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Dr. Peterson is Integrative Medicine Fellow, Department of Family Medicine, Maine Medical Center, Portland. Dr. Schneider is Associate Professor of Family Medicine, Tufts University School of Medicine; and Director of Integrative Medicine, Department of Family Medicine, Maine Medical Center, Portland. Dr. Wissink is Assistant Professor of Family Medicine, Tufts University School of Medicine; and Associate Director of Integrative Medicine, Department of Family Medicine, Maine Medical Center, Portland.
Dr. Peterson, Dr. Schneider, and Dr. Wissink report no financial relationships relevant to this field of study.
According to the U.S. Census Bureau, by 2030 the elderly population in the United States will grow such that one in every five residents will be of retirement age.1 Along with an aging population come age-related chronic diseases, including age-related cognitive changes, which range from mild cognitive insufficiency to devastating dementias of various types.
Since risk factors for age-related cognitive decline appear to be closely aligned with those of cardiovascular disease, it has been suggested that dietary and lifestyle patterns may play a role in preventing or delaying their onset. Blueberries (Vaccinium spp.), particularly dense in flavonoid antioxidants in the form of anthocyanins, the pigments that give berries (as well as other plants and flowers) their blue, red, and purple hues, have attracted attention for their potential in treating and preventing age-related cognitive decline. Native to North America, blueberries are particularly delicious in the summer, whether they are picked and eaten by the side of the trail or added to a mouth-watering blueberry pie or crumble.
In animal models, blueberries appear to slow age-related decline in hippocampal-mediated learning, and multiple studies suggest potential benefit in humans.2 This article summarizes the results from a literature search of more recent clinical studies in the elderly. The largest study included in this review used data from 16,010 participants in the Nurses’ Health Study, a longitudinal project started in 1976 when female registered nurses aged 30-55 years completed a mailed questionnaire on health and lifestyle. Additional questionnaires were given every two years thereafter and follow-up was > 90%. A food frequency questionnaire was added in 1980 and was sent every four years thereafter.
Devore et al contacted participants between 1995 and 2001 who were ≥ 70 years of age and without a stroke history to participate in an additional telephone study assessing cognitive function.3 (See Table 1.) This telephone assessment included a variety of tests that ultimately were compiled into a global composite score and a verbal memory composite score, as well as assessed intake of flavonoids (including blueberries). After the authors adjusted for multiple confounders (including age, education, depression, physical activity, cardiometabolic health markers, alcohol, and annual household income), women with greater intake of blueberries and strawberries demonstrated slower rates of cognitive decline when averaging all six cognitive tests (blueberries, P = 0.014; strawberries, P = 0.022). Based on the standard units used in interpreting cognitive testing scores, the authors posited that after adjustment for confounding, women with higher berry intake “appeared to have delayed cognitive aging by up to 2.5 years.”
Given the suggested relationship between cognitive decline and cardiometabolic risk factors, Nilsson et al conducted a randomized crossover study in 40 apparently healthy nonsmokers within 50-70 years of age. Over the course of five weeks, they examined the effects of a daily supplemental mixed berry beverage (containing 150 g blueberries, 50 g blackcurrant, 50 g lingonberries, 50 g strawberries, and 100 g tomatoes) vs. a control beverage on cognitive function and cardiometabolic risk markers.4 During four on-site experimental days before and after both the control and berry beverage intervals, participants underwent fasting serum and biometric testing prior to consumption of a standardized breakfast. Next, they underwent a series of repeated cognitive tests to assess verbal working memory and selective attention; results showed a statistically significant improvement in performance on the verbal working memory test at 30 minutes for the berry beverage group (P = 0.039). An analysis of cardiometabolic risk factors showed significant reductions in total and low-density lipoprotein cholesterol (LDL-C) in the berry beverage group compared to baseline values (total cholesterol, P = 0.029; LDL-C, P = 0.011) as well as compared to the control group post-intervention values (total-C P = 0.004; LDL-C P = 0.006). The authors concluded that this study demonstrated continued support for the health benefits of berries in both cardiometabolic and cognitive (specifically working memory, i.e., short-term memory involving immediate processing) domains. Since the studied berry beverage included a mixture of various berry types, it is difficult to draw conclusions about the role of blueberries specifically.
The remaining studies included in this review primarily were randomized, controlled trials that involved administering blueberry-based (rather than mixed berry) compounds to older adults and assessing their effects. The authors of two randomized, double-blind studies examined brain activation with the use of functional magnetic resonance imaging (fMRI) after blueberry supplementation. Boespflug et al analyzed fMRI findings before and after giving 24 g/day (about 1 cup of whole blueberry fruit, containing 348 mg of anthocyanins) of blueberry or placebo powder to 21 older adults with mild cognitive impairment for 16 weeks.5 Flavonoid consumption significantly enhanced (P = 0.01) brain activity in three brain regions (left pre-central gyrus, left middle frontal gyrus, and left inferior parietal lobe) during a working memory task without significantly affecting task performance.
