Glutathione, Brain Metabolism and Inflammation in Alzheimer's Disease

Alzheimer's disease (AD) is associated with significant, progressive cognitive decline. Key defects in mitochondrial fuel metabolism insulin resistance, inflammation and decreased brain glucose uptake are linked to AD. This trial will investigate the effects of supplementing glycine and N-acetylcysteine vs. alanine as placebo on these defects in AD, and examine the effects on cognition.

Glutathione (GSH) deficiency, oxidative stress, mitochondrial dysfunction, insulin resistance and inflammation are linked to Alzheimer's disease (AD). In prior studies, investigators have shown that GSH deficiency contributes to mitochondrial impairment and oxidative stress, and that GSH deficiency can be corrected by supplementing its precursors glycine and cysteine (provided as N-acetylcysteine, NAC), with the combination termed GlyNAC. This randomized clinical trial will evaluate the effect of GlyNAC vs. alanine placebo supplementation provided for 24-weeks to patients with AD, and measure changes in cognition, GSH concentrations, oxidative stress, brain glucose uptake, brain inflammation and insulin resistance. Participants who are positive for a beta-amyloid PET scan and meeting cognitive screening criteria will be recruited, and enrolled only after meeting eligibility criteria. Before beginning study supplementation they will undergo imaging studies (MRI, FDG-PET and TSPO-PET scans), and only the FDG- and TSPO-PET scans will be repeated after completing 24-weeks of nutrient supplementation. Cognitive measurements, metabolic and mitochondrial measurements (as described below) will be done before supplementation, and after 12-weeks and 24-weeks of completing supplementation.

Glycine and cysteine are amino-acid (protein) precursors of glutathione. Cysteine is provided as N-acetylcysteine

Inclusion Criteria: Age 55-85 years; Gradual and progressive memory loss for more than 1 year, with a Montreal Cognitive Assessment score of 10-20; Tau positivity on PET scan; Availability of a study partner. Exclusion Criteria: hospitalization in past 3 months; known diabetes or use of anti-diabetic medications; untreated thyroid disease; creatinine levels >1.5 mg/dL; hemoglobin concentration <11.0 g/dL; known liver disease, or AST/ALT level >2x ULN; history of stroke, brain tumor, active heart failure or active cancer (removable basal cell cancers will not be an exclusion criteria); untreated depression or other severe psychiatric disorders; pregnancy or nursing (unlikely in this population)