Nine years ago, Nikki Schultek, an active and healthy woman in her early 30s, experienced a sudden cascade of debilitating and agonising symptoms – including cognitive and breathing problems and heart arrhythmia – and was investigated for multiple sclerosis. But three brain scans and numerous X-rays later, there was still no diagnosis or treatment plan. “It was like living in a nightmare, imagining not watching my children – three and five years old – grow up,” says Schultek.
Now, speaking on a video call from North Carolina, she is as bright as a button and shows no signs of degenerative brain disease. It turned out she had multiple chronic infections, including Borrelia burgdorferi bacteria, which causes Lyme disease and which had stealthily reached her brain. Antibiotics restored her health, but B burgdorferi is hard to eradicate once in the brain. She may need maintenance treatment to keep the disease at bay.
Schultek is not the only person whose neurological disorder turned out to be caused by microbes in the brain. A recent paper she jointly lead-authored, published in Alzheimer’s and Dementia, compiled a long list of case reports where infectious disease was discovered to be the primary cause of dementia, meaning that, in many cases, the dementia was reversible. A few of the patients died, but most survived and saw significant improvements in cognitive function, including a man in his 70s who had been diagnosed with Alzheimer’s disease after his swift cognitive decline saw him unable to drive or, eventually, leave the house alone. A sample of his cerebrospinal fluid was taken and revealed a fungal infection caused by Cryptococcus neoformans. Within two years of taking antifungal medication, he was driving again and back at work as a gardener.
Richard Lathe, a professor of infectious medicine at the University of Edinburgh and another lead author of the paper, says these patients “were by accident found to be suffering from various fungal, bacterial or viral infections, and when they treated the patient with antifungals, antivirals or antibiotics, the dementia went away”. He, among others, has been investigating the possibility that, like the gut, the brain hosts a community of microbes – an area of largely scientifically uncharted waters, but with huge life-saving potential.
A common infection among the dementia cases was what the gardener had: C neoformans, a fungus often found in plants and animals, the spores of which are easily inhaled. The dominant bacterial infection was Borrelia. Only a few viruses were reported, among them herpes simplex and herpes zoster (which causes shingles).
Lathe is part of an international group of scientists collaborating on the Alzheimer’s Pathobiome Initiative, which is led by Schultek, as executive director and founder. (“Pathobiome” refers to the pathogenic – disease-causing – microbes and the host’s susceptibility to them.) She has brought together scientists from different fields – including microbiologists, immunologists, gerontologists and neurologists – to better understand the role of microbes in the brain, to devise ways to diagnose and treat brain infections that might ordinarily fly under the medical radar, and to identify useful preventive measures, from vaccines to lifestyle factors. First and foremost, though, says Lathe, is establishing what percentage of dementias are caused by infections that could be treated: “We know there are some. We know it’s unlikely to be 100%, but our guess is that probably half or more could potentially be treated.”
It used to be widely assumed that the brain was the last bastion of sterility in the human body – it has a blood-brain barrier, for one, which microbes were thought to be too big to pass through – but it turns out that microbes flourish in the brain. The brain microbiome is hard to study, though, because we can’t just take a sample as we would for the gut, or swab it like a vagina or a nose.
That said, the notion that microbial infection has a role in dementia goes back to Alois Alzheimer who, in 1906, discovered the disease that now bears his name, and Oskar Fischer, who also identified it a year later. Both had suspected that microbes were involved, “but weren’t able to follow this up”, says Lathe. There is a now a raft of research supporting those early hunches. In Denmark, Janet Janbek “has shown that people with multiple infections are at risk of Alzheimer’s disease, and conversely that people with Alzheimer’s have an increased risk of infections of all kinds”, says Lathe. Other researchers, such as Luis Carrasco in Madrid, have been discovering infections in the brain and nervous system.
When Lathe started looking for evidence of microbial life in samples from brains left to medical science, a clearer picture emerged. His paper, The Remarkable Complexity of the Brain Microbiome in Health and Disease, looked at brains of people who didn’t have dementia and compared them with Alzheimer’s brains. It found that, while there was a remarkable diversity of species in the control brains, there were often overgrowths of certain bugs in Alzheimer’s brains. In the control brains, microbes differed between brain regions and individuals, hosting mainly fungi, bacteria and chloroplastida (algae-related species). The virus adenovirus type C – a common culprit for respiratory infections – was often present, but there weren’t many viruses represented.
In many – but not all – of the Alzheimer’s brains, says Lathe: “We saw an overabundance of several microbes – the major ones are species such as Streptococcus and Staphylococcus in the bacteria, and in the yeasts it’s things like Candida and Cryptococcus, which are all well known to cause diverse pathologies in humans.” There was also a mysterious algae-related species, but it hasn’t been studied much in relation to human health. “It could be very important, but we don’t know anything about it.”
This paper was completed in 2023 and submitted to a journal, says Lathe, that wanted independent confirmation of the results before publishing, “which is fair enough”. Three research centres in the US have been continuing this line of inquiry. David Corry, a specialist in asthma at Baylor College of Medicine, Texas, has been taking brain samples and plating them directly on agar, says Lathe. “He’s seen some very interesting microbes coming up. This is just looking at what grows.” Next up is Brian Balin at Philadelphia College of Osteopathic Medicine, who “has been arguing that not all the microbes you see in human pathologies will grow in agar”, says Lathe. They need very specialised “media” to grow in – or, even better, human cells. “So he’s been plating the same brain samples on to human monocytes [a type of white blood cell] in tissue culture, and he sees additional organisms coming up that weren’t previously reported.” Finally, Garth Ehrlich at Drexel University College of Medicine, also in Philadelphia, is using a sophisticated gene amplification method to confirm the identities of microbes in the brain; he is finding similar clustering of microbes in samples from Alzheimer’s patients.
