Published on: Jul 11, 2025
A groundbreaking Yale study has uncovered a potential treatment target for the brain fog commonly experienced after COVID-19 and provides fresh support for a theory about Alzheimer’s disease origins.
A key feature of Alzheimer’s disease is the presence of amyloid beta plaques—clusters of short amino acid chains that accumulate in and around brain cells. Some scientists believe amyloid beta, which is structurally similar to antimicrobial peptides, may play a protective role by defending the brain against infections. As the blood-brain barrier weakens in Alzheimer’s patients, increased amyloid beta could signal that pathogens are breaching the brain's defenses.
The new study, published in Science Advances, explores whether infection with SARS-CoV-2—the virus responsible for COVID-19—could trigger similar amyloid beta buildup, leading to neurological symptoms like brain fog.
“Brain fog, or difficulty thinking clearly, is increasingly reported after COVID-19,” said senior author Dr. Brian Hafler, associate professor of ophthalmology and visual science at Yale School of Medicine. “It mirrors symptoms seen in Alzheimer’s disease. Our findings suggest SARS-CoV-2 may contribute to amyloid beta buildup in the central nervous system.”
Retina as a Window to the Brain
To investigate, Hafler’s team used donated human retinal tissue to grow retinal organoids—miniature eye-like structures developed from stem cells. These organoids were engineered to exhibit Alzheimer’s-like characteristics, including overproduction of amyloid beta due to genetic mutations.
According to Hafler, retinal organoids offer significant advantages over animal models because they accurately reflect human biology.
The team confirmed that amyloid beta accumulation, typical of Alzheimer’s-affected brains, was also present in the retina. This finding suggests the retina may serve as a non-invasive, accessible platform for studying brain-related changes.
Researchers also discovered that SARS-CoV-2 can enter retinal cells. By analyzing RNA in individual nuclei, they detected the presence of NRP1 (neuropilin-1) and ACE2—proteins that facilitate viral entry—in both neurons and glial cells from retinal tissue of COVID-19 patients.
When the scientists exposed the retinal organoids to the virus’s spike protein, amyloid beta levels significantly increased.
Even in retinal tissue from COVID-19 patients without any history of dementia, amyloid beta accumulation was elevated—similar to levels observed in Alzheimer’s patients.
However, this buildup was reversed when the tissue was treated with an NRP1 inhibitor, highlighting the protein’s potential as a therapeutic target. NRP1 is already being explored in cancer research to block new blood vessel formation, but it remains in early-stage development.
“The role of NRP1 in amyloid beta buildup offers a precise molecular target for future therapies,” Hafler said. Inhibiting NRP1 may help prevent or treat post-COVID neurological complications.
Toward Therapies for Virus-Induced Brain Changes
The findings support the “amyloid beta antimicrobial hypothesis,” which proposes that amyloid beta serves as part of the brain’s innate immune system, reacting to viral threats.
“Our research shows that exposure to SARS-CoV-2—particularly its spike protein—can lead to amyloid beta aggregation in both human retinal tissue and retinal organoids,” Hafler noted. “This not only strengthens the link between Alzheimer’s and infection but also opens the door to broader research on viral triggers.
Ongoing clinical studies at Yale aim to determine whether COVID-19 raises long-term Alzheimer’s risk—and whether early interventions can reduce that risk.
“Our ultimate goal is to prevent chronic neurological effects of COVID-19,” Hafler said, “and to evaluate NRP1 inhibitors and other treatments that target how viruses interact with human cells, to potentially stop Alzheimer’s-like changes before they begin.”
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