A research team compared two common transcranial photobiomodulation (tPBM) paradigms—continuous wave (CW) and 40-hertz (Hz) pulsed light—in a well-established Alzheimer's disease mouse model, according to a July 6 announcement. Professor Li said, "We wanted to compare the two most common tPBM paradigms head‑to‑head in a well‑established AD mouse model. CW light is traditionally used for mitochondrial enhancement, while 40‑Hz light is known to entrain gamma oscillations. But no one had systematically compared their effects on neurovascular pathology and glial cells."
The study involved treating five-month-old 5xFAD mice with aggressive amyloid deposition using 810-nanometer light for ten minutes daily over thirty-seven days. Monte Carlo simulations showed that about thirty percent of incident energy reached the brain parenchyma. Both CW and 40-Hz treatments improved spatial learning and memory in the Morris water maze, with the 40-Hz group showing slightly faster acquisition. However, results from the novel object recognition test suggested that improvements may be hippocampus-dependent.
Analysis revealed differences in amyloid-beta reduction: "In the hippocampus, 40‑Hz light reduced Aβ by 87.7%, while CW light achieved a more modest 60.1% reduction." Immunofluorescence confirmed that "40‑Hz light significantly reduced plaque numbers and area in both the dentate gyrus and CA1 subregions," while CW was more effective in certain regions like the dentate gyrus but less so elsewhere.
Professor Yan said, "The key wasn't just the reduction in plaques... We found that 40‑Hz light didn't simply increase the total number of microglia. Instead, it drove their spatial redistribution – microglia clustered tightly around Aβ plaques, forming a dense barrier that effectively cleared the amyloid without triggering the widespread neuroinflammation that often follows global microglial activation." In contrast, CW primarily targeted astrocytes; whole-brain vascular reconstruction revealed increased vessel density for both methods but through different cellular mechanisms.
Professor Wei explained, "Astrocytes physically connect neurons to capillaries and regulate blood flow. By strengthening this link, CW light restores the metabolic support that neurons need to survive and function." The study also found synaptic density correlated strongly with vessel density and astrocyte-vascular coupling under CW treatment.
The authors propose a precision medicine framework: use of CW or 40-Hz tPBM may depend on whether vascular or amyloid pathology predominates in patients with Alzheimer's disease. They note further studies are needed for molecular validation but conclude, "We now have a clear biological rationale for choosing CW or 40‑Hz light–or combining them–based on the dominant pathology in each patient," said Professor Li.