In the gut, we know that there are good microbes and bad microbes, with a healthy and diverse biome working to keep potential pathogens at bay. “Is the same true in the brain?” asks Lathe. “We don’t know – we’ll only find out when we do the analysis in more detail.” (Based on what we know so far, there won’t be the same diversity as in the gut.) But there are still doubters and the notion remains controversial. While it is hard to get any sceptics to go on the record, says Lathe, “if you submit your grant to various places, you get anonymous comments: ‘I don’t believe it.’ ‘This is impossible.’ To this day, it’s very, very hard to get funding because of the … we call them dinosaurs.”
While microbes are found in brains of all ages, more pathogens get through at ages when immunity is weaker, such as babies under one and older adults, as the body’s defences weaken and infections and inflammation seep around it more easily. So, is there anything we can do to keep our brain microbiomes healthy?
The BCG vaccine was originally used against tuberculosis, but it is also often part of a treatment programme for bladder cancer. “It stimulates the immune system,” says Lathe. A team of researchers in Jerusalem, he says, decided to look at patients who survived bladder cancer and compare dementia prevalence among patients treated with BCG and those who weren’t. “Do they differ in the rate at which they get Alzheimer’s disease?” The answer is yes – the BCG group appeared to get 75% protection against Alzheimer’s. A number of studies have now found varying levels of protection from BCG, with an average, according to one meta‑analysis, of 45%.
A raft of other vaccines have been investigated. This year, says Lathe, “there was a paper out on shingles – the zoster vaccine”. This protects against the chickenpox virus, which presents as shingles in adulthood, “which is very debilitating, particularly in elderly people, so there is now a [UK] government policy for people in their 70s to receive a zoster vaccine”. In individuals who had that vaccine, there was also a reduction in Alzheimer’s. “We did a complete list of all the vaccines … diphtheria, hepatitis, zoster, influenza, pneumococcus, typhoid. They all, to a greater or lesser extent, are protective against Alzheimer’s disease. Boost your immune system!”
BCG, meanwhile, has been shown to ward off a host of age‑related conditions, including skin infections and pneumonias. “One of the ways in which we would like to take this forward is to recommend routine vaccination of different types of elderly people to prevent not just Alzheimer’s disease, but also age-related morbidities.”
Being aware of and treating infections around the body in a timely way could also help – although at present, says Schultek, it would be rare for a clinician to test for brain infections, even at the onset of cognitive problems. Until new diagnostic tests are developed, they would need to access cerebrospinal fluid, which feeds and cleans the brain, to look for signs of brain infection. This requires a lumbar puncture – a needle going into the back of the neck – and while the procedure is routine in hospitals, it is not without risks and side-effects (such as headaches) and it can take a few days to recover. Of course, if you have Alzheimer’s, the possibility of discovering you have a treatable version would make it worth the risk.
If you have recurring herpes infections anywhere on your body, Schultek recommends treating, or preventing recurrence, with antiviral medication such as Aciclovir or Valaciclovir, which are available on the NHS. It may be worth being screened for Lyme disease, too, she says, “if you’re in an endemic area”, because the sooner you treat it, the better.
Good hygiene, such as hand-washing, may do more than stop you catching a cold or the flu. A newly published paper by members of the Alzheimer’s Pathobiome Initiative explores how “microbes invade the sensory systems of the head and neck to exploit the brain”, says Schultek. “This pertains to viruses and bacteria that can enter through the nose, like Covid, as well as microbes that enter via the mouth, eyes and ears.” These senses often become defective as Alzheimer’s develops, “and the evidence suggests part of this might be due to these infections impacting our ability to smell, but then also impacting the brain itself”.
The nose is an increasingly well‑established route for microbes to reach the brain. “A research team at Griffith University in Australia found that you could infect mice with Chlamydia pneumoniae, which can cause pneumonia or a cold, and you could cause the mice to develop an Alzheimer’s-like pathology in the brain,” says Schultek. “And this is not the only group that has shown it. Dr Balin was the first one to show this and demonstrate that this organism is able to get through the nose and enter the brain.” This triggered a flurry of media reports that avoiding picking one’s nose could help lower dementia risk. However, Schultek says there is no evidence that this is the case and that this research by members of her team was taken out of context.
Good oral health is a must. Gum disease has long been associated with dementia risk and “it has been demonstrated that certain organisms like periodontal bacteria (Porphyromonas gingivalis) may actually increase blood-brain barrier permeability – not a good thing”, says Schultek.
While she readily acknowledges that we are nowhere near to having a fully formed set of recommendations, “the best immune-boosting advice we can glean from the literature includes good diet, exercise and good general health, watching things as we age like blood sugar and cholesterol, and implementing what is mostly common sense.” This includes avoiding an ultra-processed diet, which, she says, “not only helps with inflammation, but may also help to enhance immune function.” Exercise is another evidenced way to support immune function.
This is key, because we can’t completely avoid exposure to germs. Apart from anything else, we would become exceedingly lonely. “To quote one of my mentors,” says Schultek of the doctor who saved her: “You can’t slide pizza under the door and hide.”
