Are Alzheimer’s Disease Drugs Failing Because They’re not Targeting the Viruses Now Found in AD Patients’ Brains?
Does the “brain fog” suffered by ME/CFS, Long Covid, HIV and chemotherapy patients share some mechanisms with Alzheimer’s Disease?
About 6.7 million people in just the United States are currently estimated to have Alzheimer’s disease (AD), a terrifyingly brain- and personality-destroying condition that’s estimated to affect many more people as the US population ages. By 2060, it’s estimated that 13.8 million people in the US will have AD, according to the Alzheimer’s Association. AD cannot be diagnosed definitively until after death.
Likewise, without definitive tests, it’s not known with any precision how many Americans suffer from ME/CFS or Long Covid. Since the numbers of HIV-positive individuals in the US—always qualified with the statement that a majority are unaware of their status—have stayed the same for almost 40 years, that estimate too is just a guess. However, all of these patients have two things in common: “brain fog” and viral infection. Since many cancers are at least associated with—if not definitely caused by—viruses, it’s possible that at least some cancer patients’ “chemo brain” may share causality with the other four conditions.
In a March 2022 article in The Washington Post, reporter Ariana Eunjung Cha spoke to a number of researchers studying how organic brain disease might contribute to the “fog” these patients experience. (1)
Do they share cognitive dysfunction, brain abnormalities and viral infection with AD patients?
No one yet knows the answer to that question, but scientists have begun to investigate the possibility. ME/CFS and Long Covid patients are thought by some researchers to have too much oxygen in their brain cells; when brains from people who died from Covid-19 are examined, some show shrunken grey matter similar to that seen in AD and other scientists have found tau protein, a hallmark of AD, in their brains; other individual similarities among these illnesses are turned up frequently now, but no one knows exactly how to tie them together. (1)
Does organic brain dysfunction share a cause across all of these previously unrelated diseases?
According to the UK’s National Health Service, “Alzheimer's disease is thought to be caused by the abnormal build-up of proteins in and around brain cells. One of the proteins involved is called amyloid, deposits of which form plaques around brain cells. The other protein is called tau, deposits of which form tangles within brain cells.” The group thought that governs AD research changes so infrequently that this post by NHS was last updated July 5, 2021; it’s forecast on the website to be updated again July 5, 2024. (2)
This definition of AD is accepted by pretty much every neuroscientist and practicing neurologist around the world. Therefore, every potential treatment for AD has targeted those protein plaques and tangles. Tragically, most of the treatments have failed: One or two have slightly diminished the amount of tangles and plaques in patients’ brains seen at autopsy but had little or no effect on the patients’ cognition or memory during life.
For example, there is Biogen’s drug Aduhelm, the clinical trials of which were ended in 2019 because an independent committee found that the drug “probably would not slow the cognitive and functional impairment—the decline in memory, language and judgment—that comes with Alzheimer’s,” as CNN reported December 28, 2022. (3)
Perhaps because there had been no AD drug approved by the Food and Drug Administration since 2003, a behind-the-scenes deal was made between the FDA and Biogen to steer Aduhelm toward approval. It was discovered when two House Committees investigated it, according to CNN:
“The investigation found that the FDA and Biogen [in Cambridge, MA] engaged in at least 115 meetings, calls and substantive email discussions from July 2019 to July 2020, including 40 meetings to guide Aduhelm’s potential approval. There may have been even more meetings, but the committees say the FDA failed to follow its own documentation protocol. ... The agency then collaborated with Biogen to draft a document used to brief an independent advisory committee that met in November 2020. The trial results were mixed, with only one showing a small benefit to patients.” (3)
Aduhelm—originally projected to cost $56,000 a year—like other not-very-effective AD treatments, targets the beta-amalyoid plaques that are considered the hallmark of the disease.
