Omega 3, diet and lifestyle factors influencing brain health
Omega 3, diet and lifestyle factors influencing brain health and risk for cognitive disease and impairment and relevance to vegan diets
By Dr. Radak - October 2019
As we age, the body naturally is susceptible to decreases in composition in many areas. For example, bone/bone mineral density steadily declines as we age and after attaining peak bone mass, we lose bone at about 3% per decade for cortical bone and 7–11% per decade for trabecular bone (O'Flaherty, 2000), and with some exceptions (i.e. menopause in women where it is even more accelerated), has been estimated to decline about ½ percent per year after age 50 (NASS, n.d.). Another example is the progressive loss of muscle tissue or lean body mass as we age, about 0.5% to 1.0% loss per year after age 70 (Siparsky, 2014). Like other diseases, a multitude of factors are responsible for accelerating these losses rather than a single nutrient, and overall diet and lifestyle factors like exercise play major roles in preservation.
Brain weight or volume also decreases as a normal part of aging, estimated to be about 5% per decade after age 40 (Peters, 2006), and brain size/reserve is still a hypothesis being debated in relationship to Alzheimer's disease (AD) risk (Whitwell, 2010; An, 2016; Van Petten, 2004). Dementia is a umbrella term that includes different types of dementia, including vascular dementia and Alzheimer’s. Dr. Rudolph Tanzi, a leading neuroscientist at Harvard university believes that we all start the process of AD pathology around age 40, with the question being not whether one gets AD but when (Walsh & Blacknell, 2016).
Research suggests that preserving brain size, especially the hippocampal region which is mostly composed of grey matter (GM) [but also white matter (WM)], can reduce risk for dementia (Virtanen, 2013; Zamroziewicz, 2017).
Several lifestyle-related factors can increase risk and are modifiable. The 7 risk factors listed below could result in being responsible for ½ of all AD cases: smoking, diabetes, midlife hypertension and obesity, depression, physical inactivity, cognitive inactivity (Farrer, 2001).
A recent review identified these factors: (Edwards, 2019)
• Heart Disease (atherosclerosis major risk factor for AD (Janssen, 2014)
• Type 2 Diabetes (doubled risk for AD)
• Saturated Fat, Trans-Fat, Cholesterol, High fat diet
• Traumatic Brain injury
• Late Life Depression – for onset of AD
• Sleep disturbances
• Heavy drinking
Excess adipose tissue and its associated co-morbidities in middle-age has emerged as a significant risk factor for age-related cognitive decline (Vauzour, 2017), and obesity is related to brain structure deficits in olders aduts who are cognitively normal, those with mild cognitive impairment, and those with AD (Raji, 2014). Being overweight or obese in mid-life increases risk for late-onset dementia up to 2.44 fold (Dominguez, 2018). Inflammatory markers such as CRP or IL-6 are related to brain microstructural integrity and white matter lesions and ↑ risk for AD (Medawar, 2019).
While perhaps less of a concern as added sources of trans fatty acids are being phased out in the food supply, older adults who may of consumed trans fatty acids for long periods of time could be at additional risk. Older adults aged 60 or older in one study found that those with the highest levels had a 50% and 39% increased risk to develop dementia or AD (Honda, 2019).
Essential Fatty Acids and a focus on Omega 3
Essential fatty acids are but one of many nutrients investigated in relation to brain health. Essential fatty acids, primarily Omega 3 and 6, constitute ~1/3 of total brain fatty acids mostly in the form of phospholipids of which docosahexaenoic acid (DHA) dominates for Omega 3 (trace amounts of α-Linolenic acid and eicosapentaenoic acid (ALA/EPA) and arachidonic acid (AA) (trace amounts of linoleic acid (LA) for Omega 6) (Cederholm, 2013; Luchtman,2013). In general, DHA and AA have opposing effects on synaptic signal transduction and inflammatory signaling pathways (McNamara, 2017).
Regular fish consumption or total Omega 3 intake or EPA/DHA status was associated with preservation of brain size, GM, WM, and lower white matter hyperintensities (WMH), which are associated with cognitive impairment/dementia. Other studies showed no association either via assessing blood DHA status or dietary intake, and one study suggested benefit from marine Omega 3’s that was attenuated when controlling for depression (Raji, 2014; Pottala, 2014; McNamara,2018; Bowman, 2012; Conklin, 2007; Tan, 2012; Luciano, 2017; Titova, 2013; Virtanen, 2013; Zamroziewicz, 2018).
