By Ellen Feldman, MD
Altru Health System, Grand Forks, ND
SYNOPSIS: Researchers followed participants for three years and determined daily cocoa supplement use was not associated with cognitive enhancement in older adults, whereas a multivitamin supplement was associated with significant cognitive benefits.
SOURCE: Baker LD, Manson JE, Rapp SR, et al. Effects of cocoa extract and a multivitamin on cognitive function: A randomized clinical trial. Alzheimer’s Dement 2022; Sept. 14. doi: 10.1002/alz.12767. [Online ahead of print].
We received due warning. In 1982, researchers published a paper about the “greying of America” and noted one natural consequence of longer life span would be an explosive impact on the prevalence of dementia.1 Today, Alzheimer’s disease and related dementias affect more than 45 million people globally.2 While we know modifiable risk factors for dementia include lifestyle, other psychosocial factors, and metabolic and vascular disease states, we do not have a “gold-standard” medication or intervention to prevent or slow cognitive decline.2,3
Noting the prevalence of this disease and the enormous societal cost of dementia, Baker et al designed a comprehensive study to investigate evidence of an association of prevention of cognitive decline in older adults with flavonoids (plant-based micronutrients) and/or multivitamin-mineral supplements (MVM). Both interventions have been the subject of other investigations, and both have shown mixed results.4,5
The anti-inflammatory and vasodilating effects of flavonoids are among the properties thought to have the potential to prevent cognitive decline in humans.4 Cocoa contains a large amount of a subclass of flavonoids known as flavanols, as well as theobromine and caffeine, making cocoa extract (CE) an appropriate delivery system for flavonoids for this study. The daily CE used in this investigation contained 500 mg of flavanols and lower levels of theobromine (50 mg) and caffeine (15 mg).
Additionally, other investigators have studied individual micronutrients and minerals in prevention of cognitive decline, but few have considered long-term use of an MVM daily supplement.5 The MVM used daily in this study was Centrum Silver.
Baker et al noted insufficient evidence for use of any of these interventions because of inconsistent results and methodologic inconsistencies. COSMOS-Mind is an ancillary or substudy of the much larger COSMOS investigation, which focused on the association of CE supplements and/or MVM daily use with enhanced cardiovascular and cancer outcomes.6
Out of the 5,342 participants from the Baker et al study who met age and medical criteria for COSMOS-Mind and were invited to be included in the substudy, 2,262 enrolled. The lower age limit for COSMOS-Mind was 65 years. Patients were randomized to one of the four arms of this 2 × 2 factorial study. A 2 × 2 factorial study includes two independent variables (in this case, CE and MVM) and one dependent variable (in this case, cognitive decline). Thus, the four groups consisted of the following: Group 1 received a daily CE placebo and an MVM placebo. Group 2 received CE twice daily and an MVM placebo. Group 3 received a daily CE placebo and an MVM. Group 4 received CE and an MVM.
Participants completed phone assessments of cognitive state at baseline and annually for the next three years. A global cognition score was generated by combining the results of several tests able to be administered via phone, including Telephone Interview for Cognitive Status, immediate and delayed story recall, tests of verbal fluency, and the Digit Ordering Test.7-9
Results were reported as a z-score, which indicates deviation from the mean.10 In this study, higher z-scores reflected better performance on the tests of cognition relative to individual baseline score. Secondary outcomes included a memory composite score and an executive functioning composite — also reported as z-score. Compliance declined each year, with 92% completing assessment in year 1, dropping to 84% in year 2, and down to 77% in year 3. In a subgroup comparison, participants receiving MVM vs. placebo with a history of cardiovascular disease (CVD) had a more significant difference in z-score by the end of the study period than the same population of participants who did not have such a history.
Secondary outcomes were associated with similar improvements in the participants taking active MVM vs. an MVM placebo. Mean z-score change for memory tests for these participants was 0.06 (95% CI, 0.04-0.09; P = 0.04) and 0.06 (95% CI, 0.01-0.11; P = 0.02) for executive functioning mean z-score change. Participants taking CE vs. a CE placebo showed no association with a mean z-score change for either of these functions.
