| Abstract | Alzheimer's disease (AD) is a progressive neurodegenerative disease considered the most common cause of dementia, with 6.7 million Americans aged 65 and older living with AD, and this number is projected to grow to 12.7 million by 2050. Over 11 million Americans currently provide unpaid care to family or friends with dementia, valued at $340 billion. Manifestation symptoms of AD include a decline in cognitive, motor, behavioral, and, most notably, memory function, and the disease is biologically marked by the accumulation of extracellular amyloid- plaques and intracellular hyperphosphorylated tau proteins. It has been proposed that the gut microbiome, a community of commensal microorganisms living symbiotically in our bodies, contributes greatly to normal bodily function but can also contribute to AD progression under different circumstances. Recent studies suggest that trimethylamine, a metabolite produced by some members of this gut microbiome, can be converted to TMAO in the liver, where it moves into the bloodstream and has important roles in colorectal cancer, type 2 diabetes, cardiovascular diseases, and AD progression among many others. Much of the understanding of the roles that TMAO plays come from human observational studies or rodent experimental studies, with oxidative stress, blood-brain-barrier interactions, inflammation, and various other mechanisms not as well understood playing significant, overlapping roles in the development of many of these diseases. What is understood is that neuroinflammation appears to play a significant role in the progression of AD, with astrocytes having a lead role in the development of this inflammation. Recent studies have found TMAO crossing the BBB, with subsequent induction of astrocytes into their inflammatory state, contributing to neuroinflammation directly through these astrocytes. TMAO has also been found to play more indirect roles in AD development, with neuronal damage, oxidative stress, and increased inflammation being detected at heightened TMAO levels in mice, each contributing to cognitive impairment. Additionally, TMAO leads to insulin resistance (IR) via this chronic inflammation and oxidative stress, which is important as it has been determined that IR is heavily associated with AD, with AD even being labeled as type 3 diabetes. Overall, studies to date support a significant relationship between circulating TMAO in plasma and CSF and the progression and pathology of AD, among several other diseases. However, continued research into this relationship is necessary, particularly in human experimental studies, to resolve several limitations, such as TMAO precursors being beneficial to humans, which have been found in the literature. Following a better understanding of the action of TMAO, therapies targeting this gut-microbe-derived metabolite to treat various diseases, particularly AD, may be improved. |