In another fMRI study, Bowtell et al randomized 26 participants > 65 years of age into two groups: one received blueberry concentrate providing 387 mg of anthocyanidins daily for 12 weeks and the other received a placebo (a synthetic blackcurrant and apple cordial with sugar added to match energy content).6 Participants completed a battery of cognitive tests at baseline while acquiring fMRI data, then had blood tests along with an MRI. They returned after 12 weeks to complete the same measurements. Performance on the cognitive testing showed no significant difference between the blueberry and placebo groups after 12 weeks. There was a trend toward improvement in the blueberry group compared to placebo, but it was not statistically significant. However, fMRI results showed a significant increase in brain activation responses found in several task-associated regions following blueberry supplementation compared to placebo (P = 0.001).
Miller et al used freeze-dried blueberry (24 g/day, equivalent to 1 cup of fresh blueberries) or a blueberry placebo (containing maltodextrin, fructose, artificial and natural blueberry flavor, artificial colors, and citric acid) in a randomized, double-blind study assessing cognitive function and mobility over the course of 90 days in 13 men and 24 women between the ages of 60 and 75 years.7 The usual diet for participants over the prior 12 months was assessed using the National Cancer Institute’s Diet History Questionnaire II as well as a supplemental questionnaire on berry consumption. A variety of questionnaires were used to collect information about physical activity, falls, and mood. Biometrics were measured, and cognitive, stance, and gait testing were administered at baseline, 45 days, and 90 days after blueberry product consumption. Results showed that during the task switching test (used to assess executive function), participants in the blueberry group made fewer errors than those in the control group (P = 0.033). Controlling for the fact that the blueberry group was more physically active and spent less time sitting or using a computer than the control group, they still demonstrated significantly fewer errors (P = 0.044). On the California Verbal Learning test (2nd ed), performance improved for both groups on subsequent visits with fewer repetition errors. The blueberry group made significantly fewer repetition errors on visit 4 (at 90 days into the study) compared to visit 2 (baseline) (P = 0.031). This remained significant when controlled for physical activity level and computer time (P = 0.032). No significant differences in mobility testing or additional cognitive testing (assessing short-term memory, psychomotor speed, spatial cognition, and attention) were observed between the groups.
In another study of cognitive testing with a blueberry supplement, Whyte et al randomized 122 adults between 65 and 80 years of age into four groups.8 One group (n = 30) received placebo and three groups received different doses of a wild blueberry powder: WBP500 containing 500 mg of wild blueberry powder and 1.35 mg anthocyanins (n = 30), WBP1000 containing 1,000 mg of wild blueberry powder and 2.7 mg anthocyanins (n = 31), or WBE111 containing 111 mg of wild blueberry extract and 7 mg anthocyanins (n = 31). Participants were asked to continue their usual dietary and exercise practices, as well as complete dietary and physical activity questionnaires prior to and after the study. Biometrics and mood also were monitored. Cognition was assessed using a battery of tests, including mini-mental state examination, National Adult Reading Test, and Consortium to establish a registry for Alzheimer’s Disease, at weeks 0, 12, and 24 of the study. Control visits consisted of well-being checks with a focus on lifestyle habit changes like smoking, use of alcohol, medications, and adverse effects. After three months, the WBE111 group improved on episodic memory performance (word recognition) compared to placebo (P = 0.05), but the improvement was not sustained at six months.
The authors hypothesized the lack of benefit from the blueberry powder groups may be due to lower anthocyanin dose or possibly the interference of fiber in those supplements. They also wondered if waning of improvement at six months might be due to degradation of active constituents in the capsules, increased tolerance to the supplements, or decreased adherence (three dropped out of placebo, two dropped out of WBP500, two dropped out of WBP1000, three dropped out of WBE111). Because an intention-to-treat analysis was not used, these findings are inconclusive.
As we consider clinical relevance, the final few studies included in this review involved participants with self-reported symptoms of cognitive decline.
McNamara et al conducted a randomized, double-blind study that included 94 men and women between the ages of 62 and 80 years with mild, self-perceived cognitive decline of aging.9 The intervention included exposure to fish oil, blueberry, and a combination of the two. This review is about the blueberry portion. The blueberry group received a powder equivalent to 1 cup of whole blueberry fruit made from whole frozen freeze-dried blueberries (Vaccinium spp. including V. ashei, V. corymbosum L. cultivar, and V. angustifolium). At enrollment, 24 weeks, and 48 weeks, cognitive performance was assessed both subjectively (through questionnaire) and objectively (through measurement of psychomotor speed, working memory, lexical access, and long-term memory with a battery of cognitive and mood testing). At 24 weeks, the blueberry group reported fewer cognitive symptoms (P = 0.05) and demonstrated improvement in recognition memory on the Hopkins Verbal Learning Test (P = 0.04); however, these changes were not maintained at 48 weeks. One limitation of this study was the lack of a run-in period with dietary restrictions limiting blueberry and fish oil intake.
