Reduction of human Alzheimer’s disease risk and reversal of mouse model cognitive deficit with nucleoside analog use

Abstract

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.

A pilot study to investigate the safety and feasibility of antiretroviral therapy for Alzheimer’s disease (ART-AD)

“…3TC is considered safe, is widely prescribed, and has few clinically-relevant pharmacological interactions due to its low metabolic clearance, minimal binding to plasma protein, and no detectable effects on liver function [25][26][27][28] . In addition to the positive effects of 3TC in laboratory models of Alzheimer's disease and related tauopathies, analysis of health insurance databases in the United States indicates that use of nucleoside reverse transcriptase inhibitors such as 3TC is associated with lower incidence of Alzheimer's disease 29 . Given this compelling preclinical data and the encouraging safety profile of 3TC, we conducted the first clinical trial of 3TC in older adults with predementia Alzheimer's disease.…”