A recent phase II clinical trial showed significant improvements in cognitive scale scores for Alzheimer’s patients.
Importantly, these are natural supplements that are readily available. Plus, it is rare to see a clinical trial with positive results in Alzheimer’s after just 3 months!
I’m going to break down what was used in the clinical trial as well as dig into the background science of why these supplements hold such promise.
Combined Metabolic Activators for Alzheimer’s
The placebo-controlled randomized clinical trial included 69 participants, with 47 in the active group and 22 receiving a placebo pill.
The study did baseline cognitive testing and then repeated the testing on day 28 and day 84.
The results showed significant improvements in the AD Assessment Scale-cognitive subscale (ADAS-Cog test) on day 84 compared to baseline in the active group.
There seems to be more improvement in patients with more significant cognitive dysfunction. The researchers further broke down the Alzheimer’s patients into subgroups based on the severity of their cognitive symptoms. In the supplement group and placebo group with higher ADAS-Cog test scores, the supplement group had a significant improvement in scores compared to the placebo. This was backed by MRI images showing changes in the brain.
What are combined metabolic activators?
The researchers chose to test a combination of compounds that are known to reduce oxidative stress and improve cellular energy in the brain. [ref]
Specifically, the combined metabolic activators included L-serine, nicotinamide riboside, N-acetyl-L-cysteine, and L-carnitine tartrate.
All of these are compounds that naturally occur in the body, and most of them decrease with age.
The dosing here is likely important (and likely will be further optimized with future clinical trials).
The CMA supplement contained:
- 12.35 g L-serine
- 1 g nicotinamide riboside
- 2.55 g N-acetyl-L-cysteine
- 3.73 g L-carnitine tartrate
Participants took the supplement once a day for the first 28 days and then twice a day for the next two months.
All of the individual supplements are available over the counter — and I’ll break down where to get them and the cost later in this article.
The first thing that struck me was that the doses were higher than normally taken for these supplements. For example, nicotinamide riboside usually comes in 300 mg doses. While 1g doses have been safely used in several clinical trials, it is higher than is normally found in the supplement.
However, the higher dose of n-acetylcysteine (NAC) is in line with some of the longevity studies on NAC.
Targeting multiple pathways in the brain
Each of these components individually has been looked at for neurodegenerative diseases and aging.
L-serine: brain energy, glycolytic pathway, plasticity
Serine is an amino acid that the body uses to create proteins. It is not considered an ‘essential amino acid’ to get from foods because the body can make it. Glycine can be converted into l-serine, and serine can be converted into glycine. Vitamin B6 is an essential cofactor in the reactions.
A number of studies have looked at the link between low serine and Alzheimer’s disease:
Serine was identified as a possible key compound for Alzheimer’s prevention through studies that looked at neurodegenerative diseases in Pacific Islanders. In the 1950s, US Army doctors found a puzzling neurodegenerative disease among Pacific islanders who ate animals that had consumed cycad seeds high in a neurotoxin, BMAA. More recently, l-serine was identified as a key factor in why this neurodegeneration occurred. [ref]
In 2020, researchers published a mouse study that elucidated the reason that L-serine could be so important in Alzheimer’s. First, the glycolytic pathway is impaired in the Alzheimer’s brain. Not only is this going to affect energy in the brain, but it also is going to impact serine biosynthesis. Second, serine is a co-agonist for NMDA receptors, which is important in synaptic plasticity. Importantly, the mouse study showed that supplementing with l-serine could prevent Alzheimer’s behaviors and deficits. [ref]
Other studies also explain how l-serine is formed exclusively in glial cells, which are the brain cells that support neurons. In patients with Alzheimer’s disease, serine metabolism is significantly altered in the brain. Moreover, restoring serine levels may prevent damage from altered brain energy in aging.[ref]
Nicotinamide riboside: mitochondrial energy production
Nicotinamide riboside (NR) is a form of vitamin B3 that can directly impact NAD+ levels. NAD+ is essential for cellular energy production in the mitochondria, and levels of NAD+ decrease as we age.
