky.

. J.A. discloses support from the UVA Strategic Investment Fund and National Institutes of Health (NIH) grants (R01EY028027, R01EY029799, R01EY031039, R01AG082108), the DuPont Guerry, III, Professorship, and a gift from Mr. and Mrs. Eli W. Tullis. B.D.G. discloses support from NIH grants (R01EY028027, R01EY031039, R01AG082108, R01EY032512). S.S.S., J.M., and T.H.C. disclose support from NIH grant R01DA054992 and the South Carolina Center for Rural and Primary Healthcare for projects unrelated to this study.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The study was conducted in compliance with the Department of Veterans Affairs requirements and received Institutional Review Board (IRB) and Research and Development approval. All data within the Marketscan database are Health Insurance Portability and Accountability Act-compliant and thus were deemed exempt from IRB approval by the University of Virginia IRB.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

All data produced in the present work are contained in the manuscript