Alzheimer's disease (AD) represents a significant challenge in healthcare due to its prevalence among the elderly and its substantial economic burden. Early diagnosis of AD is crucial, especially in the preclinical stage, before severe and irreversible symptoms manifest. Even that it is common to distinguish between healthy individuals and Alzheimer's disease patients in the mild cognitive impairment (MCI) stage of disease progression. Biomarker discovery based on metabolomics is essential for accurate diagnosis. Metabolomics plays a vital role in this process, as it can provide insights into the dynamic changes in metabolites in response to various stimuli and physiological conditions over time.
In the previous article (Metabolomics in Alzheimer's Disease: Pathogenesis and Sample Types), we summarized which samples are suitable for metabolome testing in Alzheimer's disease studies. In this paper, we will continue to explore the metabolic pathways associated with Alzheimer's disease.
Studies have revealed several notable findings related to energy metabolism in AD:
- AD patients often exhibit decreased glucose metabolism in the brain.
- Energy metabolism disturbances are linked to insulin resistance and reduced brain insulin expression in AD.
- Increased sorbitol levels suggest activation of the glucose-sorbitol pathway in AD.
- 3-hydroxybutyric acid, a ketone body, is consistently reduced in the urine of AD patients, indicating alterations in energy metabolism.
In AD patients, a reduction in arginine expression is observed in both cerebrospinal fluid (CSF) and plasma. This reduction suggests that arginase expression may be increased, potentially due to its interaction with nitric oxide (NO) synthase. Nitric oxide plays a crucial role in maintaining brain function, regulating cerebral blood flow, and acting as a neurotransmitter. If arginase expression remains unchanged, the decline in arginine levels could also be attributed to the metabolism of arginine into guanidine compounds. Many known guanidine compounds are neurotoxic and can contribute to increased oxidative stress reactions.
Additionally, three essential amino acids known as branched-chain amino acids (BCAAs) - isoleucine, leucine, and valine - show reduced expression in AD patients compared to control groups. This decrease in BCAA concentration may lead to decreased glutamate production, resulting in the loss of glutamate neurons in the brain. Moreover, the high concentration of valine in AD patients may be associated with increased cell apoptosis, potentially reflecting the body's response to an elevated rate of cell apoptosis.
Furthermore, the abnormal accumulation of homocysteine in the blood is linked to a heightened risk of developing AD. Elevated homocysteine levels are associated with regional brain atrophy and vascular lesions, which may impact the phosphorylation of tau protein and the degradation of cholinesterase.
Early pathological events in the development of AD involve the loss of cholinergic neurons in the basal forebrain. Acetylcholine, a fundamental neurotransmitter, is integral to the activity of the cholinergic neuron system, which includes motor neurons and neurons crucial for memory.
The production of acetylcholine depends on choline acetyltransferase (ChAT), the activity of which is significantly reduced in the brains of Alzheimer's disease patients. This reduction in ChAT activity is correlated with the severity of cognitive impairment. In AD patients, the concentration of choline increases, possibly due to decreased ChAT activity. While there are currently no drug treatments capable of reversing the progression of Alzheimer's disease, cholinesterase inhibitors are commonly used to temporarily improve some cognitive symptoms in affected individuals.
Several metabolites related to carnitine exhibit significant alterations, indicating disruptions in fatty acid metabolism in AD patients. Medium-chain acylcarnitine levels are notably reduced in the plasma of AD patients and are highly correlated with cognitive performance, as measured by the Mini-Mental State Examination (MMSE) score. Additionally, studies have revealed a decrease in arachidonic acid and an increase in its precursor, linoleic acid, in the plasma of AD patients. Both arachidonic acid and linoleic acid have been shown to induce the aggregation of tau and amyloid-beta (Aβ) proteins, suggesting their potential association with and possible induction of certain pathological changes in AD.
These findings underscore the intricate interplay between metabolic processes and AD, offering insights into potential pathways for future research and therapeutic interventions. At Metware lab in Boston, we offer comprehensive services in TM Widely-Targeted Metabolomics, Energy Metabolism, Amino Acid, and Fatty Acid metabolomics. Reach out to us to unlock new discoveries!
Reference: Mill J, Li L. Recent Advances in Understanding of Alzheimer's Disease Progression through Mass Spectrometry-Based Metabolomics. Phenomics. 2022 Feb; 2(1):1-17. doi: 10.1007/s43657-021-00036-9. Epub 2022 Feb 22. PMID: 35656096;