In another preliminary human study, Krikorian et al enrolled five men and four women with a mean age of 76.2 years (± 5.2) who reported age-related memory decline (forgetfulness, prospective memory lapses) and qualified for Mild Cognitive Impairment using the Clinical Dementia Rating.10 The degree of impairment was assigned as no impairment, mild decline, or dementia of mild, moderate, or severe degree. Those determined to be in mild cognitive impairment (MCI) were included in this 12-week study. Wild blueberry juice (V. angustifolium Aiton) commercially prepared from ripe, frozen wild (lowbush) blueberries was used. Participants consumed between 6 mL/kg and 9 mL/kg daily. They were blinded to the intervention and told they might be receiving grape, blueberry, or a berry-flavored placebo drink (designed to mimic grape for another concurrent study).
Adherence was monitored by weekly phone contact and interviews at evaluation visits. Assessments were performed at baseline and during the final week of the 12-week trial. Primary outcomes included memory function using the Verbal Paired Associate Learning Test (V-PAL) and California Verbal Learning Test (CVLT). The blueberry group improved on V-PAL (P = 0.009) and CVLT recall (P = 0.04) at 12 weeks compared to baseline. Compared to the placebo group, the blueberry group improved on the V-PAL (P = 0.03), but not on CVLT. The authors concluded that wild blueberry juice improved memory function in older adults with MCI over 12 weeks; however, because this was a small preliminary study with an inadequate placebo (since it was grape-flavored and had a higher glycemic load), no firm conclusions can be drawn.
As our population ages, healthcare providers continue to be faced with many questions about recommendations to maintain or enhance cognitive function over time. Current recommendations from the U.S. Preventive Services Task Force for preventing cognitive impairment include regular physical activity, tobacco cessation, fall prevention, healthful diet, and screening for elevated cholesterol, hypertension, and depression.11 The World Health Organization recently released updated guidelines for risk reduction of cognitive decline and dementia, with a focus on lifestyle factors and a nutritional recommendation for following a Mediterranean-like diet to help reduce the risk of cognitive decline and/or dementia.12
In addition to addressing cardiometabolic risk factors and general lifestyle risk factors, studies are being conducted to identify specific nutritional approaches — including looking at known “superfoods” — to optimize cognitive function in aging populations with a variety of cognitive function statuses (ranging from asymptomatic to mild cognitive impairment to dementia).
We reviewed human adult studies published since 2009 that involved consumption of blueberries (primarily V. angustifolium) or blueberry-based products and the potential effects on cognitive function. It is worth noting that some of the studies included in this review received materials or funding from manufacturing groups or the Wild Blueberry Association of North America. For example, Krikorian et al used material and funding support provided by the Wild Blueberry Association of North America; the Whyte et al study was funded by Naturex Inc.; and in the McNamara et al study, the U.S. Highbush Blueberry Council and Wild Blueberry Association of North America provided blueberry and placebo powders.
Overall, most of these studies suggest small improvements in cognitive testing with blueberry supplementation, specifically in the realm of verbal function and verbal memory. A few studies involving brain imaging suggested significant brain activation responses. However, those studies did not find significant alterations in cognitive testing. The largest reviewed study from the Nurses’ Health Study, while not randomized or placebo-controlled, suggested delayed cognitive aging (of 2.5 years) after tracking women for many years. Smaller, randomized studies potentially could have shown a larger effect if continued for a longer period.
In terms of clinical application, these studies included both healthy older adults as well as those with subjective cognitive impairment or meeting criteria for mild cognitive impairment. Some authors did not specify this in their inclusion or exclusion criteria, but no one examined a patient population carrying a diagnosis of dementia.
For people interested in using nutritional approaches to reduce the risk of cognitive decline or address existing symptoms, blueberries are a tasty addition to a colorful, healthy diet rich in whole, minimally processed foods. Based on the reviewed studies, including 1 cup per day (generally equivalent to 24 g of blueberries) seems to be reasonable. Blueberries neither make it onto the Clean 15 or Dirty Dozen list released by the Environmental Working Group. However, at this point, definitive conclusions regarding duration and efficacy cannot be drawn based on existing studies, and more research is needed.
Integrative Medicine Alert’s Executive Editor David Kiefer, MD; Peer Reviewer Suhani Bora, MD; Relias Media Editorial Group Manager Leslie Coplin; Editor Jonathan Springston; and Accreditations Manager Amy M. Johnson, MSN, RN, CPN, report no financial relationships relevant to this field of study.