• A combination therapy consisting of nicotinamide riboside (NR), L-carnitine, N-acetylcysteine, and serine improves the cognition of Alzheimer’s patients. 
  • The combination therapy increases brain thickness and volume. 
  • Analysis shows the combo improves mitochondrial function. 

The assumption that Alzheimer’s disease (AD) is caused by proteins called amyloid and tau has led to clinical trial failures. Now scientists are beginning to accept that AD may be caused by common hallmarks of aging, such as dysfunctional mitochondria — our energy-producing structures within cells. Because the network of interactions surrounding mitochondrial energy production is complex, targeting multiple aspects of this intricate web of cellular processes has become popular amongst aging scientists. 

In a preprint article, not yet peer-reviewed but posted on Research Square, researchers from Alanya Alaaddin Keykubat Üniversitesi in Turkey and several European institutions report their findings from a successful AD clinical trial (NCT04044131). Yulug and colleagues show that a combination therapy improves the cognitive performance and brain size of AD patients. A detailed analysis of metabolites and proteins from these patients reveals that the therapy acts on mitochondria.  

Combo Therapy Improves Cognition and Brain Structure

Sixty patients (average age 70.8 years) with mild to moderate AD were placed into either a treatment or placebo group. The treatment group received what was deemed a combined metabolic activator (CMA). One dose of CMA contains 1 g nicotinamide riboside chloride, 3.73 g L-carnitine tartrate, 2.55 g N-acetylcysteine, and 12.35 g serine, all in powder form and dissolved in water. One dose was taken daily for 28 days and two doses were taken from 24 to 84 days. 

Cognition was assessed with the ADAS-Cog test. The ADAS-Cog score ranges from 0 to 70 with lower scores indicating improved cognitive function. The average score of normal older adults has been reported as 5. Yulug and colleagues found that the scores of CMA-treated AD patients with more severe cognitive impairment (scores higher than 20) improved after 28 days (Visit 2) and improved further after 84 days (Visit 3). Overall, these findings indicate that CMA can improve the cognition of AD patients, especially patients with more severe cognitive impairments. 

(Yulug et al., 2022 | Research Square) CMA Improves Cognitive Function in Alzheimer’s Patients. In patients with severe cognitive impairments (ADAS-Cog score greater than 20), treatment with CMA improves cognitive function by Visit 2 (28 days, purple) and Visit 3 (84 days, red), as indicated by a lower ADAS-Cog score.

To determine the effect of CMA treatment on brain structure, Yulug and colleagues scanned the brains of participants using magnetic resonance imaging (MRI). Of the entire study cohort, 40 patients were compatible with the MRI scans. The scans showed that CMA-treated AD patients had increased brain cortical (outermost layer) thickness and hippocampus — essential for learning and memory — volume, suggesting a lack of neurodegeneration and possibly improved neurogenesis. 

(Yulug et al., 2022 | Research Square) CMA Improves Brain Structure in Alzheimer’s Patients. MRI brain scans of CMA-treated AD patients show increases in brain (cortical) thickness, represented by the colors yellow and red.

Yulug and colleagues further characterized the effects of CMA on AD patients by analyzing the metabolites and proteins in their blood. Using the power of computation, they found that much of the effects of CMA revolve around improving mitochondrial function, including fat breakdown (into energy). The analysis also suggests CMA reduces oxidative stress — damage caused to cellular components by reactive oxygen species, often exacerbated by dysfunctional mitochondria. Overall, CMA seems to treat AD by repairing mitochondria and reducing oxidative stress.

Treating Alzheimer’s with NAD+ Boosting Combo Therapies

Few studies have examined the effect of boosting NAD+ in AD patients. In the first study to do so, it was found that oral NADH (a form of NAD+) improved the cognition of AD patients. However, another study showed no improvements in cognition with NADH. Now, Yulug and colleagues show that CMA potentially improves cognition and brain size in AD patients. Thus, it is possible that NAD+ precursors combined with other compounds assure that AD can be treated.