For years, a scientific puzzle has bedeviled researchers aiming to fight Alzheimer‘s disease, a common and incurable form of dementia.
The results of numerous lab investigations and population studies support the preventive potential of omega-3 fatty acids, “good fats” found abundantly in fish.
However, to date the majority of studies evaluating omega-3s for averting or curtailing cognitive decline in human participants have failed to show benefits.
Now, a small clinical trial from USC provides important clues about this discrepancy, in the first Alzheimer’s prevention study to compare levels of omega-3s in the blood with those in the central nervous system.
The findings suggest that higher doses of omega-3 supplements may be needed in order to make a difference, because dramatic increases in blood levels of omega-3s are accompanied by far smaller increases within the brain.
Among participants who carry a specific mutation that heightens risk for Alzheimer’s, taking the supplements raised levels of a key fatty acid far less compared to those without the mutation.
“Trials have been built on the assumption that omega-3s get into the brain,” said senior author Dr. Hussein Yassine, associate professor of medicine and neurology at the Keck School of Medicine of USC. “Our study was specifically designed to address this question.”
The paper was published today in the journal EBioMedicine.
The researchers recruited 33 participants who had risk factors for Alzheimer’s but were not cognitively impaired. All participants had a family history of the disease, a sedentary lifestyle and a diet low in fatty fish.
Fifteen carried a gene variant called APOE4, which is linked to inflammation in the brain and increases Alzheimer’s risk by a factor of four or more; the other 18 were noncarriers.
At random, participants were assigned to a treatment group or control group. Members of the treatment group were asked to take supplements containing more than 2 grams of an omega-3 called docosahexaenoic acid (DHA) daily for six months.
Control group members took placebos each day over the same period. Participants in both groups also were asked to take daily B-complex vitamins, which help the body process omega-3s.
Dr. Yassine and his colleagues gathered samples of blood plasma and cerebrospinal fluid – a gauge for whether the omega-3s reached the brain – from participants at the outset, and again at the end of the study period.
The scientists looked at levels of two omega-3 fatty acids: DHA and eicosapentaenoic acid (EPA), a potent anti-inflammatory that the body derives from a small portion of its DHA intake.
Higher doses for omega-3s to be effective?
The researchers found that at the end of the six months, participants who took omega-3 supplements had 200 percent more DHA in their blood compared to those who took placebos.
In contrast, the DHA found in cerebrospinal fluid was only 28 percent higher in the treatment group than the control group. This result hints that measuring omega-3 levels in the blood may not indicate how much is reaching the brain.
Dr. Yassine and his co-authors also report that, within the treatment group, those without the risk-inflating APOE4 mutation showed an increase of EPA (anti-inflammatory omega-3 fatty acid) in their cerebrospinal fluid three times greater than what was seen in carriers of the gene.
“E4 carriers, despite having the same dose, had less omega-3s in the brain,” he said. “This finding suggests that EPA is either getting consumed, getting lost or not getting absorbed into the brain as efficiently with the E4 gene.”
Notably, the 2-gram dose of DHA in this study far exceeded what has been used in major clinical trials testing the preventive power of omega-3s, which typically administer 1 gram or less daily.
“If you use a lower dose, you can expect a less-than-10-percent increase in omega-3s in the brain, which may not be considered meaningful,” Dr. Yassine said.
The sacrifice of study participants advances Alzheimer’s research
The investigators worked for two years to recruit participants for the trial. The barrier to entry came from the only method capable of extracting cerebrospinal fluid: a lumbar puncture, also known as a spinal tap.
It proved challenging to find people willing to undergo that procedure, which involves a hollow needle piercing the lower back, two times.
Dr. Yassine had high praise for the study participants.
“They were generous with their time, and they were courageous to do the lumbar punctures,” he said. “The main reason they did this was their desire to advance science.”
The participants’ bravery may pay off in the creation of even more knowledge about omega-3s and Alzheimer’s.
The preliminary data from the current study was intriguing enough that the scientists were able to attract funding for a larger trial for which recruitment is underway. Following 320 participants over two years, it will examine whether high doses of omega-3s can slow cognitive decline in carriers of the APOE4 gene.
Dr. Yassine believes that the progression from a small study to a bigger one is a good model for developing therapies and preventions targeting the brain.