COMMENTARY
The findings of this comprehensive three-year study suggest regular use of an MVM, an affordable and easily accessible supplement, may be an effective way to prevent cognitive decline in older adults. This finding carries enormous potential for public health and for everyday clinical practice.
Baker et al did not isolate any risks or harms associated with the use of MVM, and there are few cited in literature. Among these are the potential of choking (smaller pills are available for elderly people with difficulty swallowing), the general risk of polypharmacy in elderly patients, and the risk of taking a poor-quality preparation (MVM quality can vary greatly; it is important to choose a reliable brand).11
It is interesting that the response to MVM was stronger in participants with a history of CVD than in those without. Notably, these participants (those with a CVD history) recorded a lower composite global cognitive functioning score at the start of the study than those without CVD. More research is needed to explore this finding further, and to investigate any relationship between specific micronutrient levels in patients with CVD and the effect of enhancing or restoring these levels on cognitive functioning. It also is possible the interaction between micronutrient levels and certain medications (e.g., antihypertensives) may be playing a role.12
These findings are compelling; however, they are yet to be generalized with certainty. The participant pool was relatively uniform in terms of race and ethnicity, since they were selected from a larger study with respondents recruited through local providers and regional media campaigns. All participants in the COSMOS-Mind study had to have phone availability, which may have restricted the heterogeneity of socioeconomic background.
Additionally, compliance with daily ingestion of pills and medical history (including CVD) was based on self-report. Unfortunately, Baker et al did not identify specific micronutrients that may have been responsible for cognitive improvements. Future studies likely will address these and other methodological issues.
For now, providers can confidently recommend daily use of a high-quality MVM over the use of a cocoa supplement for patients age 65 years and older, especially those with a history of CVD and no clinical contraindications.
It is important to emphasize to patients that the findings from this study are preliminary and that recommendations may change in the future. With or without an MVM, providers should continue to recommend healthy diets and exercise to all older patients concerned about cognitive decline; research in that area is conclusive.2,3
REFERENCES
- Beck JC, Benson DF, Scheibel AB, et al. Dementia in the elderly: The silent epidemic. Ann Intern Med 1982;97:231-241.
- Rosenberg A, Mangialasche F, Ngandu T, et al. Multidomain interventions to prevent cognitive impairment, Alzheimer’s disease, and dementia: From FINGER to world-wide FINGERS. J Prev Alzheimers Dis 2020;7:29-36.
- Livingston G, Huntley J, Sommerland A, et al. Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. Lancet 2020;396:413-446.
- Barrera-Reyes PK, de Lara JC, González-Soto M, Tejero ME. Effects of cocoa-derived polyphenols on cognitive function in humans. Systematic review and analysis of methodological aspects. Plant Foods Hum Nutr 2020;75:1-11.
- Butler M, Nelson VA, Davila H, et al. Over-the-counter supplement interventions to prevent cognitive decline, mild cognitive impairment, and clinical Alzheimer-type dementia: A systematic review. Ann Intern Med 2018;168:52-62.
- Cocoa Supplement and Multivitamin Outcomes Study.
- Telephone interview for cognitive status.
- Skirrow C, Meszaros M, Meepegama U, et al. Validation of a remote and fully automated story recall task to assess for early cognitive impairment in older adults: A longitudinal case-control observational study. JMIR Aging 2022;5:e37090.
- Hoppe CD, Müller UD, Werheid KD, et al. Digit Ordering Test: Clinical, psychometric, and experimental evaluation of a verbal working memory test. Clin Neuropsychol 2000;14:38-55.
- Z-score: Definition, formula, and calculation.
- Walrand S. Dietary supplement intake among the elderly: Hazards and benefits. Curr Opin Clin Nutr Metab Care 2018;21:465-470.
- Mohn ES, Kern HJ, Saltzman E, et al. Evidence of drug-nutrient interactions with chronic use of commonly prescribed medications: An update. Pharmaceutics 2018;10:36.
Researchers followed participants for three years and determined daily cocoa supplement use was not associated with cognitive enhancement in older adults, whereas a multivitamin supplement was associated with significant cognitive benefits.
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