Revitalizing Cognition in Older Adults at Risk for Alzheimer's Disease with Near-Infrared Photobiomodulation

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ABSTRACT There is a great need for effective treatments and prevention therapies that can provide symptomatic and disease modifying benefits for those at risk for Alzheimer’s disease. The proposed multi-site collaborative project brings together research teams at the University of Florida (UF) and University of Arizona (UA) to test a novel, relatively low cost, low risk, and potentially high impact therapeutic intervention in older adults who are at increased risk for Alzheimer’s disease. The intervention involves transcranial and intranasal delivery of near infrared (NIR) light via light emitting diodes, aka photobiomodulation. Prior research in cellular and animal models suggest that red and infrared light are neuroprotective and thought to improve mitochondrial function by promoting increased production of intracellular ATP. Transgenic mouse models of Alzheimer’s disease demonstrate reduced beta-amyloid and neurofibrillary tangles in response to transcranial NIR versus sham stimulation. Preliminary human studies have also shown promising behavioral findings in young adults and those with TBI, aphasia, and Alzheimer’s disease. From our team, pilot phosphorous magnetic resonance spectroscopy (31P MRS) and cognitive data in older adults support this mechanism of action and provide compelling evidence for a Phase II clinical trial. To more fully determine whether this novel stimulation approach has potential for enhancing cognition in cognitively normal but “at risk” individuals for Alzheimer’s disease, we plan to conduct a multi-site double blinded randomized sham-controlled Phase II clinical trial. Our overall hypothesis is that exposure to NIR stimulation will have beneficial effects on brain health via influence on mitochondrial function as measured by changes in 31P MRS-based markers of ATP, neural network changes in functional connectivity (rs-fMRI), and improved cognitive performance. To test this hypothesis, we plan to randomize 168 older adults with subjective cognitive complaints, and a first-degree family history of Alzheimer’s disease to sham or real treatment groups and evaluate neuroimaging and cognitive outcome measures, before and after a 12-week intervention involving transcranial and intranasal NIR-PBM. The protocol will involve “lab” and “home” sessions, and a 3 month post-intervention follow-up. This trial will determine: 1) whether NIR stimulation, relative to sham, improves performance on memory and executive tasks sensitive to hippocampal and frontal brain function in older adults with increased risk for Alzheimer’s disease; 2) whether NIR stimulation, relative to sham, enhances brain function and connectivity measured by changes in MRS phosphorous ATP and resting state functional connectivity; and 3) how differences in demographic, neuroimaging, and Alzheimer-related risk factors influence the brain response to NIR stimulation versus sham in older adults with increased risk for Alzheimer’s disease. Results will provide key insights into whether this novel NIR intervention can enhance cognition in older adults with increased risk for Alzheimer’s disease and will provide the necessary data for a future Phase III randomized clinical trial.