Cognitive impairment or decline/Alzheimer Disease
Observational studies on fish intake and risk for mild cognitive impairment or decline are conflicting in short term studies (Zhang, 2016, Wu, 2015; Beydoun, 2007; Roberts, 2010). One study also found higher DHA levels to be associated with slower learning performance in non-pregnant healthy women (de Groot, 2007). Fish intake has also been associated with subclinical neurobehavioral abnormalities (Carta, 2003), and the authors attributed 60% of this result to mercury blood concentrations.
A sizable number of studies suggest reduced risk for dementia or AD either for fish intake or high omega fatty acid status levels though some are conflicting with no improvement (Raji, 2014; Zhang, 2016; Cole, 2009; Alsumari, 2019; Cunnane, 2012). Some showed improvement in mental scores but no reduction for probable dementia or cognitive impairment (Ammann, 2017);others found high fish intake to worsen cognitive test performance in older adults as well as fish consumption in childhood predicting worse cognitive performance later in life (Danthiir, 2014). Some longer term studies (i.e. 10 years) found no or minimal association between fish intake and long term risk of dementia. For example, the Rotterdam Study looked at over 5000 elderly with moderate fish intakes and did not find an association with dementia nor AD at various levels of fish intake compared to those with no fish intake. This was their second study (10 years in duration) as their first study (just 2 years follow up) used the same data and had showed fish intake was helpful, though not for total omega 3 levels (Devore, 2009).
Some studies did not control for trans-fat, fruit and vegetable intake, blood glucose, exercise, all of which are associated with cognition or AD risk. Nor for medications that are associated with brain atrophy (Raji, 2014; Walsh, 2018), or for hypertension, which can predict both vascular dementia and AD 20 years before onset (Janssen, 2014) or other nutrients (including AA) that have an association with dementia risk.
Despite the inconsistency in the research, as DHA plays an important role in the brain and has been the main fatty acid of interest, could vegans who typically (but not always) show lower DHA status be at some additional risk?
To explore this further, I’ll review some of the research surrounding this topic. Both indvidual nutrients and dietary patterns will be reviewed.
Firstly, the above observational studies may suffer from self reported dietary information, use of only a single measurement, possible residual confounding due to not adjusting for numerous risk factors and being mostly cross-sectional studies (cannot draw conclusions on causality). These weaknesses are similar to observational studies looking at Omega 3/DHA and cardiovascular disease. Some also used small sample sizes. See the section below on ↑↓ Brain size/volume for the many factors influencing brain size that may not have been controlled for in these observational studies.
We don’t consume an individual nutrient or even protein group (like solely fish) in our overall diet, and it is possible that DHA may be a marker of a healthier lifestyle. Higher fish intake may also be associated with higher socioeconomic status which is protective for AD and cognitive decline (Alsumari, 2019; Sattler, 2012). Many of these studies occurred during a time when recommendations were made to reduce meat intake and replace it with healthier options such as fish, which may indicate that EPA/DHA status was a marker for a diet healthier than a meat-based diet. Meat is typically a greater source of saturated fat than fish i.e. same portion of ground beef to salmon fillet has 4.5 and .73 grams, respectively)
Other dietary hazards like meat, and AA (which competes with DHA in the brain), cholesterol and saturated fat may have been reduced/replaced by fish/seafood as part of a healthier dietary change (which often includes increased exercise, which, by itself is a significant contributor to brain health).
Why is saturated fat important? A recent meta-analysis of cohort studies suggested a strong effect for higher saturated fat intake which was associated with a 39% and 105% increased risk for AD and dementia respectively and no association was found for polyunsaturated fatty acids (PUFA), which includes Omega 3 and 6, for either AD or dementia (Ruan, 2018).
Additionally, some disease states linked with dementia or AD may not have been controlled for in these studies. Other influences besides disease may not have been controlled for. For example, pesticide exposure has been linked with cognitive function (Dardiotis, 2019), and a study looking at fluoride and aluminum in drinking water found a dose response increased risk for dementia (Ross, 2019); and confounders like these are almost never considered in these studies. All of these possible factors may dilute the strength of the findings.