“These pilot studies are so important as a step toward much larger, more complicated studies,” he said. “The bottom line is, before you embark upon very expensive clinical trials, you need to show proof of concept, that your drug is getting into the brain and changing biomarkers of disease in the right direction.”
Nutrition and cognition
Some evidence suggests that individual food bioactive components protect cognitive health (for review see Scarmeas et al8), including B vitamins, antioxidant vitamins, selenium, vitamin D, medium chain triglycerides, and long chain omega-3 fatty acids (see supplementary table on bmj.com).
This evidence is not conclusive, however. Any effects of intervention with such individual components are most likely to appear after long term exposure, and in those with a low baseline habitual intake.
Evidence that nutrition has a beneficial effect on brain function is stronger for healthy dietary patterns, probably because the synergistic effect of several bioactive components affects many physiological processes and signalling pathways underlying cognitive function and decline.
Intuitively, one would predict that the effect of nutrition would be more evident in people who are still cognitively healthy or prodromal, rather than in those with diagnosed dementia, where significant neuronal loss has already occurred, but this has not been rigorously tested.
Here we focus on fish/the omega-3 fatty acid docosahexaenoic acids (DHAs), ketogenic interventions, and a plant based dietary pattern (eg, Mediterranean diet) as approaches to nutrition with a strong potential to mitigate age related cognitive decline.
The state of advancement of knowledge and inconsistencies in these areas provide insight into the research approaches used and the challenges encountered in confirming nutrition-cognition causal relations, especially during ageing.
Omega-3 fatty acids and improved brain function
Oily fish, which includes salmon, mackerel, herring, fresh tuna, and sardines, are the almost exclusive dietary source of the long chain n-3 fatty acids, eicosapentaenoic acid and docosahexaenoic acid (DHA). Algal oil capsules provide a vegan source of DHA.
The brain is highly enriched in DHA, which constitutes 15% of brain lipids compared with less than 5% in most other tissues.11 The role of DHA in the developing fetal and infant brain is widely accepted.
In prospective cohort studies, high fish and DHA intake has been consistently associated with improved cognitive health in older age, with a 10-30% reduced risk of Alzheimer’s disease and death, brain atrophy, and cognitive decline, and effect sizes equivalent to two to four years of ageing12 13 14 15 16; there is some indication of greater effects in women.15
In a meta-analysis of 21 cohort studies, a 100 mg increment of dietary DHA was associated with lower risks of dementia (relative risk 0.86, 95% confidence interval 0.76 to 0.96) and Alzheimer’s disease (0.63, 0.51 to 0.76).14
Fish is also a source of multiple nutrients needed by the brain, including vitamin B12, selenium, and vitamin D, which may contribute to the observed cognitive benefits. Thus, where possible, fish itself rather than fish oil supplements is recommended as a source of DHA.
For a dietary component such as DHA/fish, which could be considered a signature of an overall healthy diet (such as a Mediterranean-style diet discussed below) and healthy behaviour, the possibility of residual confounding should be considered, as some of the cognitive benefits associated with DHA seen in prospective cohorts could be due to a yet unknown factor associated with intake,17 and the benefits associated with eating fish and DHA could be biased.18
A number of randomised controlled trials have reported mixed findings with DHA supplementation over periods of up to three years (see supplementary data). DHA is one of the bioactive ingredients in Souvenaid (Fortasyn Connect) medicinal food, designed to support cognitive ageing.
In the LipiDiDiet trial, Souvenaid had no effect on the primary outcome measure, but was associated with an improved clinical dementia rating score and reduced hippocampal (a main brain region affected in Alzheimer’s disease) atrophy.19
Response to DHA interventions is heterogeneous and may partly depend on DHA and cognitive status at baseline. Cognitive benefits are reported for healthy younger adults20 and in mild cognitive impairment,21 in contrast to those with more advanced disease.22
Early indications are that APOE4 carriers (25% of white populations), and particularly older women with the APOE4 variant, may have lower brain DHA uptake and status, and would benefit from higher dose DHA supplementation.2 23 24
For DHA and other dietary components, several variables need to be considered, including delivery to the brain and time taken to reach a steady state, and whether the cognitive benefits are direct effects on brain structure, perfusion, or metabolism, or an indirect effect attributable to, for example, cardiometabolic health.
