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.