Virus World

The results could pave the way for new therapeutic strategies using existing drugs to combat the growing AD crisis. 

Summary: Common HIV drugs could reduce the incidence of Alzheimer’s disease (AD). Utilizing anonymized prescription data from over 225,000 individuals, the study found that HIV-positive patients taking reverse transcriptase (RT) inhibitors showed a significantly lower rate of AD compared to the general population. This discovery builds on previous findings that Alzheimer’s-linked genes might be recombined by enzymes similar to those targeted by HIV treatments. The results could pave the way for new therapeutic strategies using existing drugs to combat the growing AD crisis.

Key Facts:

1. The study analyzed prescription data from 225,000 individuals, revealing that HIV-positive patients over 60 taking RT inhibitors had fewer Alzheimer’s diagnoses compared to their non-HIV counterparts.
2. RT inhibitors, initially developed for HIV, might inhibit similar enzymes in the brain, suggesting a potential mechanism for their effect on Alzheimer’s disease.
3. The research was supported by notable foundations and the NIH, highlighting its credibility and the significant interest in translating these findings into new treatments for AD.

Alzheimer’s disease (AD) currently afflicts nearly seven million people in the U.S. With this number expected to grow to nearly 13 million by 2050, the lack of meaningful therapies represents a major unmet medical need. Scientists at Sanford Burnham Prebys have now identified promising real-world links between common HIV drugs and a reduced incidence of AD. The study, led by Jerold Chun, M.D., Ph.D., was published in Pharmaceuticals. Chun’s new research builds on his lab’s landmark publication in Nature in 2018 that described how somatic gene recombination in neurons can produce thousands of new gene variants within Alzheimer’s disease brains. Importantly, it also revealed for the first time how the Alzheimer’s-linked gene, APP, is recombined by using the same type of enzyme found in HIV.  The enzyme, called reverse transcriptase (RT), copies RNA molecules and changes them into complementary DNA duplicates that can then be inserted back into DNA, producing permanent sequence changes within the cell’s DNA blueprint. HIV and many other viruses rely on RT to hijack a host’s cells to establish a chronic infection, so drugs that block the RT enzyme’s activity have become a common part of treatment cocktails for keeping HIV at bay. The brain appears to have its own RTs that are different from those in viruses, and the research team wondered if inhibiting brain RTs with HIV drugs actually helps AD patients.

To assess the link between real-world RT inhibitor exposure and AD in humans, the team analyzed anonymized medical records with prescription claims from more than 225,000 control and HIV-positive patients, and found that RT inhibitor exposure was associated with a statistically significant reduced incidence and prevalence of AD. “Thus, we looked at HIV-positive individuals taking RT inhibitors and other combined antiretroviral therapies as they aged, and asked the question: How many of them got Alzheimer’s disease?” says Chun. “And the answer is that there were many fewer than might have been expected compared to the general population.” Of the more than 225,000 individuals with claims data in the study, just shy of 80,000 were HIV-positive individuals over the age of 60. More than 46,000 had taken RT inhibitors during a nearly three-year observation 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, M.D. In living persons with HIV, there were 2.46 Alzheimer’s disease diagnoses per 1,000 persons among HIV-positive individuals taking these inhibitors, versus 6.15 for the general population. This control group was represented by more than 150,000 HIV-negative patients over the age of 60 with medical insurance claims related to treatment for the common cold. “You cannot feasibly run a prospective clinical trial with this number of patients,” Chun adds. “This approach is a way to look at how a drug can act on a large patient population.”

Chun underscores that the drugs patients took in this retrospective study were designed to counter RT activity in HIV and likely only had a limited effect on many different possible forms of the enzyme active in the brain. “What we’re looking at now is very crude,” says Chun. “The clear next step for our lab is to identify which versions of RTs are at work in the AD brain so that more targeted treatments can be discovered, while prospective clinical trials of currently available RT inhibitors on persons with early AD should be pursued.”

Jerold Chun, M.D. Ph.D., is a professor in the Center for Genetic Disorders and Aging Research at Sanford Burnham Prebys.

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

Funding: The work was supported by the National Institute on Aging – NIH (R01AG071465, R01AG065541 and R56AG073965), the Shaffer Family Foundation and the Bruce Ford & Anne Smith Bundy Foundation.

Research published in Pharmaceuticals (March 22, 2024):

https://doi.org/10.3390/ph17040408 

Alzheimer’s disease is a complex neurodegenerative disorder leading to a decline in cognitive function and mental health. Recent research has positioned the gut microbiota as an important susceptibility factor in Alzheimer’s disease by showing specific alterations in the gut microbiome composition of Alzheimer’s patients and in rodent models. However, it is unknown whether gut microbiota alterations are causal in the manifestation of Alzheimer’s symptoms. To understand the involvement of Alzheimer’s patient gut microbiota in host physiology and behaviour, we transplanted faecal microbiota from Alzheimer’s patients and age-matched healthy controls into microbiota-depleted young adult rats. We found impairments in behaviours reliant on adult hippocampal neurogenesis, an essential process for certain memory functions and mood, resulting from Alzheimer’s patient transplants.