The other concern with studies that show an association with DHA and brain health is the reductionist style of isolating DHA and interpreting it as the sole reason for the association. Dietary intake of seafood may provide other nutrients related to brain health beyond EPA/DHA potentially confounding associations between DHA and brain health. Fish contains Vit A, D, B-12 and B-complex vitamins, Mg, iron, iodine, selenium, zinc, and has lower saturated fat and cholesterol than meat, the underlined items of which are related +/- to cognitive decline or AD risk (Raji, 2014; Annweile 2016; Andrási, 2009; Berti, 2015; Dominguez, 2018; Medawar, 2019). Some studies did not take into account any dietary nutrients, especially the aforementioned.
It is also unclear if low DHA (found in some but not all post mortem brain studies) is a cause or consequence of AD (Pan, 2015) or other factors. Cunnane (2013) suggest that it is puzzling that, if low DHA status or low fish intake is associated with AD, why post-mortem studies do not consistently show lower brain DHA (Fraser, 2010).
Most studies correlate brain health or disease risk with levels of DHA in the blood as tissue status is more complicated to assess; however, levels in the blood may not reflect the composition in the brain/CNS (Dyall, 2015). Newer studies in vegans (Miles, 2019) indicated storage of DHA in adipose tissue despite no direct dietary source of DHA. Some research has also questioned whether new analysis methods are needed. Domenichiello et al (2015) suggest that DHA synthesis capacity may be underestimated and question whether new analysis methods are needed, such as the steady-state infusion method. Such that, if measuring DHA uptake based on what level of DHA is being used in the brain, then estimates may be far less than predicted to maintain adequate brain health.
Some studies only used a single measurement of plasma or red blood cell (RBC) DHA. Although possibly stable over time, DHA levels do change and such changes may have biased the results in studies. Pottela et al (2014), for example, used a blood sample and then analyzed MRI scans 8 years later and suggested greater brain volume preservation with higher DHA status. The assessment was in one point in time and DHA in RBC may just reflect short term dietary intake and not what is reflected in tissue. And regarding dietary intake, this study obtained no dietary information for any of the three models used in the study, and as mentioned below, several nutritional factors can affect brain volume/size and were not accounted for in the study.
That study also compared those with low and high DHA status categorized by quartiles which represented brain volume. Though this did not reach statistical significance, the Q1 subjects had more disease prevalence than those in Q4 and may have influenced results. It was also unknown what the Omega 6 intake/status was as no nutritional information was analyzed. Perhaps, those in Q1 may have had higher Omega 6 status which could of influenced brain size?
The Cardiovascular Health Study (CHS), a prospective cohort study of 5888 older adults, assessed using brain MRI scans in relationship to plasma phospholipid Omega‐3 levels and dietary intakes and found benefit with increased plasma levels of DHA and less white matter abnormalities, but not for improvement in markers that indicate less brain atrophy. However, two findings suggest benefit for ALA: plasma phospholipid ALA was associated with improvement in markers that indicate brain atrophy, and dietary ALA was associated with less white matter abnormalities (Virtanen, 2013).
The study also found that frequency of fish consumption did not correlate with mental score testing but did show fish intake correlates with higher gray matter (GM) volumes in the brain areas responsible for memory and cognition, but conversely omega 3 status in phospholipids was not related to higher GM volumes. These results lead the authors to suggest that dietary intake of fish is not necessarily the presumed biological factor that can affect the structural integrity of the brain and there are other lifestyle reasons. And that fish intake may be a marker of a healthier overall diet or something else contained in fish like selenium content (Raji, 2014). The authors say this is consistent with Omega 3 supplement studies which show little effect on prevention of dementia or cognition in AD patients.
Supplementation Trials - Dementia or AD or Cognition
These trials using long chain Omega 3 supplements showed mixed or inconclusive results on cognitive performance or decline in youth and healthy adults or adults with dementia or AD (Cederholm, 2013; Raji, 2014; Daiello, 2015; Morris, 2016; Luchtman, 2013; Abubakari, 2014; Danthiir, 2018;Phillips, 2015; Jiao, 2014), or any positive effect on cognitive decline in healthy older individuals (Cochrane meta-analysis) (Dominguez, 2018). Nor did they benefit coronary disease patients (Geleijnse, 2012). There was a possible positive effect in those with very mild cognitive impairment (Daiello, 2015; de Souza Fernandes, 2015), and some benefit for some memory indicators in young healthy adults who had low DHA status (Stonehouse, 2013). One study showed worse memory (Benton, 2013), while another showed a protective effect in those with minor memory problems for some but not for other memory domains and a protective effect in those with no memory problems (Yurko-Mauro, 2015).
