HIV Drugs Show Promise Against Alzheimer’s Disease

A class of medications commonly used to treat HIV and hepatitis B might offer an unexpected benefit: protection against Alzheimer’s disease.

In a study published May 8 in Alzheimer’s & Dementia, researchers from the University of Virginia Health System have uncovered compelling evidence that nucleoside reverse transcriptase inhibitors (NRTIs) significantly reduce the risk of developing Alzheimer’s disease. The study, which analyzed health records of more than 270,000 patients across two major U.S. health insurance databases spanning up to 24 years, found that each additional year of NRTI treatment was associated with a 6-13% reduction in Alzheimer’s risk. These findings could potentially transform prevention strategies for a disease that affects millions worldwide and has proven stubbornly resistant to effective treatments.

The discovery offers new hope in the challenging field of Alzheimer’s research, where many promising treatments have failed in late-stage clinical trials.

Beyond HIV Treatment: A New Purpose for Established Medications

NRTIs have been a cornerstone of HIV treatment for decades, working by preventing the virus from replicating inside the body. However, researchers have discovered these medications have another valuable property – they inhibit inflammasomes, protein complexes that play a crucial role in the body’s immune response.

Dr. Jayakrishna Ambati, founding director of UVA’s Center for Advanced Vision Science and lead researcher on the study, had previously identified this mechanism. His team suspected it might be relevant to Alzheimer’s disease, where inflammation has been increasingly recognized as a key factor in disease progression.

“It’s estimated that over 10 million people around the world develop Alzheimer’s disease annually,” said Ambati. “Our results suggest that taking these drugs could prevent approximately 1 million new cases of Alzheimer’s disease every year.”

Comprehensive Analysis Across Diverse Populations

The research team analyzed two major health insurance databases: the Veterans Health Administration database, which primarily includes older male veterans, and the MarketScan database, which represents commercially insured individuals across a broader demographic spectrum.

To ensure their findings were robust, the researchers implemented several methodological safeguards:

• Propensity score matching to minimize selection bias between NRTI users and non-users
• Adjustment for nearly 20 different medical conditions known to affect Alzheimer’s risk
• Time-dependent analysis to account for variations in medication exposure
• Competing risk models to address the possibility that mortality differences might skew results
• Separate analyses for patients with HIV and those with hepatitis B to ensure findings weren’t limited to a single condition

Even after these rigorous controls, the protective effect remained clear and consistent across both databases. In the Veterans Health Administration database, each year of NRTI treatment was associated with a 6% reduced risk of developing Alzheimer’s. The effect was even stronger in the MarketScan database, with a 13% risk reduction per year of treatment.

Inflammation: A Key Target in Alzheimer’s Disease

The study’s findings align with growing evidence that inflammation plays a significant role in Alzheimer’s disease development. The NLRP3 inflammasome – a protein complex involved in immune response – has been implicated in the brain’s reaction to amyloid-beta plaques and tau tangles, the hallmark physical features of Alzheimer’s disease.

When these abnormal protein accumulations occur, they can trigger the inflammasome to launch an inflammatory response that ultimately contributes to neurodegeneration and cognitive decline. This creates a destructive cycle where inflammation leads to more protein accumulation, which triggers more inflammation.

The research team’s discovery suggests that by inhibiting inflammasome activation, NRTIs may help break this cycle and protect against Alzheimer’s development.

Crucially, other types of HIV medications that don’t inhibit inflammasomes – including non-NRTIs, protease inhibitors, and integrase strand transfer inhibitors – did not show the same protective effect, strengthening the case that inflammasome inhibition is the key mechanism at work.

From Database Analysis to Clinical Trials

While the study’s findings are promising, the researchers emphasize that database analyses cannot definitively establish causation. Clinical trials will be necessary to confirm the protective effect and determine optimal treatment approaches.

However, there are reasons for optimism. Small clinical trials of NRTIs in Alzheimer’s disease are already underway, with a 24-week pilot study of the NRTI lamivudine recently reporting reductions in neurodegeneration and neuroinflammation biomarkers.

Moreover, the UVA team has developed a potentially superior option. “We have also developed a new inflammasome-blocking drug called K9, which is a safer and more effective version of NRTIs,” Ambati said. “This drug is already in clinical trials for other diseases, and we plan to also test K9 in Alzheimer’s disease.”

K9 maintains the inflammasome-inhibiting properties of NRTIs while addressing some of their limitations, such as potential mitochondrial toxicity and the risk of developing viral resistance with long-term use. Preliminary testing in animal models has shown promising results, with the compound reportedly reversing spatial memory and learning impairments.

Significant Implications for Public Health

The potential public health impact of these findings is substantial. With nearly 7 million Americans currently living with Alzheimer’s – a number projected to nearly double to 13 million by 2050 – effective prevention strategies could dramatically reduce the human and economic toll of the disease. The annual cost of Alzheimer’s care in the United States alone is expected to rise from $360 billion to almost $1 trillion by mid-century.

If clinical trials confirm the protective effect observed in this study, NRTIs or their derivatives like K9 could represent a significant advance in Alzheimer’s prevention, particularly for high-risk individuals. The fact that these medications are already FDA-approved for other conditions could potentially accelerate their implementation for Alzheimer’s prevention, though specific dosing regimens and safety profiles would need to be established for this new use.

As researchers continue to explore the connection between inflammasome inhibition and Alzheimer’s disease, this study adds substantial weight to the growing recognition that targeting inflammation may represent one of the most promising avenues for combating this devastating condition.