HIV medications known as nucleoside reverse transcriptase inhibitors (NRTIs) may significantly reduce the risk of Alzheimer’s disease (AD), according to new research led by scientists at UVA Health. Analyzing millions of health records, the researchers found that patients who took NRTIs had markedly lower rates of AD compared to those who didn’t take the drugs.
“It’s estimated that over 10 million people around the world develop Alzheimer’s disease annually,” said Jayakrishna Ambati, MD, senior author of the study and founding director of UVA’s Center for Advanced Vision Science. “Our results suggest that taking these drugs could prevent approximately one million new cases of Alzheimer’s disease every year.”
The findings, published in Science Translational Medicine, used information from two major U.S. health insurance databases: the Veterans Health Administration Database and the MarketScan database. In total, the researchers examined more than 24 years of data from the VA and 14 years of data from MarketScan of more than 270,000 patients aged 50 and older who had taken NRTIs for either HIV or hepatitis B and had no prior Alzheimer’s diagnosis.
The study showed a consistent, time-dependent reduction in AD risk, showing that for each year of NRTI use, the risk decreased by 6% in one cohort and by 13% in the other. The researchers report that this association remained “significant and substantial” even after adjusting for a range of demographic and clinical variables, including pre-existing health conditions.
Alzheimer’s disease is driven in part by inflammatory responses to amyloid-beta and tau accumulation in the brain. These responses are mediated by the NLRP3 inflammasome, which promotes further protein aggregation and neuronal damage in a feedback loop. The new findings build on previous work by the UVA team and others that suggested inflammasome inhibition could be protective in other inflammatory diseases, specifically age-related macular degeneration, a disease that shares many inflammatory mechanisms with AD.
The researchers pointed out that other classes of anti-HIV drugs such as non-NRTIs, protease inhibitors, and integrase strand transfer inhibitors, did not show similar effects on Alzheimer’s risk, which supports the conclusion that inflammasome inhibition is likely the key factor in reducing AD risk, rather than other treatment pathways addressed by other Alzheimer’s drugs.
Earlier work by other groups, including a study by Chow et al., also found reduced Alzheimer’s risk among NRTI users, though the UVA-led team reports having employed a more rigorous methodology. Mechanistically, while some have proposed that NRTIs’ reverse transcriptase inhibition might reduce somatic gene recombination in neurons, the UVA group emphasizes the role of inflammasome inhibition as the principal driver of protection.
The researchers do not limit the potential benefit of NRTIs to individuals already at high genetic risk. Instead, they suggest that these drugs, or safer derivatives, could eventually be used more broadly for Alzheimer’s prevention. While this represents a treatment that could broadly help prevent AD in populations, the researchers noted that identifying high-risk individuals would be important for the design of future prevention trials.
To address toxicity concerns associated with long-term NRTI use, the investigators used a derivative compound called K-9. This drug, already in clinical trials for diabetic macular edema (DME) and thyroid eye disease (TED), lacks reverse transcriptase inhibition and avoids potential adverse effects such as mitochondrial toxicity and lactic acidosis.
The study’s strength lies in its large and demographically distinct populations. “The consistent effects we observed across these two disparate populations suggest that socioeconomic status, while potentially influential, is unlikely to be a dominant confounder in the observed association,” the researchers wrote.
The researchers also said there are some limitations of the study, including the fact that data came from administrative claims and lacked clinical measures of cognitive decline. They also noted that Alzheimer’s diagnoses were identified via medical coding rather than clinical assessments.
Future research in this promising area will include clinical trials to evaluate K-9 and other NRTI derivatives in Alzheimer’s prevention and treatment. While early results suggest these drugs may reduce neuroinflammation biomarkers, longer studies in larger cohorts are needed.
