This article is part of our October 2023 Cognition and Mental Health special issue. Download the full issue here.
Yamashita S, Kawada N, Wang W, et al. Effects of egg yolk choline intake on cognitive functions and plasma choline levels in healthy middle-aged and older Japanese: a randomized double-blinded placebo-controlled parallel-group study. Lipids Health Dis. 2023;22(1):75.
To investigate the effect of egg yolk choline supplementation on cognitive function in Japanese adults aged 60 to 80 years with signs of memory decline but without diagnosis of dementia or depression
Dietary choline supplementation for 3 months seems to support beneficial cognitive changes in adults with mild cognitive decline.
Randomized, double-blind, placebo-controlled, parallel-group study lasting 12 weeks
Investigators enrolled 60 male and female adults aged 60 to 80 years. Thirty participants were in the intervention group and 30 in the control group; researchers ensured there were no significant differences between participants based on their age, gender, body mass index (BMI), blood pressure, pulse, MMSE (mini-mental status exam score), GDS (geriatric depression scale), Cognitrax score, plasma free choline, and egg consumption per week.
All participants had a score of at least 26 points on the MMSE (which excluded dementia diagnosis) and a GDS ≤6 (which excluded a depression diagnosis). Other exclusion criteria included psychiatric disease, cerebrovascular disease, other serious diseases (not specified), use of medications with central nervous system (CNS) effects, impaired vision or hearing, excessive alcohol or tobacco use, regular use of foods/supplements high in antioxidants or with nootropic claims, and very irregular dietary habits.
The study group took a supplement of egg yolk oil containing 300 mg choline; the placebo group took a supplement of egg yolk oil without choline. The 300-mg egg yolk came in 7 capsules that participants took after breakfast daily for 12 weeks.
Placebo and choline capsules were standardized to contain the same calories, protein, fat, carbohydrates, and salt; choline supplements contained 2,027.2 mg phosphatidylcholine, calculated to be 271.6 mg choline (vs 0 in placebo supplements).
The supplements were manufactured by Aliment Industry Co, Ltd (Yamanashi, Japan); Kewpie Corporation supplied the egg yolk oil, both with and without choline.
Study Parameters Assessed
Investigators assessed cognition changes at 0, 6, and 12 weeks using:
- Cognitrax, a digitized assessment of composite memory, verbal and visual memory, psychomotor speed, reaction time, complex attention, cognitive flexibility, processing speed, executive function, attention, and motor speed.
- Trail-making tests (TMT), to assess executive function.
Investigators assessed quality-of-life changes at 0, 6, and 12 weeks using:
- Short Form 36 (SF-36, which assesses health outcomes such as social function, bodily pain, and mental health).
- World Health Organization–Five Well-Being Index (WHO-5, which assesses recent emotions, such as feeling cheerful, calm, and/or rested).
Blood samples were taken at 0, 6, and 12 weeks to assess plasma free and fat-soluble choline levels.
Safety evaluations were done at 0 and 12 weeks and included a diet survey (to evaluate for under/overeating), medical interview, vitals, urine, and blood (complete blood count [CBC], complete metabolic panel [CMP], lipids, hemoglobin A1c, and urinalysis [UA]).
The primary outcome consisted of changes compared to baseline in Cognitrax test results including individual areas of assessment.
Secondary outcomes included changes in test results for:
- Plasma free and fat-soluble choline levels
- Brief diet history questionnaire (BDHQ)
- Safety: blood pressure, weight, CBC, CMP, lipids, hemoglobin A1c, UA
Verbal memory scores were higher at 6 weeks (P=0.003) and 12 weeks (P=0.043) in the choline group compared to placebo.
Serum choline levels were higher in the choline group at 6 weeks and 12 weeks, but levels were only statistically significant at 6 weeks (P=0.039).
IRB approval through Nihonbashi Cardiology Clinic Institutional Review Board (approval NJI-021-07-01) and registered with University Hospital Medical Information Network (UMIN) Center (UMIN 000045050). Research was funded by Kewpie Corporation (Tokyo, Japan).
Seven of the authors (SY, NK, WW, KS, YT, MK, and RM), including the PI, are employees of Kewpie Corporation. The other 3 authors stated no conflicts.
Practice Implications & Limitations
Dementia (recently renamed major neurocognitive disorder, MND1) is a common and growing problem as the population ages. There are 47 million people worldwide with MND and 5 million in the United States;2 numbers are expected to increase substantially in the next 20 to 30 years.1
Risk factors for MND include cardiovascular disease, female gender, age, obesity, diabetes, depression, tobacco use, physical inactivity, hearing loss, and the apolipoprotein E4 genotype (APOE4).2,3
Mild cognitive impairment (MCI) is a condition in which there are some cognitive deficits but with the ability to maintain activities of daily living.4 While there isn’t a clear path from MCI to dementia, within 3 years, approximately 22% of those with MCI will progress to a diagnosis of dementia.5 Thus, there is a tremendous interest in interventions to treat cognitive changes at this phase or decrease the rate of progression.