Notably, the severity of impairments correlated with clinical cognitive scores in donor patients. Discrete changes in the rat caecal and hippocampal metabolome were also evident. As hippocampal neurogenesis cannot be measured in living humans but is modulated by the circulatory systemic environment, we assessed the impact of the Alzheimer’s systemic environment on proxy neurogenesis readouts. Serum from Alzheimer’s patients decreased neurogenesis in human cells in vitro and were associated with cognitive scores and key microbial genera. Our findings reveal for the first time, that Alzheimer’s symptoms can be transferred to a healthy young organism via the gut microbiota, confirming a causal role of gut microbiota in Alzheimer’s disease, and highlight hippocampal neurogenesis as a converging central cellular process regulating systemic circulatory and gut-mediated factors in Alzheimer’s.

Piublished in Brain (Oct. 18, 2023):

https://doi.org/10.1093/brain/awad303

People who tested positive for the virus behind genital herpes tended to have reduced thickness of their outermost brain layer, which has been linked to Alzheimer's disease. Jose Gutierrez at Columbia University in New York and his colleagues analysed the MRI brain scans and blood test results of 455 adults, aged 70 on average, who took part in a long-term health-tracking study in Manhattan...

Study published Oct. 28, 2023:

https://doi.org/10.1016/j.jns.2023.120856  

Renin-angiotensin system, or RAS, is a physiological mechanism essential to human body function. The SARS-CoV-2 virus causes overactivation and malfunction of this system. Renin-angiotensin system, or RAS, is a physiological mechanism essential to human body function. The SARS-CoV-2 virus causes overactivation and malfunction of this system. The RAS regulates innate immunity, various microbiota, and the autonomic processes of the kidney, lungs, and heart. The RAS is found in every cell of every tissue and organ in the body, making it ubiquitous. The excess of the hormone angiotensin-2, which overactivates the "deleterious" RAS receptor AT1R, is directly accountable for the pathologies of Covid-19 caused by the malfunctioning. In fact, the AT1R receptor overactivated by abundant angiotensin-2 has a variety of harmful effects on the human body by inducing cellular signaling cascades. The AT1R receptor is pro-hypertensive as it induces blood vessel constriction, pro-inflammatory since it causes a toxic storm of pro-inflammatory cytokines, pro-oxidant because it increases the production of reactive oxygen particles that kill cells, pro-thrombotic because it promotes the formation of clots - or thrombi - that obstruct blood vessels, and pro-angiogenic as it promotes the growth of blood vessels and tumors, pro-hypoxemic because it reduces the load of red blood cells in oxygen and causes desaturation of blood in oxygen, pro-hypoxic because it causes a deficit of oxygen supply to various cells, tissues, and organs, pro-fibrotic because it induces organ fibrosis, pro-hypertrophying because it increases organ volume, and makes nitric oxide fall, affecting inflammatory, immune, and memory phenomena.

Alzheimer's disease is a form of dementia characterized by incapacitating neurological diseases that affect the patients' behavior, memory, thinking, and reasoning skills. Symptomatology usually develops gradually, but in the case of Covid-19 and long Covid it might occur unusually fast. Patients frequently experience memory loss (amnesia), spatial-temporal disorientation, mood and personality disturbances, reduced comprehension and/or inability to solve problems, impairments of written and/or verbal expression (aphasia), and difficulties managing daily tasks. Apraxia is the inability to perform motor movements despite the existence of these "intact" functions, as well as challenges with object recognition despite the existence of "intact" sensory functions (agnosia). Clinical doctors and pathologists have noted the onset of Alzheimer's disease in a variety of patients, including young adults, following a spontaneous infection with the SARS-CoV-2 virus or even following immunization against Covid-19.

A viral infection with SARS-CoV-2 or even an anti-Covid-19 vaccination causes a dysfunction of the RAS, via an excess of the hormone angiotensin-2 normally degraded by the receptor ECA2 (angiotensin-2 converting enzyme) on which the viral or vaccine Spike protein binds and the "deleterious" overactivation of the AT1R receptor of the RAS, at the origin of Covid-19 diseases. The overactivated AT1R receptor is pro-hypertensive, which means it provokes arterial hypertension. This impacts the brain function. Evidently, arterial hypertension has been identified as a significant risk factor for mild to severe neurodegenerative disorders such as dementia and Alzheimer's disease. RAS inhibitors, such as sartans and ACE inhibitors of angiotensin-1 converting enzyme, have been equally shown to improve neurodegenerative diseases and other cognitive dysfunctions. Thus, angiotensin-2, which is found in excess in Covid-19 due to RAS overactivation, promotes the accumulation and deposition of b-amyloid proteins (markers of Alzheimer's disease), impairing brain cell synaptic connections and cognitive functions. Furthermore, the vasoconstrictive effect of a dysfunctional RAS contributes to blood flow limitation in the brain, promoting neurovascular uncoupling, cerebral hypometabolism, and the development of neurological damage.

Publication Cited published in Infectious Disorders - Drug Targets:

https://www.eurekaselect.com/article/132146