The next drug up, which also attacks the beta-amyloid plaques, is Lecanemab, produced by Japanese drug maker Eisai in collaboration with Biogen. Despite the finding that it “resulted in moderately less decline on measures of cognition and function than placebo at 18 months” in the drug makers’ clinical trials, the FDA granted the companies an “accelerated approval” clinical trial on January 7, 2023. Lecanemab’s severe adverse effects include brain swelling and bleeding, which can be life-threatening and require numerous MRIs to diagnose and treat. In the accelerated approval process, Lecanemab must show “benefit” to actual AD patients, or FDA can begin a process to remove the drug from the market. (4)
Lecanemab, now trade named Leqembi, is estimated to cost patients $26,500 a year.
“Leqembi’s annual price tag of $26,500 is below the price set for Aduhelm—which was approved by the FDA in 2021 despite strong objections from its panel of outside advisers,” NBC News reported January 6, 2023—referring to that questionable approval process criticized by two House Committees. “That drug [Aduhelm] initially cost $56,000 per year before Biogen slashed the price in half, to $28,000 annually.” (5)
To sum up: The currently and soon-to-be approved AD drugs are not very helpful to the people who have the disease, and they cost more per year than many people who need them make in a year.
But are they even targeting the actual cause of AD?
More researchers than ever are asking this previously taboo question: Are the plaques and tangles the cause of AD, or are they a result of brain cell death?
And many are investigating an even more taboo query: Is a virus or viruses involved in causing AD?
The days of defining a viral infection by measuring the amount of active virus in blood or tissue appear to be ending. New and constantly evolving technology has contributed immensely to increasing our knowledge about how humans (and other animals) interact with viruses.
A group led by Margot Mayer-Proschel at the University of Rochester currently has a grant from the National Institutes of Health (NIH) to study the possible role that HHV-6A genes play in causing AD. (6)
Mayer-Proschel pointed out that “the role of infectious agents [in AD] has been debated for decades.” A recent large study, she noted, “revealed a specific and significant association of human herpesvirus 6A (HHV6A) with AD.” (6)
That study, however, didn’t resolve the question of which specific HHV-6A genes “might affect cells of the central nervous system (CNS) to exacerbate AD.”
According to Mayer-Proschel, HHV-6A is “mainly present in the brain in its latent form.” Therefore, her new research is going to pose the question of “whether the major latency-associated [HHV-6A] gene U94A affects host cells’ functions that are relevant to Alzheimer disease pathology.”
In their prior work, Mayer-Proschel and colleagues found that expression of that latency-associated gene does a lot of damage in the brain: It stops the growth of glial cells (which support the brain’s architecture as well as the neurons), and “leads to synapse loss in human neurons.” The synapses are the points at which neurons exchange information with other neurons; if the synapses are destroyed, the brain no longer works.
In this grant, Mayer-Proschel’s team suggested that the HHV-6A latency gene “represents a disease-modifying factor that renders neural cells vulnerable to Alzheimer disease associated risk factors, and exacerbates Alzheimer’s pathology in vitro and in vivo,” that is, in the lab as well as in people. (6)
They plan to study how this HHV-6A latency gene interacts with molecules known to exist in AD, like the Aβ protein (“amyloid-β”, pronounced amyloid-beta), in nerve cells from patients who had the familiar form of AD (which often strikes numerous individuals in a family at an early age) as well as in mouse models of familial AD.
“This work will provide insight into the potential role of infectious agents in Alzheimer’s pathology and will establish that HHV6A viral latency is not merely a benign state of viral infection, but an important disease modifying factor,” Mayer-Proschel’s grant description proposes. (6)
The University of Rochester team received two-year funding of $703,278, which will carry them through May 31, 2023; however, this is a five-year grant not planned to end until 2026, at which time they will once again be at the mercy of the NIH’s grant-giving program.