Brain DHA half life is estimated to be 2.5 years,25 and thus supplementation periods of at least a year are probably needed to detect the cognitive benefits associated with DHA enrichment of neuronal cells, and effects on β-amyloid and tau protein metabolism and synaptic plasticity.2 26
Brain glucose use, ketones, and cognitive health
One of the challenges facing the ageing brain is a chronic deficit in brain glucose uptake. Cognitively healthy older adults have about 7-8% lower brain glucose uptake than younger adults, a decline accentuated in mild cognitive impairment (the prodromal phase of Alzheimer’s disease) and even more so in Alzheimer’s disease itself.27
Although low brain glucose could be a consequence of the disease process, two facets of the declining glucose uptake, brain cell loss, cognitive decline continuum suggest that this interpretation should be reconsidered.
Firstly, brain glucose uptake is already lower in those at risk of Alzheimer’s disease (that is, older age but still cognitively normal, carriers of the presenilin mutation or APOE4, or type 2 diabetes) but before their cognition declines.28
Secondly, studies with positron emission tomography imaging and a ketone tracer (11C-acetoacetate) show that, unlike glucose, brain ketone uptake is normal during ageing, mild cognitive impairment, and Alzheimer’s disease.29 30 31 Ketones are the brain’s second most important fuel and, as for glucose, brain ketone uptake is an active, transporter mediated process.
Hence, many of the brain cells in which glucose metabolism is deteriorating owing to age or Alzheimer’s disease are not apoptotic (or dead) because they can still metabolise ketones. Rather, they are gradually becoming energy (glucose) starved, but perhaps their function could be revived or maintained by ketones, an emerging therapeutic concept called “brain energy rescue”.32
Under normal circumstances, glucose supplies about 95% of the brain’s fuel. It is, however, effectively replaced by ketones (β-hydroxybutyrate and acetoacetate) when dietary carbohydrate or total dietary energy is limited.
Furthermore, when a ketogenic supplement is included in the diet, the brain of someone with mild cognitive impairment or Alzheimer’s disease uses ketones in direct proportion to the increased ketones provided by the circulation, thereby sparing brain glucose use.33 34
Recent experimental clinical studies have shown that brain energy rescue with ketones is associated with improved cognitive outcomes in both mild cognitive impairment and Alzheimer’s disease.
These studies used either a very low carbohydrate (ketogenic) diet35 36 37 or 20-30 g/day of ketogenic medium chain triglyceride supplement.34 38 39 With ketone positron emission tomography imaging, two of these studies showed that not only did ketones access the brain of someone with mild cognitive impairment37 but that improvement on several cognitive tests was directly proportional to the rise in plasma ketones,34 implying a direct mechanistic link between restoration of brain energy levels by ketones and the improved cognitive performance.
Ketogenic interventions may also be disease modifying because preclinical and clinical reports show that the neuropathological process involving accumulation of the dementia associated proteins, amyloid β and phosphorylated tau, can be partially blocked by ketogenic supplements.37 40 41
These results are encouraging but compliance is low with ketogenic diets, and ketogenic medium chain triglycerides can cause gastrointestinal discomfort. Thus more work is needed to optimise ketogenic interventions (dose, duration, formulation) and test them in larger randomised controlled trials in order to convincingly assess their efficacy in improving cognitive outcomes in people with mild cognitive impairment or Alzheimer’s disease.
Ketogenic interventions may indirectly affect cognitive outcomes, in part, by improving insulin sensitivity or stimulating weight loss; they would also be predicted to be more efficient in slowing down Alzheimer’s disease if combined with exercise.42
Given the emerging evidence for the cardiometabolic safety of the ketogenic diet and the growing interest in its use to treat type 2 diabetes,43 a long term controlled intervention assessing its effect on cognitive outcomes and risk of Alzheimer’s disease is warranted.
Dietary patterns and cognitive health
Recent research has moved away from the reductionist approach to nutrition, health, and chronic disease,17 and focused on the effect of dietary patterns, such as the Mediterranean diet, DASH (Dietary Approaches to Stop Hypertension) diet, and the hybrid MIND (Mediterranean-DASH Intervention for Neurodegenerative Delay) diet.
