Alzheimer Disease
Conditions
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.
Interventions
DIETARY_SUPPLEMENTGlycine
The active arm will supplement a combination of glycine and N-acetylcysteine (GlyNAC)
DIETARY_SUPPLEMENTN-acetylcysteine
The active arm will supplement a combination of glycine and N-acetylcysteine (GlyNAC)
DIETARY_SUPPLEMENTAlanine
The placebo arm will supplement Alanine
Sponsors
The Methodist Hospital Research Institute
Baylor College of Medicine
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
TRIPLE (Subject, Caregiver, Investigator)
Intervention model description
Placebo-controlled trial
Eligibility
Sex/Gender
ALL
Age
55 Years to 85 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cognition | Day 0 of supplementation, and 12-weeks and 24-weeks after starting supplementation | Measured using ADAS-Cog testing |
| Brain glucose uptake | Done before supplementation and 24-weeks after starting supplementation | Measured using brain FDG-PET scan |
| Brain inflammation | Done before supplementation and 24-weeks after starting supplementation | Done using brain TSPO-PET scan |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| Inflammatory cytokines | Day 0 of supplementation, 12-weeks and 24-weeks after starting supplementation | Measured as plasma concentrations of IL6, TNFa |
| Activities of daily living | Day 0 of supplementation, 12-weeks and 24-weeks after starting supplementation | Measured using the ADCS-ADL scale |
| 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 |
| Mitochondrial energetics | Day 0 of supplementation, 12-weeks and 24-weeks after starting supplementation | Measured using the Oroboros high-resolution respirometer |
| Endothelial dysfunction | Day 0 of supplementation, 12-weeks and 24-weeks after starting supplementation | Measured as plasma concentrations of sICAM1, sVCAM1, E-selectin |
| 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 |
| Red-blood cell glutathione, glycine, cysteine and glutamic aid | Day 0 of supplementation, 12-weeks and 24-weeks after starting supplementation | Measured using UPLC |
Countries
United States
Contacts
Primary ContactRajagopal V Sekhar, M.D.
Outcome results
None listed