Mayer-Proschel’s grant has an accompanying “Public Health Relevance Statement,” which says:
“Narrative: The overall goal of this project is to determine whether the Human Herpesvirus 6A (HHV6A) latency gene U94A plays a role in Alzheimer’s disease. The study is motivated by recent multiscale network analyses of Alzheimer patients that revealed specific and significant association of Alzheimer disease (AD) with HHV6A. We use Alzheimer patient derived cells and a new mouse model to test the overall hypothesis that U94A, which is expressed during latent HHV6A infection, is a disease-modifying factor that impairs the normal function of neurons and glial cells, and may increase patient vulnerability to other AD causing factors thereby accelerating AD onset and pathology.” (6)
It's difficult to understand why this public health advisory was written, even in a grant, with no proposed remedy to the danger that it says HHV-6A causes. Should everyone be routinely tested for HHV-6A and -6B, as Dr. Bhupesh K. Prusty (Julius-Maximillians Universitat, Germany), an ME/CFS and HHV-6 researcher, has suggested?
In an article published in April 2020, Prusty et al. found evidence of reactivated HHV-6 infection—a virus is “reactivated” after it leaves latency—which is known to alter how cells work. They discovered that cells with reactivated HHV-6 infection appear to secrete “an activity” that not only “fractures” mitochondria (the cell’s energy producer) and stimulates a coordinated antiviral “program” in uninfected cells, but this never-before-described “program” can also be transferred from CFS patients’ blood cells to blood cells cultured from healthy people. (7)
“Our current data show that only a small fraction of cells needs to be latently infected with HHV-6 to trigger a secretory phenotype that is strongly protective against some of the RNA and DNA virus infection in neighboring and distant cells lacking HHV-6 DNA,” Prusty and colleagues conclude. (7)
In other words: Reactivated HHV-6 breaks apart mitochondria and causes not only the infected cell but also nearby uninfected cells to secrete molecules that protect against infection by viruses other than HHV-6A. And whatever is causing that “coordinated antiviral program” can be transferred from HHV-6A infected cells of ME/CFS patients to healthy cells in the lab; even a small number of latently infected cells can transmit this antiviral “program” to healthy cells. (7)
In a May 2022 paper in the prestigious science journal Nature, Prusty and colleagues identified an interaction between HHV-6A micro-RNA (miRNA)—which is just what it sounds like, very small RNA—and the miRNA in infected cells. Like all herpesviruses and as we’ve discussed, HHV-6A can exist within cells in a latent state. It’s long been suspected that there is a “trigger” that causes viruses to change from a latent state to a “lytic,” or destructive one—this is viral reactivation. Prusty and colleagues reported that they have discovered at least a portion of this mechanism and that it involves communication between viral miRNA and mitochondrial miRNA in the infected cells.
“Virus reactivation has been associated with cardiac dysfunction, graft rejection, as well as neuronal disorders including myalgic encephalomyelitis and chronic fatigue syndrome,” they reported. “Here, we identify miRNA-mediated inhibition of miRNA processing that HHV-6A exploits to disrupt mitochondrial architecture [as reported in 2020] … and facilitate viral reactivation from latency.” (8)
That is: Prusty and colleagues may have found the “trigger” that causes viruses to reactivate after living quietly inside cells in a latent state. While the 2020 research paper reported that HHV-6A infection “fractures” mitochondria, the 2022 Nature paper appears to describe the mechanism by which this is achieved. (8)
Perhaps if the “brain fog” that all of these patients suffer from was investigated as a whole—no matter whether the diagnosis is AD or ME/CFS—there might be an effective treatment sooner rather than later. The siloed approach of studying brain function disease by disease has not yet produced any real understanding of what has gone wrong, never mind an effective treatment to help patients currently living in a fog.
