Glutathione, Brain Metabolism and Inflammation in Alzheimer's Disease

Early Phase 1

Recruiting

• Conditions: Alzheimer Disease

• Registration Number: NCT04740580
• Lead Sponsor: Baylor College of Medicine

Brief Summary

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.

Detailed Description

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.

Study Timeline

• Study First Submitted: 2021-02-02
• Study First Submitted QC: 2021-02-02
• Study First Posted: 2021-02-05
• Study Start: 2022-02-15
• Status Verified: 2025-06
• Last Update Submitted: 2025-06-09
• Last Update Posted: 2025-06-10
• Primary Completion: 2026-04-30
• Study Completion: 2026-12-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 52

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;
• Amyloid positivity on PET scan;
• Availability of a study partner.

Exclusion Criteria

• hospitalization in past 3 months;
• use of insulin 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)

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Primary Outcome Measures

Name	Time	Method
Brain glucose uptake	Done before supplementation and 24-weeks after starting supplementation	Measured using brain FDG-PET scan
Cognition	Day 0 of supplementation, and 12-weeks and 24-weeks after starting supplementation	Measured using ADAS-Cog testing
Brain inflammation	Done before supplementation and 24-weeks after starting supplementation	Done using brain TSPO-PET scan

Secondary Outcome Measures

Name	Time	Method
Mitochondrial energetics	Day 0 of supplementation, 12-weeks and 24-weeks after starting supplementation	Measured using the Oroboros high-resolution respirometer
Red-blood cell glutathione, glycine, cysteine and glutamic aid	Day 0 of supplementation, 12-weeks and 24-weeks after starting supplementation	Measured using UPLC
Plasma concentration of Brain-derived neurotropic factor (BDNF)	Day 0 of supplementation, 12-weeks and 24-weeks after starting supplementation	Measured using an ELISA kit
Activities of daily living	Day 0 of supplementation, 12-weeks and 24-weeks after starting supplementation	Measured using the ADCS-ADL scale
Mitochondrial fuel oxidation	Day 0 of supplementation, 12-weeks and 24-weeks after starting supplementation	Measured using indirect calorimetry in the fasted and post-glucose fed state
Inflammatory cytokines	Day 0 of supplementation, 12-weeks and 24-weeks after starting supplementation	Measured as plasma concentrations of IL6, TNFa
Endothelial dysfunction	Day 0 of supplementation, 12-weeks and 24-weeks after starting supplementation	Measured as plasma concentrations of sICAM1, sVCAM1, E-selectin
Oxidative stress	Day 0 of supplementation, 12-weeks and 24-weeks after starting supplementation	Measured as plasma concentrations of TBARS and malondialdehyde
Damage due to oxidative stress	Day 0 of supplementation, 12-weeks and 24-weeks after starting supplementation	Measured as plasma concentration of isoprostanes

Trial Locations

Locations (1)

Baylor College of Medicine; 🇺🇸 Houston, Texas, United States