The Revitalize Study in Older Adults at Risk for Alzheimer's Disease

This multi-site randomized sham-controlled trial proposes to test a novel, non-invasive, low risk and low-cost brain stimulation approach for enhancing cognition and brain health in cognitively normal older adults who are at increased risk for Alzheimer's disease. The intervention involves transcranial and intranasal delivery of near-infrared light (NIR; 808-904 nm) via light emitting diodes placed on the scalp or intranasally using a dosing that resulted in positive effects in our pilot studies. We plan to test the hypothesis that targeted NIR stimulation will have positive effects on brain health via influence on mitochondrial function as measured by changes in Magnetic Resonance Spectroscopy (MRS)-based markers of adenosine triphosphate (ATP), neural network changes as indexed by changes in functional connectivity based on resting state-fMRI (rs-fMRI), and improved cognitive performance. We plan to randomize 168 older adults, ages 65-89 years, to Active or Sham intervention conditions. To be included, participants must have subjective cognitive complaints, based on an index of Subjective Cognitive Impairment (SCI), and a family history of Alzheimer's disease in a first degree relative. Performance on standardized neuropsychological measures must be unimpaired psychometrically. The intervention itself will last for 12 weeks and include lab sessions (16 total) and daily at home sessions. In the lab, both transcranial and intranasal delivery of NIR light will be delivered using Medx and Vielight stimulation technologies, whereas the daily at home sessions will involve intranasal stimulation only. The sham and active conditions are identical in all respects except that sham devices will not deliver NIR stimulation. The primary outcome is an episodic memory measure involving spatial navigation that is linked to hippocampal function, sensitive to mild cognitive impairment (MCI) and Alzheimer's disease, and an analogue to the Morris Water maze. Secondary outcomes include executive function tasks and neuroimaging indicators of ATP function (31-P MRS) and connectivity changes based on resting state-fMRI. Exploratory outcomes include 'traditional' neuropsychological measures that are used clinically, along with measures and indices (e.g., apolipoprotein E \[APOE-4\] status) that might potentially mediate or moderate study outcome. Assessments will occur at baseline (Month 1), after 12 weeks of intervention (Month 4), and 3-month post intervention (Month 7). Imaging outcomes will be assessed only at baseline and at Month 4. Our primary aim is focused on cognition and will test whether NIR intervention, relative to sham, will produce pre-post improvement on tasks of recent memory (primary outcome) and executive function in older adults who are at increased risk for Alzheimer's disease. Our secondary aim is focused on neuroimaging and will test whether NIR intervention, relative to sham, will increase functional connectivity as indexed by resting state fMRI (secondary outcome) and enhance brain markers of MRS-ATP (secondary outcome). The 3rd aim is exploratory and will evaluate how baseline demographic, genetic, neuroimaging and other factors influence individual differences in cognitive outcome for NIR intervention.