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BackgroundMild cognitive impairment (MCI), a prodromal stage of Alzheimer's 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.ObjectiveWe hypothesized that tPBM in MCI would be safe, feasible, and associated with improvements in cognition, mitochondrial function, and default mode network (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 min 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 AEs occurred. Compared with sham, active tPBM produced greater improvement in global cognition (Mini-Mental State Examination; p = 0.03, d = 1.05) and episodic memory (California Verbal Learning Test-II long-delay recognition; p = 0.02, d = 1.09). Serum pyruvate and lactate increased with a reduced lactate-to-pyruvate (L/P) ratio (p = 0.007, d = -1.37). DMN FC increased (p = 0.014, d = 1.25), and plasma IL-6 declined (p = 0.02, r = -0.52).ConclusionsHome-based tPBM was safe, well tolerated, and feasible, with high adherence and mild AEs. Cognitive, metabolic, and network-level findings are consistent with 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.
Rashidi‐Ranjbar et al. (Wed,) studied this question.