Research has previously shown that conditions affecting the body may also have an impact on brain health. One example of this is the link between metabolic dysfunctions and neurodegenerative diseases. Obesity is associated with chronic health issues, such as heart disease and type 2 diabetes. Insulin resistance (IR), which occurs when cells become less responsive to insulin, features prominently in obesity and type 2 diabetes by disrupting the brain’s ability to regulate appetite and energy expenditure. Brain IR is also a major risk factor for Alzheimer’s disease (AD) as it affects the signalling pathways that are involved in regulating tau phosphorylation, neuronal survival and Aβ clearance.
The marker of neurodegeneration, Neurofilament light chain (NfL), has also been shown to increase in type 2 diabetes. Obesity, on the other hand, is largely dependent on lifestyle habits, such as dietary intake of choline, which is an essential nutrient that supports liver health, regulates inflammation and protects long-term brain function. Part of the required choline (i.e. 30%) is produced in our bodies. However, the remainder must come from the diet (i.e. from meat, poultry, fish, dairy products and eggs). It seems, therefore, essential to understand how metabolic disorders impact brain health, also in young adults, to be able to support the brain as people age, especially in those experiencing any metabolic dysfunctions. In a recent study published in the journal Aging and Disease, a team of researchers led by Dr Ramon Velazquez (Arizona State University, US) explored the relationship between early to mid-life obesity, metabolic dysfunction, circulating choline, inflammation profiles, and neuronal axonal damage in blood from individuals with and without obesity. Researchers also validated levels of circulating choline and NfL in two cohorts of people with mild cognitive impairment (MCI) and AD.
The study involved 30 adults in their 20s and 30s, half of them with obesity and half with a healthy weight. They were recruited through online and paper advertisements in Arizona. Potential participants with diabetes, history of liver, renal, or heart disease were excluded from the study. Potential participants who smoked, participated in a weight-loss regimen, took nutritional supplements, or used prescription or over-the-counter medications were also excluded. Blood samples were obtained from all the participants after a 12-hour fasting period. Researchers also obtained human serum samples from people with MCI and AD. In the latter case, blood samples were obtained at post-mortem via cardiac puncture from two cohorts from the Arizona Study of Aging and Neurodegenerative Disorders/Brain and Body Donation programme. Several molecules, such as glucose, were measured in the blood samples, including NfL and choline levels.
The team of researchers found that, in young adults with obesity, there was greater inflammation and metabolic stress. These participants also showed elevated levels of NfL, which negatively correlated with choline concentrations. These results were validated with the cohorts of older adults with MCI or AD. Low choline and high NfL levels were also detected in the cohorts, with serum choline levels explaining 56.9% and 59.44% of the variance in NfL levels in MCI and AD cases, respectively. These findings highlight that obesity is associated with elevations of a marker of neuronal damage, i.e. NfL, also detectable in early adulthood, which is inversely correlated with circulating choline levels.
The study highlights a strong link between obesity, inflammation, circulate choline levels and early neuronal axonal damage, as well as the importance of good metabolic health and adequate choline intake as the basis for healthy brain ageing. This research also shows that the combination of elevated blood NfL and low choline levels may serve as early biomarkers of metabolic dysfunction and increased risk for AD before the onset of any symptoms. This aligns with previous studies in rodents showing that insufficient choline intake can lead to increased metabolic stress and Alzheimer’s disease pathogenesis. Further research is needed to continue exploring how early metabolic problems contribute to the risk of developing a neurodegenerative disease, and to inform new strategies to promote brain health earlier in life.
