LC–MS Reveals Metabolic Shifts in Alzheimer's Disease

Alzheimer's disease (AD) often comes with tangled problems in how the body processes energy and nutrients. Some studies suggest that combining the brain stimulation technique repetitive transcranial magnetic stimulation (rTMS) with mental exercises (cognitive training) can help ease Alzheimer's symptoms—but scientists still are not sure exactly why or how this combination works. Researchers at China's Nanjing Medical University wanted to see how combining brain stimulation (targeting both sides of the cerebellum) with mental exercises affects the mix of small molecules in the blood of Alzheimer's patients. Their goal was to find clues—biomarkers—that could help track how the disease is progressing and whether the treatment is working, and to check their findings against previous research on the topic. The team used ultrahigh-performance liquid chromatography–tandem mass spectrometry (UHPLC–MS/MS) to analyze blood samples—taken from Alzheimer's patients both before and after treatment, as well as from healthy controls—to measure the levels of various substances in the blood. A paper based on their efforts was published in the journal Frontiers in Neurology.¹

Why is rTMS Being Explored as an Alzheimer's Treatment, and Why Do We Still Not Fully Understand How It Works to Improve Cognition?

Current Alzheimer's treatment mainly comes down to medication, along with lifestyle changes and general care aimed at managing symptoms. But the drugs available today only help so much, and some come with safety concerns that are still debated. That's why finding new treatment approaches is so important as the toll of Alzheimer's continues to grow. One promising option is rTMS, a non-invasive technique that uses magnetic pulses to influence how brain cells fire and communicate with each other. It works by affecting the electrical signals nerve cells use to activate and pass messages along. rTMS is already used in clinics today to treat a range of brain-related conditions.²

There are several different approaches to using rTMS for treating Alzheimer's. Early treatment attempts mainly focused on stimulating the front part of the brain (the prefrontal cortex), though some also targeted areas toward the back and sides of the brain (the occipital and parietal lobes). However, stimulating just one of these areas on its own has not done much to improve thinking and memory in Alzheimer's patients.^3-5There is some evidence that rTMS might help the brain clear out amyloid-beta (Aβ)—the sticky protein buildup linked to Alzheimer's—by improving the brain's natural drainage or waste-clearance system. Earlier research also suggests that the body's overall metabolism and the brain and nervous system constantly influence each other in complex, two-way ways. Still, exactly how this treatment approach boosts thinking and memory on a chemical level remains a mystery.²

What Blood Chemistry Changes Did the Treatment Produce, and What Do They Reveal About Tracking Alzheimer's?

The study included 12 people with early-stage Alzheimer's and 12 healthy people for comparison. Those with Alzheimer's underwent two weeks of a combined treatment: brain stimulation targeting both sides of the cerebellum, plus mental exercise training. The researchers then used a sensitive lab technique to measure substances in blood samples—taken from the Alzheimer's group before and after treatment, and from the healthy group as a baseline. They also combed through past research on PubMed to see how Alzheimer's affects the body's chemistry and used that information to spot patterns in which biological processes were involved.¹

In total, 510 substances in the blood changed after treatment, and 202 of these changes lined up with patients feeling or doing better clinically. Fourteen biological processes were affected, including ones related to certain amino acids (building blocks of protein) that have already been tied to Alzheimer's in earlier research. Two substances—the fat molecule lysophosphatidylcholine (22:6) and citric acid—increased after treatment and moved closer to levels seen in healthy people. Meanwhile, two other substances, γ-guanidinobutyric acid and proline, decreased. On top of that, the review of past studies pointed to phenylalanine (an amino acid) as a promising early warning sign that could help detect Alzheimer's at the mild cognitive impairment stage, before it progresses further.¹

“This study's integrative analysis,” write the authors of the paper,¹ “offers preliminary insights into treatment-associated metabolic alterations in AD and identifies candidate metabolites for further investigation as markers of disease status and treatment response.”

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References

1. Chen, Y.; Shi, J. Serum Metabolomic Profiling Following Cerebellar Repetitive Transcranial Magnetic Stimulation Combined with Cognitive Training on Alzheimer's Disease. Front Neurol. 2026, 17, 1887127. DOI: 10.3389/fneur.2026.1887127
2. Lista, S.; González-Domínguez, R.; López-Ortiz, S. et al. Integrative Metabolomics Science in Alzheimer's Disease: Relevance and Future Perspectives. Ageing Res Rev. 2023, 89, 101987. DOI: 10.1016/j.arr.2023.101987
3. Yan, Y.; Tian, M.; Wang, T. et al. Transcranial Magnetic Stimulation Effects on Cognitive Enhancement in Mild Cognitive Impairment and Alzheimer's Disease: A Systematic Review and Meta-analysis. Front Neurol. 2023, 14, 1209205. DOI: 10.3389/fneur.2023.1209205
4. Koch, G.; Casula, E. P.; Bonnì, S. et al. Precuneus Magnetic Stimulation for Alzheimer's Disease: A Randomized, Sham-controlled Trial. Brain 2022, 145 (11), 3776-3786. DOI: 10.1093/brain/awac285
5. Wang, J.; Zhou, C.; Huang, Z. et al. Repetitive Transcranial Magnetic Stimulation-Mediated Neuroprotection in the 5xFAD Mouse Model of Alzheimer's Disease Through GABRG2 and SNAP25 Modulation. Mol Neurobiol. 2025, 62 (2), 1971-1997. DOI: 10.1007/s12035-024-04354-7