Whilst lower levels of BCAAs proved significant in increasing risk of AD development, there was no established relationship with total levels of BCAAs and AD risk.
“This bidirectional MR study indicates that AD is associated with decreased BCAA levels, which can serve as a marker for early diagnosis of AD,” the Chinese researchers highlight.
They add: “Therefore, the supplementation of BCAAs may be one of the strategies to delay cognitive decline in AD patients.”
Alzheimer’s and amino acids
It has been estimated that those suffering with AD are expected to triple by 2050, with current figures suggesting more than 50 million people globally are suffering from the condition. Being the most common form of dementia, the disease is characterised by extracellular amyloid- β (Aβ) plaques as well as neurofibrillary tangles. Despite this, its pathogenesis remains unclear, with a lack of treatment options.
The importance of alterations in the production of metabolites, such as amino acids and nucleic acids, has been previously reported. This has highlighted their potential role in the development of AD, with the disruption of metabolic pathways resulting from the interaction of genetic, environmental, and behavioural factors.
Specifically, studies have noted the involvement of altered BCAA metabolism in AD development. Such BCAAs, including the essential dietary types of leucine (Leu), isoleucine (Ile), and valine (Val), play critical roles in various metabolic pathways as well as protein synthesis. Yet, the results remain controversial across studies due to the significant influence of confounders.
Therefore, the researchers conducted the bidirectional Mendelian randomised study, a methodology able to assess risk factors against outcomes using genetic variants, to investigate the potential relationship between BCAA level and AD risk.
Study findings
The study utilised genetic data available from the genome-wide association study (GWAS) of BCAAs and Alzheimer’s disease. Total BCAAs were obtained from the UK biobank with 115,047 participants, valine from 115,048, leucine from 115,074, and isoleucine from 115,075. 21,982 patients with AD and 41,944 controls were obtained from the International Genomics of Alzheimer’s Project.
Analysis to establish a causal effect included the inverse variance-weighted (IVW) method, MR-Egger, and weighted median, accompanied by multiple pluripotency and heterogeneity tests.
Following this, it was determined that there was no causal effect of total BCAA levels on AD risk.
However, the reverse analysis showed a significant association between AD and reduced levels of BCAAs.
Scientific significance
“The results do not show evidence that BCAA levels are causally related to the risk of AD. Conversely, the reverse MR analysis suggests that AD is significantly associated with decreased BCAA levels, suggesting that AD is the cause but not the result of changed BCAA levels,” the report emphasises.
The researchers highlight the significance of the results with regards to the importance of BCAAs in the mammalian brain, including neurotransmitter synthesis, energy production and protein synthesis roles.
The report hypothesises the reasons behind these reduced BCAA levels: “First, changes in gastrointestinal function have been observed in the AD mice model. This may lead to reduced absorption of BCAAs from the diet in AD. Second, AD or MCI patients usually experience subclinical malnutrition. This resulted in reduced protein reserve and proteolysis levels in AD. Third, a series of studies in recent years have demonstrated the imbalance of gut microbiota in AD. This may lead to changes in the abundance of gut microbiota related to BCAAs metabolism and ultimately reduce the level of circulating BCAAs.”
Whilst the study provides strong evidence to suggest a causal relationship between BCAAs and AD, controlling for confounders whilst using large valid datasets, the scientists call for further study to establish the specific mechanism.
Source: Frontiers In Nutrition
https://doi.org/10.3389/fnut.2023.1103303
“Investigating the causal association between branched-chain amino acids and Alzheimer's disease: A bidirectional Mendelian randomized study”
Xiao-hang Qian, Xiao-li Liu4, Bin Zhang, Yuan Lin, Jian-hua Xu, Gang-yu Ding and Hui-dong Tang