Post by Nadica (She/Her) on Aug 1, 2024 3:06:19 GMT
Can infections cause Alzheimer’s? A small community of researchers is determined to find out - Published July 30, 2024
Following up tantalizing links between pathogens and brain disease, new projects search for causal evidence
PHILADELPHIA— This week, thousands of researchers are flocking to downtown Philadelphia for what’s billed as the largest international conference dedicated to Alzheimer’s disease. But several kilometers away a much smaller group congregated for an alternative meetup: a daylong dive into whether and how pathogens might cause the fatal dementia.
Saturday’s gathering of about 80 scientists on the city’s periphery is something of a metaphor for where the idea sits in the larger Alzheimer’s community, long dominated by the view that the plaque-forming brain protein amyloid beta drives the disease. But the links between pathogens and Alzheimer’s appear to be slowly tightening. The COVID-19 pandemic lent momentum to the field: debilitating neurological symptoms, such as those in some people with Long Covid, reinforced that a virus can chronically disrupt the brain.
More recently scientists have found evidence that infection can mobilize a signature protein of Alzheimer’s called tau. And just last week they reported that a vaccine against shingles, caused by a virus that lurks in the nervous system, is associated with a lower dementia risk.
Just holding this meeting “has been such a turnaround,” said William Eimer, a Harvard University neuroscientist who presented the findings on tau there. He lamented “fighting uphill to get things published and get funded.” A 2-year-old effort called the Alzheimer’s Pathobiome Initiative (AlzPI), which spearheaded the meeting, now hopes to strengthen the case that pathogens play a role by encouraging specialists to swap samples and share data.
Eimer and his then-mentor Robert Moir found one clue in 2016, reporting that amyloid beta protected against infection in mouse and worm models of Alzheimer’s disease. The finding suggested pathogens might help mobilize the protein. And in 2018, they reported more direct evidence, showing that amyloid beta aggregates in the presence of herpes simplex virus-1 (HSV-1), another clue that the protein represents some kind of protective response.
In 2019, another team reported that Porphyromonas gingivalis, a bacterium that causes gum disease, appears in the brains of Alzheimer’s patients. When repeatedly applied to the gums of mice, it appeared to trigger Alzheimer’s pathology in their brains, including excess amyloid beta. A year later came news that HSV-1 could cause Alzheimer’s-like changes in a 3D stem-cell derived tissue culture meant to model human brain tissue. Numerous pathogens have been found to be more common in the brains of people who had Alzheimer’s than those who did not, including the bacterium Chlamydia pneumoniae, which causes respiratory infections.
The animal evidence has continued to build. At Baylor College of Medicine, immunologist David Corry and his postdoctoral fellow Lynn Bimler are examining a common fungus, the yeast Candida albicans. Analysis revealed yeast cells in the brains of infected mice, Corry and his colleagues reported in 2023. More recently, they’ve found mice show increased anxiety, memory problems and brain shrinkage 6 months after infection. They’re now preparing another publication describing the animals’ behavior, and are also studying how Candida behaves when it finds its way to human brain tissue.
Eimer’s team has not-yet-published work showing that when human neuronal cells are exposed to HSV-1, another protein congregates and offers protection: tau, widely considered another toxic driver of brain damage and Alzheimer’s symptoms. The work supports their previous preliminary evidence that like amyloid beta, tau might be an antimicrobial protein. “Infection is boosting tau response,” Eimer said at the meeting.
Human studies are also helping to advance the case. Last week, researchers in the U.K. published an analysis in Nature Medicine of health records from more than 200,000 people in the U.S., which found that those who’d gotten the shingles vaccine Shingrix had a 17% lower risk of dementia in the next 6 years than those who’d gotten an earlier, less effective vaccine. A May preprint from a second team showed that in Wales, this earlier vaccine cut dementia risk by 20% versus not getting a shingles shot at all. The effect was more pronounced in women than in men.
That infections may lead to Alzheimer’s is plausible, especially because amyloid beta can be a reaction to various insults, including infection, says Lon Schneider, director of the California Alzheimer’s Disease Center at the Keck School of Medicine of the University of Southern California. The big hurdle is going beyond associations and establishing that pathogens lead to disease pathology and illness in people, says Schneider, who wasn’t at the 27 July meeting. Right now, “there are major missing links.”
