PROJECT SUMMARY The prevalence of Alzheimer disease (AD) is projected to increase as the population ages, and current treatments are only minimally effective. Recently, emphasis has been placed on understanding and treating the factors that influence early brain pathology in order to slow the ultimate clinical expression of AD. Transcranial photobiomodulation (t-PBM) with near-infrared (NIR) light penetrates robustly into the cerebral cortex, stimulating the mitochondrial respiratory chain, and also significantly increases cerebral blood flow (CBF). Early data suggests t-PBM may be efficacious in improving cognitive deficits in early AD and in amnestic mild cognitive impairment (aMCI). This project aims to test, in a randomized controlled trial, the efficacy and safety of 24 sessions of t-PBM, delivered over 8 weeks and compared to sham, in improving clinical symptoms of aMCI. Additionally, we will explore the brain mechanisms of t-PBM in aMCI, by testing whether baseline tau burden (measured with 18F-MK6240), or changes in mitochondrial function measures over 8 weeks (measured by 31P-MRSI) moderate the changes observed in cognitive functions after t-PBM therapy. We will also use changes in fMRI blood-oxygenation-level dependent (BOLD) after a single treatment, to demonstrate t-PBM-dependent increases in prefrontal cortex (PFC) cortical blood flow (CBF). The study will be done in parallel at New York University, Nathan Kline Institute and at Massachusetts General Hospital. The importance of this study is threefold: (1) it targets aMCI, an important prodromal stage of AD, which lacks adequate approved treatments, (2) it evaluates the efficacy and safety of t-PBM, an innovative, non-invasive technology which has a well-established safety profile, for improving brain function and cognition at the prodromal AD stages, and, (3) explores the association of t-PBM treatment effects with important biomarkers relevant for AD illness progression. If effects are confirmed, the present study will both support short-term clinical development of an easy to scale device for the treatment of aMCI and AD, while also validating biomarkers for the development of future, novel modulation strategies.