On May 22, 2019, Vielight Inc, a Toronto company, announced that it was commencing the recruitment of participants for a pivotal trial using near infrared light as an intervention for Alzheimer disease (AD). Vielight’s proposed intervention is based on photobiomodulation (PBM) involving the delivery of low-power near infrared light from light emitting diodes (LEDs) to the brain (Figure 1). In light of recent failed trials, why would another trial by a small Canadian company be expected to succeed against the odds? The proposed justification is that PBM works by “helping the brain repair itself,” rather than by targeting a single biological mechanism.
Understanding failed trials
No new drug for treating AD has been approved since 2003, at which time memantine (a blocker of the N-methyl-D-aspartate receptor [NMDA] subfamily glutamate receptor) received FDA approval. There have been several reasons offered to explain the repeated failures of AD drug trials—ranging from targeting the wrong biological mechanisms, to suboptimal methodologies, to the late disease stage of the participants. There is a trend in new drug trials to target populations with preclinical and prodromal disease, and increasingly towards non β-amyloid (Aβ) mechanisms of action in the earlier phases of drug development. There has been negli gible discussion on any physical treatment modality, which appears to have been eclipsed by a continued search for prospective drugs despite multiple repeated failures.
Broadly speaking, drug development takes the approach of molecular screening, which may or may not be based on alteration of phenotypes. Over the years, many of these single molecule candidates have been related to Aβ oligomers and/or plaques or tau misfolding. AD has been found to have a much more complex etiology, with multiple risk factors that argue against single molecule targeting. On the other hand, PBM is an intervention that is able to modify multiple pathways, which may be an elegant answer to a complex problem.
The multifactorial and complex risk factors related to AD
Between 60% and 80% of the risk of AD is genetic, and many genes seem to be involved. Other risk factors include a history of head injury, depression, and hypertension. AD is generally characterized by diffuse atrophy of the entire brain, accompanied by extracellular Aβ plaques and intraneuronal neurofibrillary tangles composed of hyperphosphorylated tau protein. AD mechanisms have been widely discussed, but there is still a lack of fundamental understanding with much ongoing debate.
Neuroinflammation and reactive gliosis are also hallmarks of AD. Accumulating evidence suggests that that microglia with the M1 phenotype are contributors to inflammation in AD.1 However, the M2 microglial phenotype is non-inflammatory and is also proposed to be able to clear the amyloid plaques by phagocytosis. PBM is capable of switching the microglial phenotype from M1 to M2, which partly explains its well-known anti-inflammatory effects.
Reductions in mitochondrial activity and glucose metabolism are widely seen in AD, including changes in cytochrome c oxidase and morphological changes in mitochondria. PBM is consistently cited to be able to improve mitochondrial activity.2
Recent theories have implicated changes in the gut microbiome. The bacteria may secrete bacterial amyloid that may trigger cross-seeding of amyloid plaques, or else the bacteria may overstimulate the innate immune response. Bacteria such as Porphyromonas gingivalis have been found in AD brains.3 Aβ peptide may be an endogenous response for antimicrobial defense. Emerging evidence suggests that PBM can improve the gut microbiome.4
Dr Hamblin is Principal Investigator, Wellman Center for Photomedicine, Massachusetts General Hospital, Associate Professor, Department of Dermatology, Harvard Medical School, Boston, and Affiliated Faculty, Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA. He reports that he receives financial compensation as a Scientific Advisory Board Member and Consultant to Vielight Inc. For the sake of completeness other potential conflicts of interest are Scientific Advisory Boards: Transdermal Cap Inc, Cleveland, OH; BeWell Global Inc, Wan Chai, Hong Kong; Hologenix Inc. Santa Monica, CA; LumiThera Inc, Poulsbo, WA; Vielight, Toronto, Canada; Bright Photomedicine, Sao Paulo, Brazil; Quantum Dynamics LLC, Cambridge, MA; Global Photon Inc, Bee Cave, TX; Medical Coherence, Boston MA; NeuroThera, Newark DE; JOOVV Inc, Minneapolis-St. Paul MN; AIRx Medical, Pleasanton CA; FIR Industries, Inc. Ramsey, NJ; UVLRx Therapeutics, Oldsmar, FL; Ultralux UV Inc, Lansing MI; Illumiheal & Petthera, Shoreline, WA; MB Lasertherapy, Houston, TX; ARRC LED, San Clemente, CA; Varuna Biomedical Corp. Incline Village, NV; Niraxx Light Therapeutics, Inc, Boston, MA. Consulting; Lexington Int, Boca Raton, FL; USHIO Corp, Japan; Merck KGaA, Darmstadt, Germany; Philips Electronics Nederland B.V. Eindhoven, Netherlands; Johnson & Johnson Inc, Philadelphia, PA; Sanofi-Aventis Deutschland GmbH, Frankfurt am Main, Germany. Stockholdings: Global Photon Inc, Bee Cave, TX; Mitonix, Newark, DE.
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