Helping to fill those gaps is a primary goal of AlzPI. “Can these agents really be causative? We believe they can be, but proving that is a difficult process,” says Brian Balin, a neuroscientist at the Philadelphia College of Osteopathic Medicine, where the meeting was held.
Balin co-founded the consortium with patient advocate Nikki Schultek, who formerly worked in the pharmaceutical industry and has studied infectious disease, along with other scientists; it’s run with seed grants from foundations. The group is working to help participating scientists from around the world share brain tissue, in part to standardize techniques for detecting microbes in the brain.
Eimer and others believe it may take repeated infections to trigger Alzheimer’s, and they suspect pathogens that can move in and out of latency—sitting quietly without replicating, before surging again—might be especially damaging. Herpesviruses, which include the shingles virus, “stay [in the body] for life,” says Ruth Itzhaki at the University of Oxford, a pioneer in the study of pathogens’ role in Alzheimer’s.
One team at Tulane University presented recent efforts to mimic this cycle between active infection and latency, injecting mice with the herpesvirus cytomegalovirus every
3 months. In January, they published a paper describing brain inflammation, cognitive effects, and other changes after a year of injections.
Various groups are examining how pathogens can affect different cells in the brain that are key to Alzheimer’s disease, including neurons and immune cells called microglia. “We need the mechanisms,” says Kevin Zwezdaryk, a virologist leading the Tulane group, along with neuroscientist Elizabeth Engler-Chiurazzi.
As evidence accumulates, a couple of teams are already testing antimicrobials to treat Alzheimer’s. A team at Columbia University is leading a trial of the herpes antiviral valacyclovir. And Lighthouse Pharma, a co-sponsor of the pathogen meeting, is raising money for a 300-person study of a drug that inhibits P. gingivalis. Although the company’s earlier trial of a related compound in 643 people with mild or moderate Alzheimer’s failed, the company said it showed effectiveness in some who were found to harbor the bacteria.
But as with all potential Alzheimer’s treatments, such measures may do less good after damage is done. And trying to head off damage before symptoms appear could mean years of antimicrobials, hardly a safe option. If pathogens do pan out as causal, these and other tough questions are waiting in the wings.
doi: 10.1126/science.z4j53ca
Following up tantalizing links between pathogens and brain disease, new projects search for causal evidence
PHILADELPHIA— This week, thousands of researchers are flocking to downtown Philadelphia for what’s billed as the largest international conference dedicated to Alzheimer’s disease. But several kilometers away a much smaller group congregated for an alternative meetup: a daylong dive into whether and how pathogens might cause the fatal dementia.
Saturday’s gathering of about 80 scientists on the city’s periphery is something of a metaphor for where the idea sits in the larger Alzheimer’s community, long dominated by the view that the plaque-forming brain protein amyloid beta drives the disease. But the links between pathogens and Alzheimer’s appear to be slowly tightening. The COVID-19 pandemic lent momentum to the field: debilitating neurological symptoms, such as those in some people with Long Covid, reinforced that a virus can chronically disrupt the brain.
More recently scientists have found evidence that infection can mobilize a signature protein of Alzheimer’s called tau. And just last week they reported that a vaccine against shingles, caused by a virus that lurks in the nervous system, is associated with a lower dementia risk.
Just holding this meeting “has been such a turnaround,” said William Eimer, a Harvard University neuroscientist who presented the findings on tau there. He lamented “fighting uphill to get things published and get funded.” A 2-year-old effort called the Alzheimer’s Pathobiome Initiative (AlzPI), which spearheaded the meeting, now hopes to strengthen the case that pathogens play a role by encouraging specialists to swap samples and share data.
Eimer and his then-mentor Robert Moir found one clue in 2016, reporting that amyloid beta protected against infection in mouse and worm models of Alzheimer’s disease. The finding suggested pathogens might help mobilize the protein. And in 2018, they reported more direct evidence, showing that amyloid beta aggregates in the presence of herpes simplex virus-1 (HSV-1), another clue that the protein represents some kind of protective response.
