A Multimodal Evaluation of Transcranial Photobiomodulation in Mild Cognitive Impairment: Cognitive, Metabolic, and Neuroimaging Outcomes of a Pilot Randomized Control Trial

Abstract

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 over 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; four 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 (MMSE), and in episodic memory, as measured by the delayed recognition test of the California Verbal Learning Test-Second Edition (CVLT-II). 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.