BIBLIOGRAPHY
1. Ariana Eunjung Cha; "How Covid 'Brain Fog' May Overlap With 'Chemo Brain' and Alzheimer's"; Washington Post, March 27, 2022. https://www.washingtonpost.com/health/2022/03/27/covid-brain-fog-chemo-brain-alzheimers-disease/
2. NHS: “Causes—Alzheimer’s disease.” Last reviewed July 5, 2021. https://www.nhs.uk/conditions/alzheimers-disease/causes/
3. Jen Christensen. “House investigation says FDA approval process of Alzheimer’s drug was ‘rife with irregularities’ ”; CNN, December 29, 2022. https://www.cnn.com/2022/12/29/health/biogen-aduhelm-alzheimers-drug-investigation/index.html
4. Jacqueline Howard and Brenda Goodman. “Alzheimer’s drug lecanemab receives accelerated approval amid safety concerns”; CNN, January 7, 2023. https://www.cnn.com/2023/01/06/health/lecanemab-fda-approval/index.html
5. Berkeley Lovelace Jr. “A new Alzheimer’s drug will cost $26,500 a year. Who will be able to get it?” January 9, 2023. https://www.nbcnews.com/health/health-news/new-alzheimers-drug-will-cost-26500-year-will-able-get-rcna64883
6. Mayer-Proschel, Margot et al. “Impact of the Human Herpesvirus 6A (HHV6A) latency gene U94A on Alzheimer disease pathology”; RePORTER project #5R01AG075978-02; https://reporter.nih.gov/search/TjuRQe__hUq1aM1Diby8Fw/project-details/10491975
7. Schreiner, P.; Harrer, T.; Scheibenbogen, C.; Lamer, S.; Schlosser, A.; Naviaux, R.K. and Prusty, B.K. “Human Herpesvirus-6 Reactivation, Mitochondrial Fragmentation, and the Coordination of Antiviral and Metabolic Phenotypes in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome”; ImmunoHorizons April 1, 2020; 4: 201-215. doi: https://doi.org/10.4049/ immunohorizons.2000006
8. Hennig, Thomas et al.; contact Bhupesh K. Prusty. “Selective Inhibition of miRNA Processing by a Herpesvirus-encoded miRNA”; Nature May 4, 2022. doi: https://doi.org/10.1038/s41586-022-04667-4
ABOUT THE AUTHOR
Neenyah Ostrom was the first reporter in the United States to report weekly for a decade on ME/CFS. Her reporting on the Chronic Fatigue Syndrome epidemic from 1988-1997 is getting increased attention thanks to Robert F. Kennedy Jr. He discusses her work extensively in his 2022 best seller, The Real Anthony Fauci. Ostrom’s groundbreaking reporting on Chronic Fatigue Syndrome and AIDS appeared in the New York Native from 1988 to 1997.
Ostrom is the author of four books about the Chronic Fatigue Syndrome epidemic: What Really Killed Gilda Radner? Frontline Reports On The Chronic Fatigue Syndrome Epidemic (1991; TNM Inc., New York, NY), 50 Things Everyone Should Know About The Chronic Fatigue Syndrome Epidemic And Its Link To AIDS (1992; TNM Inc. and St. Martin’s Press, New York, NY; published in Japanese by Shindan-to-Chiryo, 1993; and in French by Les Editions Logiques, 1994), and America’s Biggest Cover-Up: 50 More Things Everyone Should Know About The Chronic Fatigue Syndrome Epidemic And Its Link To AIDS (1993; TNM Inc., New York, NY); and America’s Biggest Cover-Up: 50 More Things Everyone Should Know About The Chronic Fatigue Syndrome Epidemic And Its Link To AIDS, Updated 2nd Edition (2022, available as a Kindle ebook and paperback on Amazon.com). Her most recent book, Ampligen: The Battle for a Promising ME/CFS Drug (2022) is available as a Kindle ebook and paperback on Amazon.com
In 1995, Ostrom and New York Native were recognized as having reported one of the top 25 most-censored stories in the U.S. press by 1995’s Censored: The News That Didn’t Make The News And Why (The 1995 Project Censored Yearbook by Sonoma State University Professor Carl Jensen, introduction by Michael Crichton; published by Four Walls Eight Windows, New York, NY, 1995).
Ostrom is ghostwriter/editor of seven popular science books. Additionally, she was an editor of Total Breast Health: The Power Food Solution For Health And Wellness by Robin Keuneke, which was chosen as a Publishers Weekly “Best Book of 1998” in the category of Breast Health (Kensington Publishing Corp., April 1998).