Antiretroviral Drug Use Associated with Lower Risk of Alzheimer's Disease
Transposable elements in the genome are the remnants of ancient viral infections, capable of hijacking cellular machinery to copy themselves haphazardly across the genome, causing damage to existing genes. They can further provoke inflammation and cell dysfunction via the presence of the viral machinery that these transposable element sequences code for; innate immune mechanisms in cells have evolved to detect such apparently foreign molecules. Transposable elements are effectively suppressed in youth, but with age this suppression breaks down. It has been suggested that activation of transposable elements is an important contributing factor in age-related conditions, particularly in neurodegenerative conditions such as Alzheimer's disease.
As today's open access paper notes, one way to obtain evidence for this proposition is to look at the long term outcome of antiretroviral drug use. These drugs are used to treat patients and animals infected with retroviruses, most prominently HIV, but also a number of others. In additional to suppressing infectious retroviruses, antiretroviral drugs also suppress the activity of transposable elements. After thirty years of a strong focus on treating AIDS, there is now a sizable patient population in later life, at the point at which transposable elements would be expected to become active.
Alzheimer's disease (AD) is the most common form of dementia, affecting an estimated 6.5 million Americans including more than 10% of Americans over 65 years of age. There are no therapies that demonstrably stop the disease despite hundreds of clinical trials. The recent identification of reverse transcriptase (RT)-mediated somatic gene recombination (SGR) in the human brain, which becomes dysregulated in sporadic AD, implicates FDA-approved reverse transcriptase inhibitors (RTIs) as potential therapeutics for AD.
Multiple FDA-approved RTIs, the first of which was approved in 1987, are currently used to treat human immunodeficiency virus (HIV) and hepatitis B. RTIs can be orthosteric (bind to the active site) nucleoside RTIs (NRTIs) or allosteric non-NRTIs (NNRTIs), and together with integrase inhibitors and protease inhibitors (PIs), represent the components of combined antiretroviral therapy (cART). Because of effective cART, tens of thousands of people with HIV have lived to older ages but are now at risk for AD, providing an opportunity to retrospectively examine the incidence of AD by assessing medical claims databases.
This retrospective, proof-of-concept study evaluated the incidence of AD in people with HIV with or without exposure to NRTIs using de-identified medical claims data. Eligible participants were aged ≥60 years, without pre-existing AD diagnoses, and pursued medical services in the United States from October 2015 to September 2016. Cohorts 1 (N = 46,218) and 2 (N = 32,923) had HIV. Cohort 1 had prescription claims for at least one NRTI within the exposure period; Cohort 2 did not. Cohort 3 (N = 150,819) had medical claims for the common cold without evidence of HIV or antiretroviral therapy.
We identified a statistically significant positive association between NRTI exposure and decreased risk for sporadic AD in patients with HIV and ≥60 years of age. Age-adjusted and sex-adjusted hazard ratio (HR) showed a significantly decreased risk for AD in Cohort 1 compared with Cohorts 2 (HR 0.88) and 3 (HR 0.84). Post-marketing surveillance of NRTIs has shown acceptable safety data sufficient to allow NRTIs to be prescribed, as a class, continuously since 1987, and tens of thousands of patients ≥60 years of age are currently taking these medications, providing support that these agents will be well tolerated in aged patients. The data presented here support controlled clinical trials using NRTIs on patients with mild cognitive impairment (MCI), pre-symptomatic familial AD, Down syndrome, and sporadic AD, along with asymptomatic APOE4 carriers.