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

INTRODUCTIONMild cognitive impairment (MCI), a prodromal stage of Alzheimers disease and related dementias (ADRD), represents a critical window for intervention. Although mitochondrial dysfunction is increasingly implicated in neurodegeneration, most therapies target downstream protein aggregation. Transcranial photobiomodulation (tPBM) delivers near-infrared light to enhance mitochondrial respiration. We hypothesized that tPBM in MCI would be safe, feasible, and associated with improvements in cognition, mitochondrial function, and default-modenetwork (DMN) functional connectivity (FC). METHODSWe conducted a single-blind, randomized, sham-controlled pilot trial (NCT05563298) in adults [≥]50 years with MCI. Twenty participants were randomized 1:1 to active or sham devices. Active devices delivered pulsed 810-nm light for 20 minutes per session; shams emitted light for 2 seconds. Stimulation targeted DMN hubs and the olfactory bulb. Participants self-administered treatment at home six days per week for six weeks. RESULTSAdherence was high (active 96.9%; sham 94.2%). Adverse events (Aes) were reported by 10 of 20 participants (4 active, 6 sham) No serious AE occurred. Compared with sham, active tPBM produced greater improvement in global cognition (MMSE; p=0.03) and episodic memory (CVLT-II long-delay recognition; p=0.02). Serum pyruvate and lactate increased with a reduced lactate-to-pyruvate ratio (p=0.007). DMN FC increased (p=0.014), and plasma IL-6 declined (p=0.02). DISCUSSIONHome-based tPBM was safe, tolerable, and feasible, with strong adherence and mild AEs. Cognitive, metabolic, and network-level findings suggest enhanced mitochondrial efficiency and anti-inflammatory effects. These results support larger, double-blind multicenter trials to evaluate tPBM as a mitochondria-targeted therapy in early ADRD.