Alzheimer’s disease is the most frequent form of dementia, and it is both cruel and tragically common. The world’s slowest, most painful disappearing act affects 5.7 million Americans — and with the large boomer generation reaching age 65 and beyond, that number is projected to more than double in the next 30 years. Care for those with Alzheimer’s is both labor and time intensive, and the economic burden of the disease is predicted to reach a trillion dollars by mid-century, according to the Alzheimer’s Association.
All that money and suffering has attracted a lot of research into the disease. However, so far, the results have been beyond disappointing. A class of drugs called “acetylcholinesterase inhibitors” offer marginal functional improvements, but that’s been it. Things are starting to change, though.
The Prevailing Alzheimer’s Hypothesis
For the last two decades, the focus of most Alzheimer’s research has been on a disease model called “the amyloid hypothesis,” which begins with the “amyloid beta” precursor protein (APP). This protein performs important functions in the membrane of brain cells, and when it wears out, APP is chopped into fragments and then released outside the cell. From there, APP typically is further degraded and removed, except in Alzheimer’s, where these APP fragments tend to glob together into collections, called plaques. The plaques are thought to then trigger a cascade of dysfunction. This includes causing another protein called “tau” to clump together inside the cell, forming what are called neurofibrillary tangles.
Scientifically speaking, amyloid’s fingerprints are all over the Alzheimer’s crime scene. Unfortunately, numerous therapies designed to lower levels of APP fragments have been unsuccessful to the point where even the experts are getting discouraged. A 2018 editorial in The New England Journal of Medicine stated, “Although it may not be quite time to give up on Aß (APP fragments) immunotherapy for treating Alzheimer’s disease, it would be foolish to ignore the continued failures of the anti-amyloid approach … Whether a multifaceted strategy or something entirely unforeseen is the answer, the field is clearly in need of innovative ideas.”
So, members of the Establishment — the big movers in this research — are admitting that it might be time to test new Alzheimer’s theories.
Bats in Guam: A Possible Alzheimer’s Solution?
Dr. Paul Cox is a 65-year-old Harvard-trained ethnobotanist whose quirky intelligence and odd brand of sleuthy science has gotten him featured in big publications like The New Yorker, Time and Fortune.
Cox heads up his own Brain Chemistry Labs in Jackson Hole, Wyo., but his curiosity about neurodegenerative diseases like Alzheimer’s began in Guam, where the Chamorro people have long been noted to have high rates of Alzheimer’s, amyotrophic lateral sclerosis (ALS) and Parkinson’s.
Being an ethnobotanist, Cox focused on the plants the Chamorros were eating — in particular, the cycad seed, which locals grind into flour for tortillas. Cycad seeds contain a high level of beta-methylamino-L-alanine, or BMAA, a potent neurotoxin. So, the connection seemed close and obvious, until research showed that the amount of BMAA being ingested in tortillas was infinitesimally small.
That led Cox to a local Chamorro delicacy: boiled flying fox bat. These bats eat cycad leaves and store up high levels of BMAA in their tissues. And that discovery led to an indictment of cyanobacteria, which are rife with BMAA and other toxins and comingle with the odd root structures of the cycad tree. Cyanobacteria are found almost everywhere in the world.
Cox concluded that BMAA is a toxic Trojan horse, rolled into nerve cells where it then pathologically replaces the amino acid “L-serine” in various nerve cell proteins. This led Cox to knit together an international team of researchers to investigate how the ubiquitous cyanobacteria might cause BMAA to leach into our food systems, and to possibly prove that BMAA is the biochemical smoking gun behind the amyloid hypothesis.
Clinical trials to investigate the therapeutic benefit of using L-serine to outcompete BMAA are underway, and Cox strikes a hopeful tone.
“We think that chronic exposure to BMAA is a risk factor for ALS and Alzheimer’s,” he said in an article in Fortune. “It’s not deterministic. It’s like tobacco and lung cancer: If you smoke, you might not get it, and if you don’t smoke, you still might get it … If the research pans out, we could possibly provide L-serine to all people who are deemed at risk of developing the disease in the future.”
Developing an Alzheimer’s Vaccine
Meanwhile, a mother-daughter (Chang Yi Wang and Mei Mei Hu) biotech company in Dublin, called United Neuroscience, is working on developing vaccines for Alzheimer’s and other neurodegenerative diseases. The company says it envisions a world where “neurodegenerative diseases are prophylactically eradicated” and has pinned its hopes on what it calls “endobody vaccines.”
For obvious reasons, the human immune system is calibrated to attack foreign invaders (the flu virus you were vaccinated against, a sliver in your finger or unfortunately, even a transplanted kidney) and to not attack normal human tissue. United Neuroscience claims that its endobody vaccines are capable of convincing the human immune system to find clumps of amyloid-beta and remove them.
United Neuroscience has completed early clinical trials on its Alzheimer’s endobody vaccine and is raising capital for a larger study. It’s also developing a vaccine focused on removing tau proteins, and another for Parkinson’s disease.
Could it Be Bacteria that Live in our Mouths?
There’s also some scientific evidence to suggest that the unrecognized injury triggering Alzheimer’s disease could be coming from our mouths. Unhealthy bacteria can cause tooth damage and inflammation of the gums (gingivitis), but can they get to our brains?
“Porphyromonas gingivalis,” one of the major bacterial purveyors of gum disease, produces several protein-degrading enzymes called “gingipains.” Recently, researchers found gingipains in more than 90 percent of the 54 Alzheimer brain samples they examined, and when another group of scientists infected mice with P. gingivalis, subsequent autopsies found Alzheimer’s changes, as well as evidence that P. gingivalis had directly infected the brain. (The researchers and scientists are international — from the U.S., Poland, Norway, Australia, New Zealand and the United Kingdom.)
It might all sound like a zombie-apocalypse subplot, but these findings have spurred development of gingipain blockers, as well as a vaccine against P.gingivalis.
What About Bacteria in our Colons?
Researchers also are asking whether there is a colon-brain Alzheimer’s connection. In a 2016 study from the University of California, Davis, researchers found two biochemical byproducts of E.coli, a normal bacterial resident of the colon, in brain samples of those with and without Alzheimer’s. But levels were significantly higher in the Alzheimer’s patients, and one of the byproducts, “lipopolysaccharides,” seemed to concentrate around amyloid plaques.
So Far, Answers Lead to More Questions
After more than two decades of research and the failure of over 100 clinical trials of single drugs aimed at amyloid beta, it might be a good time to question our most basic assumptions about Alzheimer’s.
Maybe amyloid plaques are just the collateral damage from some yet unrecognized war. After all, association is not causation, and umbrellas don’t make it rain. Or maybe it’s amyloid beta’s sidekick, the abnormal tau proteins, that are the real pathological trigger. There’s increasing evidence to suggest that’s true.
Wherever the answers lie, millions of people are hoping we get there soon.
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