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.

Study Overview

• Status: Recruiting
• Conditions: Alzheimer Disease
• Intervention / Treatment: Dietary supplement: Glycine; Dietary supplement: N-acetylcysteine; Dietary supplement: Alanine

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 Type: Interventional
• Enrollment (Estimated): 52
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: Rajagopal V Sekhar, M.D.; Phone Number: 7137983908; Email: rsekhar@bcm.edu

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030
      • Recruiting
      • Baylor College of Medicine
      • Contact: Rajagopal V Sekhar, MD; Phone Number: 713-798-3908; Email: rsekhar@bcm.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 55 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Glycine plus N-acetylcysteine; Glycine and cysteine are amino-acid (protein) precursors of glutathione. Cysteine is provided as N-acetylcysteine	Dietary supplement: Glycine; The active arm will supplement a combination of glycine and N-acetylcysteine (GlyNAC); Dietary supplement: N-acetylcysteine; The active arm will supplement a combination of glycine and N-acetylcysteine (GlyNAC)
Placebo Comparator: Alanine; Alanine is an amino-acid (protein), and not a precursor of glutathione synthesis	Dietary supplement: Alanine; The placebo arm will supplement Alanine

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Baylor College of Medicine
• Collaborators: The Methodist Hospital Research Institute
• Investigators: Principal Investigator: Rajagopal V Sekhar, M.D., Baylor College of Medicine

Study record dates

Study Major Dates

• Study Start (Actual): February 15, 2022
• Primary Completion (Estimated): April 30, 2026
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: February 2, 2021
• First Submitted That Met QC Criteria: February 2, 2021
• First Posted (Actual): February 5, 2021

Study Record Updates

• Last Update Posted (Actual): June 10, 2025
• Last Update Submitted That Met QC Criteria: June 9, 2025
• Last Verified: June 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mental Disorders; Pathologic Processes; Neurocognitive Disorders; Dementia; Tauopathies; Neurodegenerative Diseases; Alzheimer Disease; Inflammation; Anti-Infective Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antiviral Agents; Neurotransmitter Agents; Antioxidants; Protective Agents; Expectorants; Respiratory System Agents; Free Radical Scavengers; Antidotes; Glycine Agents; Acetylcysteine; N-monoacetylcystine; Glycine
• Other Study ID Numbers: H48186

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No