In 2019, another team reported that Porphyromonas gingivalis, a bacterium that causes gum disease, appears in the brains of Alzheimer’s patients. When repeatedly applied to the gums of mice, it appeared to trigger Alzheimer’s pathology in their brains, including excess amyloid beta. A year later came news that HSV-1 could cause Alzheimer’s-like changes in a 3D stem-cell derived tissue culture meant to model human brain tissue. Numerous pathogens have been found to be more common in the brains of people who had Alzheimer’s than those who did not, including the bacterium Chlamydia pneumoniae, which causes respiratory infections.
The animal evidence has continued to build. At Baylor College of Medicine, immunologist David Corry and his postdoctoral fellow Lynn Bimler are examining a common fungus, the yeast Candida albicans. Analysis revealed yeast cells in the brains of infected mice, Corry and his colleagues reported in 2023. More recently, they’ve found mice show increased anxiety, memory problems and brain shrinkage 6 months after infection. They’re now preparing another publication describing the animals’ behavior, and are also studying how Candida behaves when it finds its way to human brain tissue.
Eimer’s team has not-yet-published work showing that when human neuronal cells are exposed to HSV-1, another protein congregates and offers protection: tau, widely considered another toxic driver of brain damage and Alzheimer’s symptoms. The work supports their previous preliminary evidence that like amyloid beta, tau might be an antimicrobial protein. “Infection is boosting tau response,” Eimer said at the meeting.
Human studies are also helping to advance the case. Last week, researchers in the U.K. published an analysis in Nature Medicine of health records from more than 200,000 people in the U.S., which found that those who’d gotten the shingles vaccine Shingrix had a 17% lower risk of dementia in the next 6 years than those who’d gotten an earlier, less effective vaccine. A May preprint from a second team showed that in Wales, this earlier vaccine cut dementia risk by 20% versus not getting a shingles shot at all. The effect was more pronounced in women than in men.
That infections may lead to Alzheimer’s is plausible, especially because amyloid beta can be a reaction to various insults, including infection, says Lon Schneider, director of the California Alzheimer’s Disease Center at the Keck School of Medicine of the University of Southern California. The big hurdle is going beyond associations and establishing that pathogens lead to disease pathology and illness in people, says Schneider, who wasn’t at the 27 July meeting. Right now, “there are major missing links.”
Helping to fill those gaps is a primary goal of AlzPI. “Can these agents really be causative? We believe they can be, but proving that is a difficult process,” says Brian Balin, a neuroscientist at the Philadelphia College of Osteopathic Medicine, where the meeting was held.
Balin co-founded the consortium with patient advocate Nikki Schultek, who formerly worked in the pharmaceutical industry and has studied infectious disease, along with other scientists; it’s run with seed grants from foundations. The group is working to help participating scientists from around the world share brain tissue, in part to standardize techniques for detecting microbes in the brain.
Eimer and others believe it may take repeated infections to trigger Alzheimer’s, and they suspect pathogens that can move in and out of latency—sitting quietly without replicating, before surging again—might be especially damaging. Herpesviruses, which include the shingles virus, “stay [in the body] for life,” says Ruth Itzhaki at the University of Oxford, a pioneer in the study of pathogens’ role in Alzheimer’s.
One team at Tulane University presented recent efforts to mimic this cycle between active infection and latency, injecting mice with the herpesvirus cytomegalovirus every
3 months. In January, they published a paper describing brain inflammation, cognitive effects, and other changes after a year of injections.
Various groups are examining how pathogens can affect different cells in the brain that are key to Alzheimer’s disease, including neurons and immune cells called microglia. “We need the mechanisms,” says Kevin Zwezdaryk, a virologist leading the Tulane group, along with neuroscientist Elizabeth Engler-Chiurazzi.
As evidence accumulates, a couple of teams are already testing antimicrobials to treat Alzheimer’s. A team at Columbia University is leading a trial of the herpes antiviral valacyclovir. And Lighthouse Pharma, a co-sponsor of the pathogen meeting, is raising money for a 300-person study of a drug that inhibits P. gingivalis. Although the company’s earlier trial of a related compound in 643 people with mild or moderate Alzheimer’s failed, the company said it showed effectiveness in some who were found to harbor the bacteria.
But as with all potential Alzheimer’s treatments, such measures may do less good after damage is done. And trying to head off damage before symptoms appear could mean years of antimicrobials, hardly a safe option. If pathogens do pan out as causal, these and other tough questions are waiting in the wings.
doi: 10.1126/science.z4j53ca