With 14 million Americans projected to be living with Alzheimer’s disease by 2020 for a price tag of over a trillion dollars, it’s imperative that we identify interventions that may help stem the tide of this devastating illness, and of age-related cognitive decline in general. And considering that once-promising therapeutic avenues have been disappointing, we need to explore other options. In the case of supporting healthy cognitive function, rather than thinking “outside the box,” perhaps it’s time to think inside the berry. Blueberries, to be specific.

In the past we covered a study in which healthy individuals aged 65 to 77 drank a concentrated blueberry juice daily providing 387 mg of anthocyanidins (equaling 230 g of blueberries). After twelve weeks improvements were noted in cognitive function, working memory, blood perfusion to the brain, and activation of the brain while performing cognitive tests.

Indeed, the polyphenol compounds called anthocyanins—which are responsible for the bold red, blue, and purple pigments in foods such as blueberries, raspberries, blackberries, grapes and red onions—are known to increase synthesis of nitric oxide, a potent vasodilator, and to protect the vascular system by promoting healthy endothelial function, which may be responsible for the observed increase in blood flow to the brain.

Additionally, it’s increasingly recognized that Alzheimer’s disease and its precursor, mild cognitive impairment (MCI), are associated with altered brain glucose metabolism, which may be secondary to chronic hyperinsulinemia. With this in mind, it’s noteworthy that anthocyanin-rich fruit extracts have been shown to inhibit the carbohydrate-digesting enzymes α-amylase and α-glucosidase. Blueberry and blackberry extracts (high in anthocyanins) were shown to be more effective for inhibiting intestinal α-glucosidase in rats compared to extracts from raspberries or strawberries. Alpha-glucosidase breaks down starch and disaccharides into glucose, so if this potentially has implications for improving postprandial blood sugar by reducing glucose absorption from a meal, it’s possible it may have a beneficial effect on cognition by affecting the metabolic dysregulation associated with cognitive impairment. 

Cognitive decline is associated with reduced neuronal ATP synthesis and altered synaptic function. Rodent hippocampal neurons treated with blueberry extract were observed to show improved intracellular Ca²⁺ activity and reduced depletion of ATP. Researchers noted that blueberry extract may promote neuroprotection by “restoring the frequency of synaptic currents and reversing the decrease in neurotransmitter-containing vesicles.” Rodent hippocampal neurons treated with a high-antioxidant blueberry extract showed increased glutathione synthesis and reduced susceptibility to the toxicity to Aβ₄₂, the primary amyloid peptide implicated in synaptic failure and neuronal dysfunction in Alzheimer’s disease.

Let’s shift from rodent data to research conducted in humans. In a 2018 double-blind RCT assessing the effects of blueberry supplementation on neuronal activation in subjects (aged 68 or older) with MCI, 16 weeks of supplementing with freeze-dried whole fruit blueberry powder equivalent to one cup of whole blueberries resulted in significantly increased blood oxygen level-dependent activation of multiple brain regions during working memory load conditions. Despite this, “there was no clear indication of working memory enhancement associated with blueberry supplementation.” The study sample size was very small, however—just 8 subjects. The authors noted that significant results might have been observed with a larger sample size.

A 2019 systematic review of RCTs looking at blueberry interventions for cognitive function and mood found that while studies were somewhat heterogeneous and had relatively small sample sizes, on the whole, blueberry supplementation resulted in improved long- and short-term memory and spatial memory. The studies included in the review employed whole fresh blueberries, freeze-dried blueberries, or blueberry concentrate and were not all standardized for anthocyanin content, not to mention for content of the numerous other bioactive phytochemicals that may be responsible for the observed effects. They also included subjects with a wide range of ages (children through elderly) and varying health statuses—including healthy individuals with no known cognitive impairment and studies conducted in older individuals with diagnosed MCI or self-perceived cognitive decline. Overall, however, blueberry supplementation was shown to have favorable effects on cognition, and the review authors speculated this may be due to the effects of various blueberry compounds on blood glucose, cortisol levels, blood pressure, cardiovascular function and inflammation. (Rodent research suggests blueberry extract—leaf extract, to be specific—may also have acetylcholinesterase inhibiting effects, which could potentially boost memory.) Since the precise compounds responsible for each of these effects, and the doses or concentrations required to achieve them, are not yet known, it may be best to use whole blueberry concentrates or powders that would contain the full complement of compounds and any synergies that may exist among them when aiming for a clinical effect.

A 2017 RCT evaluating the effects freeze-dried blueberry powder (equivalent to one cup of blueberries) on cognitive function in healthy older adults (aged 60-75) found that compared to placebo, 90 days of supplementation with blueberry powder resulted in significant improvement in select executive function tasks. Improvements were not seen in all tasks, however, so this is not a slam dunk, but considering that pharmaceutical interventions developed to date have proven ineffective for having any serious impact on age-related cognitive decline, alternative interventions that show any level of efficacy may be worth exploring further.    

Additionally, considering the complexity of Alzheimer’s disease and other forms of cognitive decline, it’s unlikely that a monotherapy—for example, use of blueberry extracts alone—will be effective for substantially improving cognition. Blueberry supplementation may be a helpful adjunct to augment other interventions that are showing promise, such as ketogenic diets and exercise, MCT oil or exogenous ketones.