In the largest and one of the longest double-masked randomized clinical trials yet (National Institute of Health AREDS2 study), lasting 5 years, >3500 participants who were at risk for developing late age-related macular degeneration were enrolled in a secondary cognitive study and given cognitive function testing: fish-oil supplements had no change in cognitive function compared to placebo and failed to reduce cognitive decline (Chew, 2015).
Some suggest the reason for DHA supplements not being effective in AD is possibly the other nutrients in fish not contained in fish oil, many of which have an established association with brain function (Cunnane, 2013).
Only one study (Witte, 2014) I could find used DHA supplements in a randomized trial which suggested an increase in GM volume and some (but not all) cognitive functions compared to a control group. However, this study had several methodological concerns which are detailed in my presentation and it is interesting that 5 years later, no study has replicated these results. Numerous non-DHA factors directly ↑↓ brain size/volume and were not controlled for in this study. See slides 29-34 for a detailed account of those concerns.
Short and Long Term studies
Dementia and AD is not a process that develops quickly, similar to other chronic diseases. That does not mean short term studies have no value, and certainly long term studies are not the only way to base decisions on risk factors for brain health. For example, short term studies like trials have been valuable in showing increases in brain volume with specific interventions.
Other fatty acids
While not a long term study, the research by Zamroziewicz et al (2017) on fluid intelligence and underlying GM structure found that ALA and downstream products like stearidonic acid and eicosatrienoic acid (but not EPA or DHA) were linked to fluid intelligence and preservation of total GM volume of the left frontoparietal cortex (FPC) which fully mediated the relationship between the omega-3 PUFA pattern and fluid intelligence. The authors suggest dietary consumption of precursor omega 3 may support neuronal health through the unique neuroprotective benefits of ALA and its immediate downstream products (Zamroziewicz, 2018). This was also suggested in another study where not only ALA but several other fatty acids, including Omega 6, were related to memory function and white matter microstructure suggesting that both Omega 3 and 6 may slow age-related decline and memory (Zamroziewicz, 2017).
Arachidonic acid (AA), which is the 2nd most prevalent PUFA in the brain and 20% of fatty acids in neuronal tissue, is considered an underappreciated risk factor for cognition/AD. AA produces PGH2 eicosanoids which are neuro-inflammatory which is why non-steroidal anti-inflammatory drugs have been shown to reduce risk for AD (Thomas, 2016). In AD patients, ↑ AA incorporation occurred via PET scan compared to healthy controls (Rapoport, 2008). Chicken and egg product intake represent almost 1/2 of AA from food sources in the US diet (National Cancer Institute, 2019). A two week long study suggested improved mood scores when restricting meat, fish, and poultry from the test diets with the authors suggesting these foods may negatively impact brain health (Beezhold, 2012).
Non DHA Factors
Numerous non-DHA factors directly ↑↓ brain size/volume and most are modifiable.
↑↓ Brain size/volume: exercise (Edwards, 2019; Jackson, 2016), Mediterranean-type diet (but not fish in this diet) (Luciano, 2017), fruit and vegetable/nut/whole grain intake (Croll, 2018), meditation (Dodich, 2019), chronic life stress (Gianaros, 2007), obesity (Raji, 2014), trans fat (Bowman, 2012), B12 and also homocysteine levels (Hooshmand, 2016), higher blood glucose level in the normal range (e.g. 5.5 mmol/L versus 5.0 mmol/L) (Walsh, 2018).
Other areas of exploration
Studies assessing serum, plasma, and cerebrospinal fluid have identified several metabolic pathways that have association with AD: bile acids, sphingolipids, antioxidants, phospholipids, and amino acids (Snowden, 2017). Other factors like impaired cerebral glucose uptake and insulin resistance and resultant inflammation may play a role in the pathogenesis of AD suggesting that AD is a metabolic disease mediated by brain insulin and insulin-like growth factor resistance (Toledo, 2017; Lazar, 2018). The extent of cognitive decline in those who were mildly cognitively impaired or who have AD is associated with the degree of glucose metabolism loss, nearly 35% in some brain regions (Weiser, 2016). Those who do not have diabetes or impaired fasting glucose and who have a slightly higher blood glucose level within the normal range still were at risk and experienced brain atrophy, predicted at a rate of approximately 0.06% reduction in total brain volume each year (Walsh, 2018). Some, as a result, are calling AD “Type 3 Diabetes”.