In addition to ATP production, NAD+ is also pivotal for DNA repair and mitochondrial health. Research shows that NAD+ levels are reduced in the brains of animal models of Alzheimer’s. Importantly, restoring NAD+ levels reduces neuroinflammation.[ref]
A pilot study in people with mild cognitive impairment showed that 10 weeks of nicotinamide riboside (NR) at 1g/day was safe and associated with positive functional changes in the brain and frailty measures. However, cognitive test results weren’t significantly different in the MCI group at 10 weeks. [ref]
N-acetylcysteine (NAC): reducing oxidative stress in the brain
N-acetylcysteine (NAC) is a precursor of l-cysteine. It is widely used as a supplement and in mucolytic therapy (e.g. mucus thinner in COPD). The cysteine in NAC can be used by cells to create glutathione, which is an intracellular antioxidant. In the brain, NAC may be able to combat neuronal damage due to oxidative stress. Additionally, NAC modulates glutamate, which is an excitotoxic neurotransmitter.
Oxidative stress in the brain is linked to increased amyloid-beta secretion and lipid peroxidation. In animal studies, NAC supplementation increases glutathione in the brain. This improved learning and memory in mouse Alzheimer’s studies. In Alzheimer’s brain culture studies, NAC has been shown to be protective against amyloid-beta and against cell death in the neurons.[ref]
L-carnitine: brain energy
Carnitine helps support mitochondrial energy by transporting long-chain fatty acids into the mitochondria.
Animal models of dementia show that high homocysteine levels can cause excitotoxicity in the neurons. Supplemental l-carnitine decreased homocysteine and reduced the homocysteine-induced Alzheimer’s symptoms in the animals.[ref]
Circling back to the altered cell metabolism and glycolytic pathway in Alzheimer’s, l-carnitine has been shown to mitigate cell damage caused by glycolysis-inhibiting drugs. [ref]
A 2023 study found that low l-carnitine levels were found in Alzheimer’s patients and in early Alzheimer’s progression.[ref]
The clinical trial using l-serine, NR, NAC, and l-carnitine approaches the pathology of Alzheimer’s from multiple angles. Studies in animals show that all of these supplements could be helpful, but none of them alone seems to be the magic bullet in humans.
All of the ‘ingredients’ for the clinical trial are available over the counter in the US and most countries.
Does this mean that we should all rush out and take high doses of these supplements? Not necessarily. The biggest improvement was seen in people with more severe Alzheimer’s symptoms, and there is no clear research showing that we can prevent Alzheimer’s with these supplements.
As with any supplement, talk with your doctor if you have questions. Specifically, if you are on medications, talk with your doctor or pharmacist about interactions with supplements. Additionally, you can check for drug interactions here.
L-serine can be found as a powder or in capsules. Most l-serine capsule options contain 500 mg.
It is less expensive to get l-serine as a bulk powder, and it doesn’t have a terrible taste. You could easily dissolve it into a drink or smoothie.
There are lots of brand options for NAC in capsules. NAC is less expensive as bulk powder, but there is a sulfur-like aftertaste that I find hard to hide in a drink or food. Everyone is different in how they taste things, so you may not find it as offensive as I do.
L-carnitine is the least expensive of the four supplements in the Alzheimer’s study. In capsules, you’ll usually find 500 mg/capsule with a recommended serving of two capsules. Again, l-carnitine tartrate is less expensive as a bulk powder. It doesn’t have a lot of taste to it, so you could put it into a drink or smoothie. You do need to keep it dry so that it doesn’t absorb moisture out of the air.
I would love to see further clinical trials on this combination of supplements for Alzheimer’s.
While I doubt that any single pill is going to cure Alzheimer’s, I’m hopeful that the combination of lifestyle (exercise, social interactions) and brain energy-targeting supplements will bring help to those who need it now.