INTRODUCTION Mild cognitive impairment (MCI), a prodromal stage of Alzheimer’s disease and related dementias (ADRD), offers a critical window for early intervention. Mitochondrial dysfunction is increasingly recognized as a driver of neurodegeneration, yet most therapies target downstream protein aggregation. Transcranial photobiomodulation (tPBM)—delivery of near-infrared (NIR) light to stimulate mitochondrial respiration—offers a non-invasive, metabolism-based therapeutic strategy.

METHODS In a single-blinded, randomized, sham-controlled pilot trial (NCT05563298), we evaluated the safety, feasibility, and biological effects of home-based tPBM in individuals aged ≥50 with MCI. Participants received either active (n = 10) or sham (n = 10) treatment using visually identical NIR devices targeting default mode network regions and the olfactory bulb. Active devices emitted pulsed 810 nm light for 20 minutes per session, six days per week for six weeks; sham devices emitted light for only 2 seconds per session. No serious adverse events occurred; three mild-to-moderate events were reported, and adherence exceeded 98%.

RESULTS Active tPBM led to greater improvements in global cognition, as measured by the Mini-Mental State Examination, and in episodic memory, as measured by the delayed recognition test of the California Verbal Learning Test–Second Edition. Blood analyses showed increased serum pyruvate and lactate, a reduced lactate-to-pyruvate ratio, and lower plasma IL-6. Neuroimaging revealed enhanced default mode network connectivity and focal cortical volume and thickness gains.

DISCUSSION These data demonstrate safety, preliminary efficacy, and support future definitive clinical studies.

NRR has received consulting fees from Vielight Inc. (2021 - 2023). RZ has received consulting fees from Vielight Inc. (2018 - present). RS holds the Elizabeth S. Barford Early Career Professor in Multiple Sclerosis in the Department of Medicine at the University of Toronto. He has received a Discovery Grant from MS Canada and additional funding from Brain Canada to study the effects of Epstein-Barr Virus on Multiple Sclerosis. He has received consulting fees from Novartis and EMD Serono and payments or honoraria for lectures, presentations, and educational events from Biogen-Idec, Sanofi-Genzyme, EMD Serono, Roche and Eli Lilly. RS has participated on advisory boards for Novartis and EMD Serono. He has also received support for attending scientific meetings from EMD Serono. LL is the Chief Executive Officer of Vielight Inc. CEF has received research grants from Hoffmann-La Roche (2018 - 2022), Vielight Inc. (2019 - 2023) and Novo Nordisk (2021 - 2024). All other authors declare no competing interests. The remaining authors declare no competing interests.

NCT05563298

https://www.clinicaltrials.gov/study/NCT05563298

We gratefully acknowledge TDRA-MITO2i for awarding a fellowship to the first author, and Temerty-Tanz-TDRA for their seed funding, which enabled the inception of this work. We also thank Hilary and Galen Weston Foundation for generously funding the study.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

REB# 22-128 - A pilot study evaluating the feasibility, safety, and efficacy of the Vielight Neuro RX Gamma for the treatment of amnestic MCI REB APPROVAL: Original Approval Date February 09, 2023 Annual/Interval Review Date February 09, 2024 Thank you for your application submitted on May 30, 2022. At the Unity Health Toronto Research Ethics Board (REB) meeting held on June 29, 2022, the above referenced study was discussed and subsequently the views derived from this discussion have been documented and resolved. Please note that no member of the REB associated with this study was present or involved in its deliberation, review or approval. The REB approves the study as it is found to comply with relevant research ethics guidelines, as well as the Ontario Personal Health Information Protection Act (PHIPA), 2004. The REB hereby issues approval for the above named study for a period of 12 months from the date of this letter. Continuation beyond that date will require further review of REB approval.

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The data that support the findings of this study are available from the corresponding author upon reasonable request.