Additionally, the World Health Organization and Public Health England have advocated whole diet approaches to delay or prevent cognitive decline.7 44 A Mediterranean diet is high in fruits, vegetables, olive oil, whole grains, unsaturated fatty acids, and fish, with restrictions of red meat, and moderate but regular drinking of alcohol.
A meta-analysis of 34 168 participants showed that higher adherence to a Mediterranean diet was associated with a 21% reduced risk of developing cognitive disorders and a 40% reduced risk of Alzheimer’s disease.45 In a recent analysis of the EPIC (European Prospective Investigation into Cancer and Nutrition)-Norfolk cohort, the global cognitive benefit of high versus low adherence to a Mediterranean diet was equivalent to 1.7 fewer years of cognitive ageing.46
Numerous foods in modern Western-style diets are not traditionally included in a Mediterranean diet, such as high fat dairy products, processed meats, carbonated drinks, sweets, and pastries. The PREDIMED, MIND, and DASH diets are Mediterranean-style diets and all three improved cognitive outcomes,47 48 with respectively a 53%, 54%, and 39% lower incidence of Alzheimer’s disease after 4.5 years.49 A
multidomain lifestyle intervention trial (FINGER), which included modified eating behaviour as one of four concurrent interventions, improved cognitive outcomes. After two years, a 25% improvement in global cognition (as assessed by the neuropsychological test battery), and higher executive function (150%) and processing speed (89%) was evident in the intervention versus control group.50 51
These findings indicate that whole diet approaches that encourage Mediterranean-style elements and discourage energy dense foods typical of a Western-style diet are beneficial for cognitive health.
Although the PREDIMED study reported a lower prevalence of mild cognitive impairment after a Mediterranean diet,52 longitudinal randomised controlled trials, with incident mild cognitive impairment/Alzheimer’s disease as the primary end point, are still lacking.
The totality of evidence supports the protective effect of adherence to diets rich in whole foods for dementia and cognitive function, but there are inconsistencies within and between diets.45 Contradictory findings may be due to the geographical region, with a recent systematic review reporting that 80% of cohort studies conducted in Mediterranean regions showed significant associations with cognitive health, compared with only 50% in non-Mediterranean regions.53
Possible reasons for this geographical disparity are firstly, diet adherence scores may reflect different food patterns in Mediterranean versus non-Mediterranean countries – for example, olive oil, fish, and legumes are more commonly eaten in Mediterranean regions; secondly, adherence scores do not consider foods reflective of Western-style diets in non-Mediterranean regions; or, thirdly, in Mediterranean regions the Mediterranean diet score is “capturing” a lifestyle with characteristics protective of cognitive decline, including increased social interactions when eating, and physical activity.54 55
Heterogeneity in dietary response could also be due to individual differences in nutrient metabolism. Beneficial changes in the gut microbiome, together with taxonomic shifts in microbiota composition, have been seen in those following plant based diets.56
A higher intake of plant based foods is associated with lower trimethylamine oxide levels and increased faecal short chain fatty acids, fibre degrading microbiota, and gut microbial diversity.57 58 These gut microbial changes are linked to the gut-brain axis.
Thus short chain fatty acids—in particular, butyrate, enhance brain derived neurotrophic factor expression, and trimethylamine oxide is linked to reduced expression of synaptic plasticity related proteins, including N-methyl-D-aspartate-receptors, both important factors for learning and memory.59 60
If the microbiome can affect the gut-brain axis then diet induced changes in the gut microbiota, through plant based or Mediterranean diets associated with higher consumption of fibre, polyphenols, and probiotics could affect development of cognitive impairment. Equally, microbiome speciation and metabolism could influence the cognitive response to dietary change and may emerge as a tractable target for interventions.
In addition to the nutrients needed for brain function, the reduced content of refined sugars in Mediterranean-type diets may also help to improve glucose tolerance. This would help the ageing brain meet its energy needs (both glucose and ketones) by reducing creeping insulin resistance during ageing, thereby improving the chance of maintaining optimal cognition.
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More information: Isabella C. Arellanes et al, Brain delivery of supplemental docosahexaenoic acid (DHA): A randomized placebo-controlled clinical trial, EBioMedicine (2020). DOI: 10.1016/j.ebiom.2020.102883
