Nucleoside Transcriptase Inhibitor Use Protective Against Alzheimer Disease

Use of nucleoside reverse transcriptase inhibitors (NRTIs) is associated with a significantly lower risk of developing Alzheimer disease (AD), according to findings published in Alzheimer’s & Dementia.

While antiretroviral therapies are typically used to treat HIV and hepatitis B virus (HBV) infections, emerging data suggest that certain classes, particularly NRTIs, may exert protective effects against neurodegenerative diseases through their anti-inflammatory properties.

Researchers conducted a retrospective cohort analysis to assess whether NRTI use is associated with reduced AD incidence. The study included 271,198 adults aged 50 years and older with HIV or HBV infection and no prior AD diagnosis, drawn from the Veterans Health Administration (VA) database (n=72,193) from 2000 to 2024 and the MarketScan commercial claims database (n=199,005) from 2006 to 2020. Baseline characteristics differed between datasets, with the VA cohort being older, predominantly men, and having higher comorbidity burden, while the MarketScan cohort was more demographically balanced.

Patients were assessed until AD diagnosis, death, or end of enrollment, with cumulative NRTI exposure measured over time. Propensity score matching and multivariate Cox regression were used for statistical analysis.

In the VA cohort, each additional year of NRTI exposure was associated with a 6% reduction in AD risk among matched patients (adjusted hazard ratio [aHR], 0.94; 95% CI, 0.89-0.999). In the MarketScan cohort, the reduction was more pronounced, at 13% per year of exposure (aHR, 0.87; 95% CI, 0.779-0.972).

After adjusting for mortality in the VA cohort, NRTI exposure was associated with a 37% reduced hazard of AD (aHR, 0.63; 95% CI, 0.46-0.85). Post hoc analyses confirmed similar protective effects in patients with either HIV or HBV alone. No reduction in AD risk was observed with other antiretroviral classes such as non-NRTIs, protease inhibitors, or integrase inhibitors, reinforcing the unique association between NRTIs and inflammasome inhibition.

Study limitations include a retrospective design, reliance on administrative data for AD diagnosis, and lack of genetic or cognitive assessment data.

“The repurposing of existing, approved therapies could accelerate drug development. Prospective randomized controlled trials in humans are warranted to gain better insight into the effects of NRTIs or suitable derivatives on clinical outcomes in AD,” the study authors concluded.

Disclosures: This research was supported by the National Institutes of Health and the Department of Veterans Affairs. Multiple study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.