Taking care of gums and teeth to protect for dementia?
Infection by bacteria is implicated in the pathogensis of dementia and AD (Olsen, 2015; Choi, 2019). Poor oral health and gum disease leading to infection with oral bacteria Porphyromonas gingivalis has been suggested to be associated with increased risk for dementia and AD with this bacteria being found in the brains of AD patients and contributing to neuro-inflammation, and interestingly also prior to onset to dementia (Dominy, 2019).
As previously mentioned, many studies did not control for medications that are associated with brain atrophy (Raji, 2014; Walsh, 2018), but medications can also affect dementia risk. For example, anticholinergic drugs are associated with an increased risk for dementia with a recent study suggesting an 11% increase in risk for being eventually diagnosed with dementia and a 30% increased risk for drugs with a high level of anticholinergic effect. These types of medications are routinely prescribed for conditions such as depression, Parkinson’s disease, urinary incontinence, epilepsy, and allergies and even as medications for AD itself (Richardson, 2018; Kennedy, 2018), and common medications like Benadryl also contain anticholinergic effects.
Diet vs Supplements
Diet rather than supplementation should be emphasized, with the exception of Vitamin B12, similar to protective strategies for other chronic diseases. Dr. Tanzi a leading neuroscientist at Harvard university believes that “For heart and brain health, there’s nothing better than a plant-based diet.” (Tanzi, 2014). A 2014 International Conference on Nutrition and the Brain concluded with several guidelines including “Vegetables, legumes (beans, peas, and lentils), fruits, and whole grains should replace meats and dairy products as primary staples of the diet” (Barnard, 2014) and a recent review suggested there is mounting evidence in support of plant based diets for reducing or preventing age related cognitive decline and dementia via their neuroprotective effects (Rajaram, 2019). A recent study investigating dietary patterns in both Canada and France in over 2800 older people found those following healthy diet patterns characterized by higher intakes of plant-based foods rather than traditional diet patterns or Western diet patterns resulted in higher global cognitive performance. The researchers noted unexpectedly that Omega 3 fatty acids were not associated with healthy diet patterns but rather Western diet patterns despite them being touted as beneficial (Allès, 2019).
Supplements in studies for AD or dementia or cognitive decline have largely been without success or significant benefit, including Vitamin E, D, B vitamins, calcium, copper, zinc, selenium and mixed to low evidenced of benefit for beta-carotene and Vitamin C (Rutjes, 2018; Kryscio, 2017)
In 2019, the FDA cracked down on 17 supplement companies who had false claims for brain health on their labels (FDA, 2019) including vitamins, minerals, Omega 3, and herbal products.
“There is zero evidence from any reasonably rigorous study that any supplement or dietary aid has any benefit on cognitive function or decline in late life,” says Dr. David Knopman at the Mayo Clinic in Rochester, Minnesota (Knopman, 2019). Other concerns about fish oil supplements in particular include adding insult to significant depletion and overfishing of fish stocks and increasing concern regarding sustainability. Pollutants are also a concern. A 2013 study examining children’s fish oil supplements found that every sample contained levels of polychlorinated biphenyls (Ashley, 2013).
Calcium: An Example.
Calcium intake is yet another factor that is rarely if ever controlled for, particularly calcium supplements. In elderly women with evidence of cerebrovascular disease who were followed for 5 years, calcium supplements doubled the risk for developing dementia compared to those who did not supplement (Kern, 2016). In women with a previous history of stroke, calcium supplements increased the risk 7-fold for developing dementia compared to those who did not supplement. Women without history of stroke did not have an increased risk from supplements (Kern, 2016). Another study in both elderly women and men showed increased brain lesions with calcium supplement use compared to those who did not supplement (Payne, 2014). Another study in elderly women and men found combined dietary and supplement calcium increased brain lesion volume (Payne, 2008). Excess calcium could possibly play a role in its relationship to calcified carotid plaque and may constrict blood vessels within the brain which could result in lesions.
