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IT’S BEEN 16 years since the FDA last approved a new drug to treat the cognitive deficits of Alzheimer’s disease (AD). More than 400 clinical trials in the interim have failed to produce any new medications, notes Ohio State neurologist Rawan Tarawneh.
Most AD research has focused on the buildup of amyloid plaque in the brain, a primary marker of AD, because it interferes with transmission of messages between brain cells. And drugs now on the market treat AD symptoms but not the underlying causes, nor do they slow progress of the disease. Also the drugs work only for about half the people who take them and, in that group, for only six to 12 months.
In an alternative approach to both treatment and disease, some researchers have turned their attention to infection—to the “amyloid protection hypothesis,” which links beta-amyloid buildup to the brain’s immune response to chronic infections, such as Lyme disease and herpes simplex. For the latter, a recent study from Taiwan reported that long-term antibiotic treatment lowered AD risk, although only to the level of people with no history of herpes infection.
In 2017, a “first-of-its-kind symposium opened the way for a paradigm shift in studying the pathogenesis of AD… to a new ‘innate immune system dysregulation hypothesis,’ which may well permit and lead to the discovery of new treatments for for AD patients,” according to the symposium report.
People looking for ways to forestall or combat Alzheimer’s disease—along with the statistic that up to 80% of older Americans have dormant, if not active, herpes infection—ask why not take a daily “maintenance” dose of the antibiotic valacyclovir, prescribed for active herpes infections.
One concern is that valacyclovir works only when herpes infection is active, a rare occurrence for most who have the virus. A trial now underway at Columbia University is investigating the effects of valacyclovir versus placebo on 130 herpes-positive people with AD.
“The possibility that amyloid beta is part of the brain’s way of fighting infection “revolutionizes our way of thinking about amyloid,” notes Tarawneh. And while “there has been no single study with strong enough evidence to show cause and effect…new approaches to Alzheimer’s disease are vital.”
The Harvard laboratories of Robert Moir and Rudolph Tanzi observed the protective action of plaque formation in response to two common forms of the herpes virus. “Amyloid beta is not junk or functionless,” said Moir. “Instead it appears to be a key player in the brain’s own immune system, created to trap any kind of infection that enters the brain.”
“The overproduction of plaque that occurs in Alzheimer’s may be caused by a chronic infection, such as gum disease,” said Moir, or “a sign that the brain’s immune system has gone off the rails. Plaque buildup…if it continues to increase…will eventually lead to inflammation in the brain.”
Said Tanzi: “amyloid is the match… neuroinflammation is a forest fire…microbes are what’s lighting the match.” And according to a Dana Foundation report, “since innate immunity is a general reaction to foreign material, the theory suggests a mechanism by which other factors might raise AD risk, such as fine particulate air pollution.”
“It’s not known whether microbes are causative or a passenger of the AD process,” emphasizes National Institute on Aging neuroscientist Mack Mackiewicz. “Long-dormant viruses may be activated by a disease process already underway…rather than a factor initiating it.”
And while “data tying antiviral treatment to lower risk of dementia is compelling,” says recent Alzheimer forum leader Philip Pellett from Wayne State University, the herpes-AD connection “meets some but not all of the criteria for causation.”
For example, Pellett points out: ApoE4, the gene most strongly linked to Alzheimer’s disease, has “pleotropic [multiple] effects on the immune system and increases susceptibility to viral bacterial and parasitic infections.”
But because herpes infection in the brain appears more common in those with AD who have the ApoE4 variant, one theory is that ApoE4 increases the likelihood of the herpes virus entering the brain—which could be part of the reason people with ApoE4 are at increased risk for AD. Alternatively, herpes virus in the brain may influence the behavior of genes like ApoE4 linked to amyloid buildup.
The forum’s conclusion: “Herpesviruses do not cause AD. And yet, because they seed, and speed, amyloid plaque deposition and inflame the immune system, they likely press on the gas pedal to accelerate the disease process.”
On the other hand, amyloid plaque is very common in older people’s brains, but not everyone with amyloid will develop dementia. Likewise, herpes is very common, but AD is much less so.
Thus, “even if these viruses accelerate the amyloid pathology in the brain, the role of amyloid plaques in mediating AD itself is controversial,” notes NIH Alzheimer’s expert Avindra Nath.
Commenting on the Taiwan paper, Nath pointed out that “a wide variety of substances accelerate amyloid formation.” And in an email to mylittlebird, Nath wrote, “My guess is that any infection of any sort would cause inflammation and thus would bring out an underlying neurodegenerative disease in a vulnerable population. The idea of viruses and Alzheimer’s has been bouncing around long before I was born. But the data is very weak.”
As for the possibility of a Lyme-Alzheimer’s connection, some people who take a “maintenance” dose of doxycycline have noticed a diminution of symptoms. But a population study found, instead, that the 13 states with the highest incidence of Lyme disease reported the lowest number of deaths due to Alzheimer’s.
Until the roles of these variables are clearer, another hope for combating AD comes from flavenols, a large class of compounds found in most fruits and vegetables. Of 921 men and women with no dementia, average age 81 and average follow-up six years, 220 developed AD: those in the highest one-fifth on flavanol consumption had a 48% lower risk of AD than those in the lowest fifth.
While people consuming more flavonols tend to have higher levels of education and to participate in more cognitive and physical activities, the study, published in early 2020 controlled for these factors as well as for age, sex and the ApoE4 gene. While earlier research assessing five flanonols —tea, apples, broccoli, onions and tofu—found no association, it may be that a broader high-flavonol diet, for example, including leafy vegetables and berries, may offer better protection. Food is a better source than supplements, the researchers note.
—Mary Carpenter
Every Tuesday, well-being editor Mary Carpenter delivers health news you can use.
Your article reassures me that other avenues of inquiry into the root causes of AD are being followed by major research scientists, ones not concentrating on the formation of amyloid plaques but the infections that might cause inflammation in the brain. Thank you!