Brain & Neurons

Study Shows Metabolic Activator Mix Reverses Cognitive Decline in Alzheimer’s Patients

Treatment with serine, N-acetyl-cysteine, carnitine tartrate, and an NAD+ booster enhanced cognitive functions in Alzheimer’s patients with severe cognitive defects.

By Noemi Canditi

Key Takeaways:

  • Treatment with a combination of metabolic activators has a positive impact on cognitive abilities and metabolic abnormality markers, particularly in patients with advanced Alzheimer’s disease.
  • The improvements in cognitive function were associated with distinct changes in brain volume and thickness, but the findings were not statistically significant.

A class of metabolic activators improves critical cognitive function in Alzheimer’s patients, at least in those who are severely affected, according to a Phase II clinical study. Led by Istanbul Medipol University Hospital, the study claims that the combination of L-serine, N-acetyl cysteine (NAC), nicotinamide riboside (NR), and L-carnitine tartrate made the hippocampus, which is in charge of learning and memory, and the cortex, which is in charge of thinking, grow bigger. The results were published in Translational Neuroscience.

Alzheimer’s and Abnormal Metabolism

An abnormal accumulation of the toxic proteins tau and amyloid-beta is what causes Alzheimer’s disease. This results in problems with the health and communication of brain cells (neurons), a loss of connections between brain cells (synapses), and a loss of mental abilities. Approaches that target amyloid-beta or tau have not been shown to improve cognitive function in human clinical trials, despite the fact that it is still frequently believed that the accumulation of toxic proteins causes cognitive problems in Alzheimer’s.

Several studies with healthy people show that there is a strong link between metabolism and cognitive ability. This is especially true for higher-order cognitive tasks, which are the most metabolically demanding for the brain. “Brain burnout” would make the brain more susceptible to neurodegenerative and age-related changes that are marked by neuronal metabolic dysfunction.

So, it has been suggested that a therapeutic strategy with a higher chance of successful translational results is to target multiple pathways to reduce cell stress and metabolic abnormalities and improve bioenergetics. Along these lines, research has shown that treating rats with Alzheimer’s disease with a mix of metabolic boosters (N-acetylcysteine, L-carnitine tartrate, nicotinamide riboside, and serine) improved their behavior and brain structure.

Metabolic Activators Mitigate Cognitive Decline In Severe Alzheimer’s Patients

This international, multi-center trial was led by Burak Yulug and his colleagues at the Alanya Alaaddin Keykubat University in Antalya, Turkey. It looked at the effects of adding N-acetylcysteine, L-carnitine tartrate, nicotinamide riboside, and serine to Alzheimer’s patients’ diets.

This research team looked for Alzheimer’s patients over the age of 50. At the end of the 84-day trial, 60 patients (40 who got the metabolic activator combo and 20 who got a placebo) had finished the study. 12.35 g L-serine (61.75%), 1 g nicotinamide riboside (5%), 2.55 g N-acetyl-L-cysteine (12.75%), and 3.73 g L-carnitine tartrate (18.65%) were included in one dose of the metabolic activator mix.

After 84 days, the cognitive functions of Alzheimer’s patients improved by 29% in the group that was given combined metabolic activators but only by 14% in the group that was given a placebo. The authors claim that this is consistent with a placebo effect that is seen in other Alzheimer’s clinical trials. More interestingly, the cognitive functions of patients who had more severe cognitive deficits (higher ADAS-Cog scores) at the start of the trial improved less in the group that was given combined metabolic activators than in the placebo group.

The use of a combination of metabolic activators enhances cognitive scores in Alzheimer's patients with severe cognitive impairments.
(Yulug et al., 2023 | Translational Neuroscience) A combination of metabolic activators improves cognition score in Alzheimer’s patients with severe cognitive defects. There was a significant decline (P = 0.0073) in Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS-Cog) scores, indicating an improvement of cognitive functions in the group treated with the combined metabolic activators (CMA) compared to the placebo group in patients with severe cognitive defects (higher ADAS-Cog scores). The subjects were tested on day 0 (visit 1), day 28 (visit 2), and day 84 (visit 3) of the trial.

By comparing the differences at the beginning and end of the study, the author’s claimed that their results showed several changes in the brain that support improved cognition. For example, they claimed that the average volume of the brain region involved with learning and memory (hippocampus) was maintained after the combined metabolic activators (CMA) treatment, and that this region was reduced in the placebo group.

The Takehome Message

It’s important to note that there were no differences in the effect of the combined metabolic activators compared to the control when either all of the Alzheimer’s patients were analyzed or only those who had mild cognitive defects at the start of the trial. 

Furthermore, Almost none of the study’s major claims were statistically significant—meaning that the likelihood of their occurrence could have just been “by chance.” To this end, the authors conclude their paper by stating, “Our results should be interpreted with caution until being confirmed by a randomized, double-blinded and placebo-controlled phase 3 clinical trial.”

Model & Dosage

Model: Human patients older than 50 years with mild to moderate Alzheimer’s

Dosage: 12.35 g L-serine (61.75%), 1 g nicotinamide riboside (5%), 2.55 g N-acetyl-L-cysteine (12.75%), and 3.73 g L-carnitine tartrate (18.65%) daily for 84 days.


Yulug B, Altay O, Li X, Hanoglu L, Cankaya S, Lam S, Velioglu HA, Yang H, Coskun E, Idil E, Nogaylar R, Ozsimsek A, Bayram C, Bolat I, Oner S, Tozlu OO, Arslan ME, Hacimuftuoglu A, Yildirim S, Arif M, Shoaie S, Zhang C, Nielsen J, Turkez H, Borén J, Uhlén M, Mardinoglu A. Combined metabolic activators improve cognitive functions in Alzheimer’s disease patients: a randomised, double-blinded, placebo-controlled phase-II trial. Transl Neurodegener. 2023 Jan 26;12(1):4. doi: 10.1186/s40035-023-00336-2. PMID: 36703196; PMCID: PMC9879258.

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