In May of 2020 Amanda Finley sat straight up in bed, determined to write an important note on the whiteboard she keeps nearby for moments like this. Instead, she drew a large smiley face on her brand-new sheets and felt like she’d achieved her goal.
Months after her first COVID-19 diagnosis in March 2020, Finley, a former archeologist and opera singer, was still plagued by myriad long COVID symptoms. But the most troubling to her was the nebulously named “brain fog.” Her experiences inspired Finley to create the COVID-19 Long-Hauler’s Facebook group in July 2020 to raise awareness and support for those struggling with long-term symptoms. Then in 2021, she was reinfected, this time with the Delta variant. The several months following that second diagnosis were a blur. “I don’t remember a lot of the summer,” she says, “That’s terrifying … I really value my mind.”
Scientists are racing to understand why some patients have persistent symptoms, especially brain fog, after a bout with COVID-19. Though little is currently known, some of the findings may yield insights into another condition that has long vexed researchers: Alzheimer’s disease, which currently affects nearly six million Americans, a number expected to triple by 2060.
Long COVID sufferers describe some cognitive symptoms that neurologists say are very similar to Alzheimer’s disease. Finley was disoriented and losing things. She also experienced personality changes, which are common in Alzheimer’s patients. “I try not to be a mean person,” she says, but over the summer she says that changed, and she became “cruel.” She doesn’t remember everything, but based on old text messages, she says, “I’m ashamed of the things I said and did.”
In the century since Alzheimer’s disease was first characterized, scientists have considered many reasons why these patients have unrelenting memory loss. The most widely accepted possible cause involves high concentrations of two abnormal proteins: beta-amyloid, which clumps in the space between neurons, cutting off the lines of communication; and tau, which accumulates inside nerve cells and disrupts neuronal signaling.
Nearly a quarter of the more than 2,000 clinical trials for Alzheimer’s disease treatments before 2019 tested drugs thought to clear beta-amyloid from the brain. While many of these drugs did, indeed, reduce beta-amyloid, patients’ symptoms didn’t improve and their cognitive decline didn’t slow down. The trials led to several high-profile failures. One drug, aducanumab, was finally approved by the U.S. Food and Drug Administration in 2021, but whether it actually benefits patients is still debatable.
Another hypothesis gaining traction is that a viral, bacterial, or even fungal infection could set off a series of events leading to neurodegeneration. Though the theory is far less popular than the amyloid hypothesis, it was starting to garner renewed attention even before the pandemic.
“Over the past 10 years or so there’s been growing interest in the idea of neuroinflammation and crosstalk between the immune system and the brain,” says Sean Naughton, a neuroscientist and toxicologist at the Icahn School of Medicine at Mount Sinai. “The COVID situation has reignited a lot of that interest.”
Scientists are trying to understand why patients like Finley experience ongoing cognitive deficits after COVID-19. And a handful of studies have been published that shed light on how a virus—SARS-CoV-2 or otherwise—might ignite a molecular cascade that could lead to dementia.
The scourge of Alzheimer’s disease
Alzheimer’s occurs as neurons in the hippocampus—a small, seahorse-shaped region of the brain between the ears responsible for encoding short-term memories—gradually die off. As they do, patients start forgetting very recent events, such as where they left their keys or what they had for lunch. Over time, the memory losses stretch farther back to the point where many forget most of their adult lives.
Researchers currently categorize two types of Alzheimer’s disease: early-onset, which begins during a person’s 40s or 50s, and late onset, which doesn’t strike until age 65 or older. Early-onset Alzheimer’s, which affects only 5 percent of patients, has a strong, well-known genetic link, but little is known about what triggers the much more common late-onset form of the disease.
The amyloid hypothesis arose in 2010 after a neuropathologist John Q. Trojanowski and his team published a study showing accumulation of beta-amyloid in patients long before symptoms set in. Trojanowski suggested that Alzheimer’s starts when beta-amyloid proteins clump into plaques between neurons in the hippocampus and gradually spread outward. As these accumulate, they trigger the formation of abnormal tau proteins inside the cells that then interrupt neuronal communication and memory formation.
Swedish psychiatrist and geneticist Torsten Sjogren first described the notion that infections might trigger Alzheimer’s in 1952, but the idea quickly fell out of favor, and there has been little interest from the pharmaceutical industry. As of 2019, only 0.5 percent of clinical trials tested antiviral or antibacterial drugs targeting a microbial root for Alzheimer’s.
Still, recent evidence has emerged supporting the idea, including studies that have found viruses such as Herpes Simplex 1 in the brains of Alzheimer’s patients. And when the pandemic struck, researchers quickly discovered that the viral disease wreaks havoc on the brain.
What COVID-19 does to the brain
Autopsy studies of patients who died from severe COVID-19 provide a spectrum of results, with some showing no evidence of the virus in the brain, some showing small quantities hiding in the brain’s blood vessels, and others showing the virus distributed throughout the brain.
One autopsy study from June 2021 took brain samples from eight patients with severe COVID-19. It showed no signs of virus in the brain, but did find microglia, cells that act as part of the brain’s immune system, with pathological changes resembling those seen in Alzheimer’s patients.