Vegetarian and Vegan populations
When looking at the first Adventist Health Study, Vegetarians and Vegans showed a lower risk for developing dementia compared to meat eaters (which also included fish intake). Those who consume meat were twice as likely to have dementia and when past meat consumption was factored in, the risk three-fold (Giem, 1993). These results were observed despite DHA levels in the vegetarian populations typically being considered as lower than in omnivores and there also was a trend towards later onset of dementia in the vegetarian groups.
DHA of course is involved in more than just brain health and we therefore would expect to observe harm in other areas where DHA resides or is utilized in those who had status or intake levels considered as “low”, and so far, the literature does not suggest this. In my recent talk on this topic I do mention studies indicating low DHA levels (as we do not see deficiency symptoms or other evidence to indicate this is harmful, the term ‘low’ is somewhat subjective) in vegans but also include data showing that several studies in vegans did not have ‘extremely low levels’, and in one case Welch (2010) higher plasma levels that in other dietary groups. Sarter (2015) showed similar Omega 3 index (a measure of EPA/DHA in red blood cells) and no significant difference in DHA compared to matched omnivore subjects. Rosell (2005) looked at those who were vegetarian or vegan for long periods of time (from less than a year to 76 years) and found that while DHA levels were 59% lower than omnivores, overall, when viewed over time, plasma EPA/DPA/DHA proportions were not significantly different in regard to how long they followed the diets. This suggests that endogenous production of EPA and DHA occurs to provide low but stable levels of EPA and DHA.
Recent research from the Adventist Health study 2, suggests adipose levels of EPA (as a percent of fatty acids) were similar in both vegans and non-vegans. DHA levels in vegans were .12 with a range of .10 - .15 compared to non-vegetarians who had DHA levels at .18 with a range of .15 - .21 (Miles, 2019). So in vegan adipose tissue, DHA represented 12% of all fatty acids. This is quite interesting and may suggest that we need to consider tissue sample status rather than solely plasma status when making associations with levels in brain tissue.
Vegans might be at a distinct advantage (with the exception of those with higher Omega 6 status). Less Omega long chain fatty acids may be needed in vegans as they do not consume preformed inflammatory Omega 6 AA found only in animal products which may affect cognitive function. AA and EPA compete for incorporation and so theoretically vegans should be able to convert EPA to DHA more efficiently due to less or no AA from the diet.
As previously mentioned, AA produces PGE2 eicosanoids which are neuro-inflammatory. The pro-inflammatory prostaglandin PGE2 is made from AA via the COX-2 enzyme, which is expressed in the brain and the COX-2 enzyme is upregulated in the brains of AD patients (Scali, 2002). Higher PGE2 are related to memory disruption and neuronal disease (Johnston, 2017) and is believed to be implicated in pre-clinical AD (Johansson, 2015). Vegetarians and vegans compared to omnivores in several studies were found to have lower PGE2 levels which could be another explanation for why these diets are considered anti-inflammatory and may possibly confer an advantage for brain health. Omnivores placed on a vegan diet for 8 weeks showed a 50% reduction in PGE2 levels (Tanaka, 2001). It has been suggested that Vitamin C, Β-carotene and carotenoids all inhibit COX-2 enzyme activity, all of which are consistently shown to be higher in vegetarians/vegans compared to omnivores, and may help explain why PGE2 levels are lower in those following plant-based diets (Johnston, 2017).
Another reason may be that growth factors such as insulin-like growth factor 1 (IGF-I) increase cox-2 expression by several complementary mechanisms (McCarty, 2012) and IGF-1 is released in excess amounts by the liver with animal protein and lowered by plant protein or those following plant based diets (Levine, 2014; Allen, 2002; Ornish, 2005).
Vegans also typically have lower intakes of saturated fat, cholesterol, and less hypertension, obesity and heart disease all of which are associated with increased risk for cognitive disorders or AD. Vegans typically consume more fruit and vegetables conferring additional antioxidant protection.
Lower levels of serum uric acid increase the risk for AD and Parkinson’s while higher levels in several studies reduce risk for dementia and were associated with improved cognition (Katsiki, 2013). Dairy products lower uric acid levels and increase risk for Parkinson’s (Jiang, 2014). Omnivores and fish eaters typically have lower levels, while vegans in some studies show higher levels, which may put vegans at an advantage (Schmidt, 2013), however excessive levels can lead to health problems and risks. Uric acid may be neuroprotective due to its antioxidant capacity and is the most abundant antioxidant found in plasma (Sakuta, 2016; Kueider, 2017).