Other dietary sources of choline include chicken liver, soy, salmon, and quinoa, though eggs are the richest source of choline by volume.
Acetylcholinesterase inhibitors are the mainstay of MND treatment, though they are not usually used for MCI due to side effects.6 The use of natural acetylcholinesterase inhibitors, such as Salvia rosmarinus (rosemary),7 huperzine A (from Huperzia serrata), and Salvia officinalis (sage),8 is supported by clinical research and traditional use. These herbs are generally very safe for even long-term use. A complementary approach would be to address availability of the major dietary substrate of acetylcholine: choline.
There is evidence that dietary choline plays a role in animal cognition. Mice placed on a choline-enriched diet for 4.5 months performed similarly to mice 1 year younger, whereas those on the choline-deficient diet performed similarly to mice 1 year older.9 Mice with induced dementia who were given choline for 4.5 months showed increased memory performance and improved levels of choline and acetylcholine in their brains.10 This suggests that, at least in mice, dementia is not due to malabsorption of choline but, perhaps instead, lack of dietary sources.
The most common dietary source of choline, in the form of phosphatidylcholine (sometimes confusingly called “natural choline”13), is chicken egg yolks.11 There is evidence that chicken egg consumption has a supportive effect on cognition. A relatively large study of male Finns found that increased dietary egg consumption, but not increased cholesterol consumption, over 4 years’ time was associated with higher scores on the trail-making tests (TMT) and verbal fluency tests.2 These tests assess executive and frontal-lobe function. The protective effects of egg consumption were also conferred on those with APOE4 gene, which is generally considered an “unmodifiable” risk factor for MND.
This study aimed to further elucidate whether there was a component in the chicken egg other than choline responsible for cognitive changes. The choline and placebo egg yolk oil supplements were standardized to be equivalent in terms of kCal, protein, fat, and salt. The researchers also assessed safety, including increases in cholesterol, at the beginning and end of the 3-month protocol. This is not an insignificant dietary intervention: Because 1 egg contains about 17 grams of yolk,12 the amount of phosphatidylcholine needed to provide 300-mg choline in an egg yolk oil supplement is equivalent to approximately 17 eggs.
The egg yolk oil supplements, both placebo and choline-containing, increased daily dietary fat by 10.5 g. There was a mild but insignificant increase in total cholesterol, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) in both groups after 3 months. There were no adverse events in either group.
The choline group demonstrated increased plasma free choline. This choline is presumed to reach brain tissue and serve as an acetylcholine precursor.
There were some conflicting results, possibly due to the relatively short duration of the study. Tests for simple attention and motor speed were not different between the groups. At 6 weeks, the processing rate score (P=0.045) and correct response on SDC test (symbol digit coding, P=0.021) were higher in the placebo group but were not statistically different between groups at 12 weeks. The reason for this is unclear but may have been a transient effect. There were also differences in the PCS score (physical component score) in the choline vs placebo groups, which the authors postulate may have been related to changes in activity due to the Covid-19 pandemic.
The study supports the intervention of 300 mg dietary choline over 3 months to positively affect verbal memory in adults with memory decline but not dementia. The choline intervention also appeared to support increased processing speed (number of correct hits, delayed). The study also demonstrated safety of this intervention.
Limitations include the relatively short duration of the study and a limited population of healthy Japanese people. Because choline content of food is not listed on nutritional labels, investigators did not analyze or standardize the amount of dietary choline that participants consumed outside of the intervention.
However, the intervention was well-tolerated. Evaluating patient diets for choline (the Institute of Medicine defines adequate intake as 435 mg/day for women and 550 mg/day for men aged ≥ 19 years12), and addressing deficiencies through diet or supplementation seems to be a reasonable approach for supporting the cognition of our patients with MCI.
Other dietary sources of choline include chicken liver, soy, salmon, and quinoa, though eggs are the richest source of choline by volume.12 Patients following a vegan diet or who, for other reasons, are not consuming eggs might consider supplementation. However, choline (in the form of phosphatidylcholine) seems to be better absorbed compared to lab-manufactured choline bitartrate.13
The company that sponsored the study, Kewpie Corporation, is well-known in Japan (and has a cult following in other countries) as a manufacturer of mayonnaise. Could choline-enhanced mayonnaise be the next functional food for the aging population?