“We were surprised,” says senior author of the study, Tony Wyss-Coray, a neurologist who studies the role of the immune system in Alzheimer’s disease at Stanford University. When an individual is suffering from disease, their microglia can activate specific genes that are otherwise dormant. Scientists have identified unique patterns of gene activity associated with certain neurodegenerative diseases, including Alzheimer’s.
Others see the virus’s influence on the brain as more direct.
There is evidence that the virus might enter the brain via the olfactory bulb, where scents are analyzed, says Geidy Serrano, director of the Civin Laboratory for Neuropathology at the Banner Sun Health Research Institute. From the olfactory bulb, the virus might travel toward the amygdala, which is involved in regulating emotions, then to the hippocampus.
“It makes sense that if the virus is going through that pathway that is involved with cognition and memories, that it will then eventually look very similar to other types of dementia,” she says.
Most recently, National Institutes of Health scientists conducted autopsies on 44 patients who had been infected by COVID-19. Some of the patients died from the disease, while others lived up to seven months after acute infection. Of the 11 brains they examined, 10 contained widespread SARS-COV-2 when the patient died.
Unfortunately, autopsies can only tell us so much, says Serena Spudich, a neurology professor at the Yale School of Medicine. “Autopsy data has been super informative. But there are caveats about this type of data, because these are people who had severe COVID or people who died,” says Spudich. “When they’re in the last stages of life, all sorts of terrible things happen to the body and the brain.”
Fortunately, other researchers are now starting to glean clues from living patients.
Clues to an Alzheimer’s-COVID-19 overlap
In October 2020 neurocritical care specialist Jennifer Frontera and her team at NYU Langone Grossman School of Medicine published a study showing that 13.5 percent of patients hospitalized with COVID-19 developed a new neurologic disorder—encephalopathy (cognitive dysfunction triggered by infections and the body’s immune response), seizure, or stroke.
Some patients who are sick enough to visit the intensive care unit (ICU) for any cause do develop neurological symptoms. To better understand what was happening to COVID-19 patients specifically, Frontera teamed up with Thomas Wisniewski, head of the Alzheimer’s Disease Research Center, and analyzed blood samples that patients had provided when they were admitted to the hospital.
In a study published this month the scientists wrote that hospitalized COVID-19 patients who had cognitive symptoms but no prior history of dementia had high levels of proteins in their blood that signaled brain damage. Some of the proteins are commonly seen when patients experience neuronal injury caused by strokes or lack of oxygen, but others, like phosphorylated tau-181 (ptau), are considered likely to be specific to Alzheimer’s disease.
The findings are far from definitive. “We’re just learning about some of these blood biomarkers and what they might portend, so the next step is for us to track outcomes” says Frontera.
Another researcher, Magnus Gisslen, an infectious disease specialist at the University of Gothenburg, published a similar study probing cerebrospinal fluid biomarkers in 2020. He was surprised to hear that Frontera and her team saw elevated ptau, because his team did not. “It is thought to be very specific, much more specific to Alzheimer’s than the other markers,” he says.
Since that first study, Frontera and her team have been following the patients who were discharged from the hospital, conducting phone screens to assess their cognitive status. The work isn’t published yet, but she says that six to 12 months after hospitalization, about half of patients showed improved cognitive scores. “So that’s encouraging,” she says.
What does it all mean?
The scientists say it’ll be years, if not decades, before they know if contracting COVID-19 contributes to the risk of developing Alzheimer’s disease. And while there is a subset of symptoms that overlap between long COVID and Alzheimer’s, many differ. Alzheimer’s develops gradually over time, whereas brain fog from COVID-19 sets in quickly. Generally, Alzheimer’s is a disease of those over 65, while cognitive impairment after COVID-19 can occur even in children, explains Ziyad Al-Aly, director of the clinical epidemiology center at the Veterans Affairs St. Louis Health Care System in Missouri. Even short-term memory issues may differ between COVID-19 and Alzheimer’s patients.
But it’s possible that a better understanding of this type of injury to the brain could open the door to developing unique dementia treatments.
For example, neuroscientist Dervis Salih and his team at University College London found that the way innate immune cells in the brain respond to a buildup of beta-amyloid is very similar to the way these cells in the lung respond to a SARS infection. “There’s a significant overlap,” Salih says, and so interrupting this process might help both types of patients.
Naughton emphasizes that even if viruses are found to initiate the disease, “that wouldn’t be the end all be all” of Alzheimer’s disease. There are many other factors—diet and exercise, sleep quality, exposure to air pollution—that can influence a person’s risk of developing dementia as they age. It could be that of the millions of people with late-onset Alzheimer’s, there are a variety of causes that scientists haven’t yet identified.
Still, teasing apart the different risk factors may help scientists find and personalize better Alzheimer’s treatments. A similar movement to better characterize types of cancer has ushered in far more effective therapies.
Though she still experiences brain fog occasionally, Finley says she’s improved over time. She feels like the haze has lifted, and that she has a better grasp on her day-to-day life, something that generally never happens to patients with Alzheimer’s disease. She feels more like herself again, though she struggles to access and pay for medical care and often needs more rest than she used to. Finley, who alternates between living with friends and camping in a tent, has enlisted trusted individuals to step in if her condition worsens. “I need you to watch for these things,” such as forgetfulness, disorientation, and personality changes, she told them. If you notice anything, “please tell me.”