Hussein (2005) states, “The fact that DHA can be formed from ALA, albeit at a very low rate, but cannot be increased by increased dietary ALA suggests that DHA concentrations, at least in circulating phospholipid pools, are regulated to satisfy a relatively low metabolic demand that can be satisfied by the relatively low levels observed in vegans with no dietary DHA intake and with erythrocyte DHA levels lower than EPA" (p.278).
Conversely, the population that may benefit the most from ingesting EPA/DHA may be omnivores who consume significant inflammatory AA from animal product intake. Long chain Omega 3 can compete with AA to produce less inflammatory molecules. Additionally, those following the standard American diet, high in processed food and oil and whom may have very unbalanced Omega 3/6 ratios, may also benefit,
especially as several studies that are primarily plant-based (such as the MIND diet) show protection by reducing risk for cognitive decline or AD (Wu, 2019; Morris, 2015; Cherian, 2019).
In my research thus far, what I view as the most important is as follows:
It is not necessarily increasing DHA levels but preserving them, as well as other important fatty acids in neuronal and glial cells (similar to preserving bone mass and lean muscle mass) particularly from oxidation as oxidation of brain lipids (including DHA and AA) are present in autopsies of AD patients and oxidative stress and inflammation are the underlying mechanisms of AD pathology (Alsumari, 2019). The good news for vegans is that they have some of the highest antioxidant and phytochemical status and a well planned vegan diet can be considered an anti-inflammatory diet. This may be why higher intakes of fruits and vegetables are associated with less brain shrinkage (Croll, 2018), less cognitive decline (Chou, 2019; Jiang 2017; Mottaghi, 2018; Fuller-Thompson, 2020) and why blueberries and strawberries alone may delay cognitive aging by up to 2.5 years (Devore, 2012) and have positive effects on areas of congnition in clinical trials (Miller, 2018; Krikorian, 2010).
And why about 2 cups or beetroot juice naturally high in nitrates given to young adults (who are expected to be at peak brain health)
improved prefrontal cortex cerebral blood-flow blood flow (a sensitive marker of cerebrovascular function associated with dementia risk) and cognitive performance, and did so within 90 minutes (Wightman, 2015).
A recent study looking at flavonols, plant-derived phytochemicals found in fruits and vegetables with powerful antioxidant properties suggested that onset of AD was significantly reduced in those with the highest intakes of flavonals compared to lowest intake levels. One flavonol, Kaempherol for example reduced risk of developing AD by an impressive 50% (Holland, 2020).
Additionally, another study found that just one daily serving of leafy greens (even lettuce) was protective against cognitive decline with one study showing that those with highest compared to lowest intake had equivalency to being cognitively 11 years younger (Morris, 2017).
Figure. Morris MC, et al. Nutrients and bioactives in green leafy vegetables and cognitive decline. Neurology. 2017 90:e214-e222.
A whole foods minimally processed well-balanced vegan diet (several plant-based dietary patterns are shown to be protective, rather than a reductionist single nutrient approach), low in saturated fat, with reasonable intakes of both omega 3 and 6, and adequate Vitamin B12 may be the most important for brain health and preservation.
Why are reasonable intakes of both omega 3 and 6 important?
Often plant-based researchers promote high intakes of plant-sourced ALA for vegans. Wood (2015) suggests that too much ALA may affect DHA synthesis as there are 2 ∆ 6 desaturase enzymes (ALA > EPA, and EPA > DHA) and too much ALA may use the first enzyme and be rate-limiting to the second one. Other research suggests that trials giving high ALA may displace DHA in membrane phospholipids which could provide a rationale to not focus so heavily on increasing ALA (Hussein, 2005) as ALA would be curvilinear (meaning there is a certain point where increasing amounts provide no benefit). What this may mean for vegans is placing less of an importance on very high intakes of ALA from plant sources and instead a more moderate intake of both ALA and LA.
Why is adequate vitamin B-12 important?
Vitamin B12 it is associated with being neuroprotective especially the hippocampal region, and a meta-analysis found that Vitamin B12 deficiency was associated with stroke, AD, vascular dementia, Parkinson’s disease and in even lower concentrations with cognitive impairment (Medawar, 2019). As Vitamin B12 deficiency contributes to cognitive decline, increases homocysteine levels and risk for stroke (Spene, 2016), meeting adequate intakes is especially important and fortunately quite easy to ensure.
