If you your gums bled when you brushed your teeth this morning, you might want to get that attended to. Scientists believe they may have finally found the long-elusive cause of Alzheimer’s disease: Porphyromonas gingivalis, the key bacteria in chronic gum disease.
That’s bad, as gum disease affects around a third of all people. But the good news is that a drug that blocks the main toxins of P. gingivalis is entering major clinical trials this year, and recently published research shows it might stop and even reverse Alzheimer’s. There could even be a vaccine.
The bacteria Porphyromonas gingivalis, known as Pg, lead to the gum infection chronic periodontitis, causing chronic inflammation and potential tooth loss.
This same bacteria were also found in 51 out of 53 brain autopsies of Alzheimer’s disease patients, according to new research by Dr. Stephen Dominy and Casey Lynch, founders of the pharmaceutical firm Cortexyme. The pharmaceutical company, which is focused on developing therapeutics to alter the course of Alzheimer’s disease, funded the research.
Following on from their findings, the team also tested blocking the bacteria in mice by injecting small molecules targeting Pg, to inhibit it, and found that it could reduce neurodegeneration in the brain, showing a potential new way to tackle Alzheimer’s disease.
Alzheimer’s is one of the most baffling mysteries in medicine. As populations have aged, dementia has skyrocketed to become the fifth most prolific cause of death worldwide. Alzheimer’s constitutes some 70 per cent of these cases and yet, we don’t know what causes it.
Bacteria in the brain
The disease often involves the accumulation of proteins called amyloid and tau in the brain, and the leading hypothesis has been that the disease arises from defective control of these two proteins.
But research in recent years has revealed that people can have amyloid plaques without having dementia. So many efforts to treat Alzheimer’s by moderating these proteins have failed that the hypothesis has been seriously questioned.
Evidence has been growing that the function of amyloid proteins may be a defense against bacteria, leading to a spate of recent studies looking at bacteria in Alzheimer’s, particularly those that cause gum disease, which is known to be a major risk factor for the condition.
Bacteria involved in gum disease and other illnesses have been found after death in the brains of people who had Alzheimer’s, but until now, it hasn’t been clear whether these bacteria caused the disease or simply got in via brain damage caused by the condition.
Gum disease link
Multiple research teams have been investigating P. gingivalis, and have so far found that it invades and inflames brain regions affected by Alzheimer’s; that gum infections can worsen symptoms in mice genetically engineered to have Alzheimer’s; and that it can cause Alzheimer’s-like brain inflammation, neural damage, and amyloid plaques in healthy mice.
In the newest study, Cortexyme have now reported finding the toxic enzymes – called gingipains – that P. gingivalis uses to feed on human tissue in 96 per cent of the 54 Alzheimer’s brain samples they looked at, and found the bacteria themselves in all three Alzheimer’s brains.
The bacteria and its enzymes were found at higher levels in those who had experienced worse cognitive decline, and had more amyloid and tau accumulations. The team also found the bacteria in the spinal fluid of living people with Alzheimer’s, suggesting that this technique may provide a long-sought after method of diagnosing the disease.
When the team gave P. gingivalis gum disease to mice, it led to brain infection, amyloid production, tangles of tau protein, and neural damage in the regions and nerves normally affected by Alzheimer’s.
Cortexyme had previously developed molecules that block gingipains. Giving some of these to mice reduced their infections, halted amyloid production, lowered brain inflammation and even rescued damaged neurons.
The team found that an antibiotic that killed P. gingivalis did this too, but less effectively, and the bacteria rapidly developed resistance. They did not resist the gingipain blockers.
New treatment hope
Some brain samples from people without Alzheimer’s also had P. gingivalis and protein accumulations, but at lower levels. We already know that amyloid and tau can accumulate in the brain for 10 to 20 years before Alzheimer’s symptoms begin. This, say the researchers, shows P. gingivalis could be a cause of Alzheimer’s, but it is not a result.
Gum disease is far more common than Alzheimer’s. But Alzheimer’s strikes people who accumulate gingipains and damage in the brain fast enough to develop symptoms during their lifetimes.
Cortexyme reported in October that the best of their gingipain blockers had passed initial safety tests in people, and entered the brain. It also seemed to improve participants with Alzheimer’s. Later this year the firm will launch a larger trial of the drug, looking for P. gingivalis in spinal fluid, and cognitive improvements, before and after.
They also plan to test it against gum disease itself. Efforts to fight that have led a team in Melbourne to develop a vaccine for P. gingivalis that started tests in 2018. A vaccine for gum disease would be welcome – but if it also stops Alzheimer’s the impact could be enormous.
Alzheimer’s disease is the most common form of dementia, which is characterized by memory loss that worsens over time. The condition is believed to be caused by a buildup of beta amyloid plaques and neurofibrillary tangles called tau in the brain. So far, there is no cure for the disease.
In 2014, it was estimated that as many as 5 million Americans live with Alzheimer’s diseases, according to the US Centers for Disease Control and Prevention. In the UK, 850,000 people live with dementia, according to the Alzheimer’s Society.
Previous research observed that Alzheimer’s disease patients with the oral infection showed cognitive decline over a six-month period when compared with another group of Alzheimer’s disease patients without the infection.
The new study found that toxic enzymes from the bacteria Pg, called gingipains, were also found in the brains of Alzheimer’s disease patients and that their levels correlated with levels of tau.
When the research team orally infected mice with Pg, an increase of amyloid beta — the plaque associated with Alzheimer’s disease — was seen in the brain.
But the study notes that the bacteria also exist in low levels in 25% of healthy people who did not have any oral disease.
Now, for the first time, we have solid evidence connecting Pg and Alzheimer’s pathogenesis while demonstrating the potential for a class of small molecule therapies to change the trajectory of the disease.
Trying to stop Pg buildup, the team designed small molecule inhibitors targeting the toxic enzyme gingipains. With a series of experiments, the researchers showed that one compound, COR388, was able to reduce the bacterial load of a Pg brain infection in mice. This means neurons in the hippocampus, the brain’s part responsible for memory, were protected in the mice.
The experiment in mice showed “small increases in the levels of one of the Alzheimer’s associated proteins with Pg infection that were prevented with the experimental drug,” commented Tara Spires-Jones, deputy director of the Centre for Discovery Brain Sciences at the University of Edinburgh.
It’s great news that a recent trial by this company showed this drug is safe in people and this study provides some evidence that it may affect Alzheimer’s related proteins. Larger clinical trials are needed to see if it will be beneficial to people living with Alzheimer’s disease.
Finding new strategies
Tiago Outeiro, professor of neurodegeneration at Newcastle University, mentioned that studies like this, which identify microbes associated with disease, are “extremely attractive, as this might lead to the identification of strategies, such as antibiotics, which may specifically affect those microbes which associate with disease.”
Outeiro, who was not involved in the research, also warned that in this case, the question remains whether the bacteria are specific to Alzheimer’s disease or a signal of general changes taking place during neurodegeneration.
Alzheimer’s disease patients also have disruption of their blood-brain barriers, making them more susceptible to getting infections in their brains, so while these data are interesting, it is possible that the infection is a by-product instead of a cause of disease.
Cortexyme has completed a stage one trial testing the safety of the COR388 compound in humans. Nine adults with Alzheimer’s were given a range of doses of the compound for 28 days. It was well-tolerated, and the nine patients with Alzheimer’s disease showed improved results, compared with another group who did not receive the treatment, when completing several cognitive tests.
In 2019, Cortexyme said, it plans to conduct more trials of COR388 in over 500 people with mild to moderate Alzheimer’s disease.