Glutathione, Brain Metabolism and Inflammation in Alzheimer's Disease

Study Overview
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Brief Summary
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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
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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.

Official Title
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Glutathione, Brain Metabolism and Inflammation in Alzheimer's Disease

Conditions
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Alzheimer Disease

Intervention / Treatment
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* Dietary Supplement: Glycine
* Dietary Supplement: N-acetylcysteine
* Dietary Supplement: Alanine


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 55 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Placebo-controlled trial
Masking: Triple


Arms and Interventions

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

What is the study measuring?
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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 |