The above considerations, along with regular consistent exercise are the factors to recommend the most for brain health and coincidentally for most other chronic diseases too (just like with preserving bone mass and lean muscle mass). Few studies looking at brain health control for these, or for many other factors including AA, fruit and vegetable intake, obesity/BMI, and level of exercise, all associated with cognitive decline/AD.
As but one important example of a nutrient not controlled for:
Magnesium (mg) has significant associations with cognitive function and AD and mg concentrations are reduced in AD patients compared to healthy and medical controls. Additionally, postmortem examinations of AD brains have found decreased mg levels compared to healthy controls (Dominguiez, 2018). Mg is abundant in fatty fish like salmon.
So while some studies show lower DHA in brain of AD autopsies, some do not, and there is still contradictory research about this (Fraser, 2010) and that doesn’t mean levels or dietary intake of DHA is the culprit, as other things like Mg are low, and oxidation is high, or perhaps reverse causality could be at play.
Observational studies looking at brain size and DHA may be distorted by things like Mg (perhaps Mg is the important factor) and many other nutrients, diseases or lifestyle habits as well, as I have mentioned. Other good news for vegans is that they typically have the highest intakes of Mg compared to other groups (Schupback, 2017).
Cunnane (2013) suggest is it puzzling that if low DHA status or low fish intake is associated with AD, why post-mortem studies do not consistently show lower brain DHA. Additionally, “… the literature on measurements of DHA in human plasma or brain shows highly varied results which neither support nor refute the putative link between lower DHA and risk of AD” (p. 63).
Vegans concerned about brain health
Barceló-Coblijn (2009) wrote: “In other words, can a terrestrial animal (humans) that is an omnivore truly requires dietary DHA in order to have optimal physiological performance despite the true rarity of DHA in the world’s food web, but a web where ALA exists in abundance” (p. 361). Several researchers suggest no, and that ALA is sufficient for development and maintenance of the brain (Langdon, 2006; Carlson, 2007).
It is reasonable to ensure getting some omega 3 sources, i.e., walnuts, flax, others. A handful of walnuts will meet your ALA daily recommended requirements. However, ALA is found in many foods including beans, squash, leafy greens, seeds, and nuts. My prior talks show a sample vegan meal plan that meets and easily exceeds the daily requirements without added oil, flax, walnuts, chia etc but from everyday foods.
A whole foods minimally processed vegan diet, low in saturated fat, with reasonable intakes of both omega 3 and 6 will also help improve the higher omega 6 to 3 ratios seen in vegetarians/vegans.
An algae supplement could be considered for those who want to match DHA intakes recommended by some health professionals. Though most health professionals commonly mention there is little downside to DHA supplementation, it should be noted that a few studies showed increases in LDL Cholesterol with algae supplementation in vegetarians or omnivores which could affect CHD Risk (Sanders, 2009; Bernstein, 2012). One meta-analysis did and another found a trend for a slight increased risk for prostate cancer for EPA/DHA, as did for another study when assessed via blood concentration levels of DPA/EPA/DHA from fish/oil (Crowe, 2014; Alexander, 2015; Brasky, 2013 ). The Institute of Medicine noted that high doses of DHA and/or EPA (900 mg/day of EPA plus 600 mg/day DHA or more for several weeks) might reduce immune function due to suppression of inflammatory responses (IOM, 2019) and it is unknown if algae could also have similar effects. And some studies have shown that dietary DHA suppresses the conversion of ALA to EPA/DHA (Barceló-Coblijn, 2009) which could result in less of an ability to take advantage of the independent benefits associated with the other ALA downstream products.
Algae or fish oil supplements are a processed oil, and ‘free oils’ (both omega 3 and 6) as Dr. McDougall has suggested, are incorporated into atherosclerotic lesions and plaques, similar to other dietary fats.
A recommended article: Cunnane SC, et al. Docosahexaenoic acid homeostasis, brain aging and Alzheimer's disease: Can we reconcile the evidence? Prostaglandins Leukot Essent Fatty Acids. 2013 Jan;88(1):61-70.
Note. Animal studies were not reviewed as part of this summary.
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