Low Circulating Choline, Obesity, and Alzheimer's Disease
Excess weight is a risk factor for Alzheimer's disease, but nowhere near as strongly as, say, for type 2 diabetes. It is likely not as straightforward a relationship in terms of the underlying biochemistry. Here, researchers note that obesity correlates with low levels of choline in blood samples, and low levels of choline in turn are established in animal studies to worsen age-related inflammation and progression of neurodegeneration. The researchers propose that low choline contributes to the metabolic consequences of obesity, but note that it is unclear as to whether obesity causes low choline. As is usually the case when looking at human data, correlations are easily established, but finding definitive evidence of causation is challenging.
Here, we demonstrate a relationship between early-life obesity, insulin resistance, circulating choline, and inflammation, emphasizing their potential as risk factors for disorders such as Alzheimer's disease (AD). Choline levels were lower in obese participants compared to those with a healthy body mass index (BMI). Importantly, several metabolic indicators were elevated in the obese group, and body composition markers (BMI and %Body Fat) and insulin sensitivity markers (insulin levels and HOMA-IR) were negatively correlated as well as associated with choline levels.
Obese participants also exhibited dysregulated inflammatory profiles; 11 cytokines were elevated. Additionally, levels of aldolase B and sorbitol dehydrogenase - liver enzymes involved in sugar metabolism - were higher in obese individuals and negatively correlated with choline levels, paralleling our previous findings in AD mice on a choline-deficient diet. Evidence of neuronal axonal damage was observed in obese participants; as plasma NfL was elevated and inversely correlated with choline levels, this relationship was validated in independent mild cognitive impairment (MCI) and AD cohorts.
Collectively, these findings support the idea that low circulating choline levels may contribute to the metabolic and inflammatory dysfunctions associated with obesity and may increase the risk of neurodegenerative diseases.