Anti-HIV drugs may reduce risk of Alzheimer’s disease

Summary: Conventional HIV medications may reduce the incidence of Alzheimer’s disease (AD). Using anonymous prescription data from more than 225,000 people, the study found that HIV-positive patients taking reverse transcriptase (RT) inhibitors had significantly lower rates of AD compared with the general population.

The discovery builds on previous findings that genes associated with Alzheimer’s disease can be recombined using enzymes similar to those affected by HIV treatment. The results could pave the way for new therapeutic strategies using existing drugs to combat the growing Alzheimer’s disease crisis.

Key facts:

1. The study analyzed prescription data from 225,000 people and found that HIV-positive patients over 60 years of age taking RT inhibitors had fewer Alzheimer’s disease diagnoses compared to their non-HIV counterparts.
2. RT inhibitors, originally developed to treat HIV, can inhibit similar enzymes in the brain, suggesting a potential mechanism for their effects on Alzheimer’s disease.
3. The study was supported by prominent foundations and the NIH, highlighting its credibility and significant interest in using these findings in new treatments for AD.

Source: Sanford Burnham Prebys

Alzheimer’s disease (AD) currently affects nearly seven million people in the United States. With this number expected to rise to nearly 13 million by 2050, the lack of meaningful treatments represents a major unmet medical need. Scientists at Sanford Burnham Prebys have now identified a promising real-world link between common HIV medications and reduced incidence of AD.

The study, conducted by Jerold Chan, MD, was published in the journal Pharmaceuticals.

Chun’s new research builds on his lab’s landmark publication in Nature in 2018, which described how somatic gene recombination in neurons can produce thousands of new gene variants in Alzheimer’s brains. Importantly, this is the first time the Alzheimer’s disease-linked gene APP has been discovered to recombine using the same type of enzyme found in HIV.

An enzyme called reverse transcriptase (RT) copies RNA molecules and turns them into complementary duplicates of DNA, which can then be inserted back into the DNA, causing permanent sequence changes in the cell’s DNA blueprint.

HIV and many other viruses rely on RT to hijack host cells and develop chronic infection, so drugs that block RT enzyme activity have become a common part of treatment cocktails to control HIV.

The brain appears to have its own RTs that are different from those of viruses, and the research team wondered whether suppressing brain RT with anti-HIV drugs actually helps AD patients.

To assess the association between real-world exposure to RT inhibitors and AD in humans, the team analyzed anonymous medical records with prescription claims from more than 225,000 control and HIV-positive patients and found that exposure to RT inhibitors was associated with a statistically significant reduction in incidence. and prevalence of blood pressure.

“So we looked at HIV-positive people taking RT inhibitors and other combination antiretroviral drugs as they aged and asked the question: How many of them got Alzheimer’s disease?” says Chun.

“And the answer is that there were far fewer of them than would be expected compared to the general population.”

Of the more than 225,000 people whose claims data were included in the study, only 80,000 were HIV-positive people over the age of 60. More than 46,000 took RT inhibitors during a nearly three-year follow-up period from 2016 to 2019. The data was obtained through a collaboration with health information technology and clinical research firm IQVIA, led by Tiffany Chow, MD.

In people living with HIV, per 1,000 people, there were 2.46 Alzheimer’s disease diagnoses among HIV-positive people taking these inhibitors, compared with 6.15 for the general population.

This control group consisted of more than 150,000 HIV-negative patients over 60 years of age who had health insurance claims related to cold treatment.

“It is impossible to conduct a prospective clinical trial with this number of patients,” adds Chun. “This approach is a way to look at how a drug might work in a larger patient population.”

Chun emphasizes that the drugs the patients took in this retrospective study were designed to counteract RT activity in HIV and likely had only a limited effect on the many different possible forms of the enzyme active in the brain.

“What we’re looking at now is very crude,” Chun says. “The obvious next step for our laboratory is to determine which versions of RT act in the AD brain so that more targeted treatments can be found, while prospective clinical trials of currently available RT inhibitors in people with early AD should continue.” .

Jerold Chun, MD, PhD, is a professor at the Center for Genetic Disorders and Aging Research at Sanford Burnham Prebys.

Other study authors include Tiffany W. Chow, Mark Raupp, Matthew W. Reynolds, Siying Li and Gwendolyn E. Kaeser.

Financing: This work was supported by the National Institute on Aging–NIH (R01AG071465, R01AG065541, and R56AG073965), the Shaffer Family Foundation, and the Bruce Ford and Ann Smith Bundy Foundation.

About Alzheimer’s disease and neuropharmacological research news

Author: Greg Calhoun
Source: Sanford Burnham Prebys
Contact: Greg Calhoun – Sanford Burnham Prebys
Image: Image courtesy of Neuroscience News.

Original research: Open access.
“Nucleoside reverse transcriptase inhibitor exposure is associated with lower risk of Alzheimer’s disease: a retrospective proof-of-concept cohort study”, Jerold Chun et al. Pharmaceuticals

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Abstract

Nucleoside reverse transcriptase inhibitor exposure is associated with lower risk of Alzheimer’s disease: a retrospective proof-of-concept cohort study.

Somatic brain gene recombination (SGR) and the endogenous reverse transcriptases (RTs) that produce it have been implicated in the etiology of Alzheimer’s disease (AD), suggesting that RT inhibitors are novel preventative or therapeutic agents.

This retrospective proof-of-concept study assessed the incidence of AD in people with human immunodeficiency virus (HIV) with or without exposure to nucleoside RT inhibitors (NRTIs) using anonymized medical claims data.

Eligible participants were aged ≥60 years, without a pre-existing diagnosis of AD, and sought medical care in the United States from October 2015 to September 2016. Cohorts 1 (N = 46,218) and 2 (N = 32,923) were infected with HIV.

Cohort 1 had prescription claims for at least one NRTI during the exposure period; Cohort 2 did not do this. Cohort 3 (N = 150,819) sought medical care for a cold without evidence of HIV or antiretroviral therapy.

The cumulative incidence of new cases of asthma during the subsequent 2.75-year follow-up period was lowest in patients receiving NRTIs and highest in the control group.

Age- and sex-adjusted hazard ratios showed a significantly reduced risk of developing asthma in cohort 1 compared with cohort 2 (HR 0.88, P <0.05) and 3 (RR 0.84, P <0.05).

A subgroup found a reduced risk of asthma in patients taking NRTIs but not protease inhibitors (PIs).

Prospective clinical trials and development of next-generation agents targeting brain RT are warranted.