There is a 99.6% failure rate of pharmaceutical drugs for the treatment of dementia and Alzheimer’s Disease [AD] (Cummings, Morstorf & Zhong, 2014).
Read that again.
Of all the advances in modern medicine, the one area where nearly every single potential therapeutic agent has failed is in the realm of neurodegenerative disease and cognitive decline. In the context of nutrition and health, the awkward term “non-communicable diet-induced disease” has emerged as an adjective for conditions in which diet/nutrition are a significant causative risk factor: obesity, metabolic syndrome, cardiovascular disease and type-2 diabetes.
Is there enough evidence to suggest that AD and dementia be included in that spectrum? Like all of the aforementioned conditions, genetic factors play a role. Additionally, there are features of the pathogenesis of AD and dementia that remain poorly understood or subject to debate. Nonetheless, and in the particular light of the complete failure of pharmaceutical agents for the treatment of AD and dementia to date, diet and nutrition thus assume particular significance as a modifiable factor which may contribute to the prevention of dementia (Morris, 2009).
This article will give an overview of the evidence for nutrients in the prevention of dementia and AD. To date, the strongest evidence suggests that dietary fish and the omega-3 essential fatty acids, antioxidants, and B-vitamins may be neuroprotective and attenuate cognitive decline (Morris, 2009).
Fish intake could be considered the strongest and most consistent dietary trait associated with lower risk of AD and dementia. Epidemiology has consistently shown this correlation (Barberger-Gateau et al., 2002; Kalmijn et al., 1997; Morris et al., 2003). The minimum effective dose evident in the population research is an average consumption of one fish meal per week (Barberger-Gateau et al., 2002; Morris et al., 2003).
The effect appears to be particular to fatty/oily fish, as reduced risk of dementia appears to relate specifically to the omega-3 essential fatty acid DHA (Morris et al., 2003). Higher phospholipid DHA content was associated with a reduced risk of dementia in the Framingham Heart Study, in subjects followed-up 9-years from baseline (Schaefer et al., 2006).
In human intervention trials, the results tend to differ relative to the degree of cognitive decline in the subjects studied. In elderly adults with onset AD, it doesn’t appear that DHA supplementation attenuates further cognitive decline, despite increases in phospholipid DHA content (Quinn et al., 2010). In elderly adults with age-related cognitive decline, but without dementia, 900mg DHA per day improved cognitive function over 24-weeks (Yurko-Mauro et al., 2010). Interestingly, 500mg DHA per day failed to have an effect over 24-months in healthy older adults, which suggests a dose-response (Dangour et al., 2010). It may be that higher levels of DHA are required to have any effect.
The cumulative weight of evidence does suggest that fish intake and essential fatty acids, in particular DHA, is protective against cognitive decline (Morris, 2009; Cole & Frautschy, 2010). It may, however, not mean much once dementia and/or AD onset. This reflects an overall theme in the realm of nutrition and cognitive decline – prevention is currently the only cure.
In the Chicago Health and Ageing Project Study [CHAP Study], overall Vitamin E intake from both diet and supplements was associated with less cognitive decline (Morris et al., 2002). One of the issues, observed in both the dietary fish population research and the vitamin E research, is that higher levels of both fish and vitamin supplement use is consistently correlated with higher overall education status and overall dietary antioxidant intake (Morris et al., 2002). Controlling for these variables, inverse associations remain between food sources of vitamin E and cognitive decline [i.e. higher vit E intake from food = less cognitive decline] (Morris et al., 2002),
This is important because the evidence from controlled trials in support of vitamin E supplementation is less convincing. While vitamin E supplementation may benefit subjects with onset AD (Dysken et al., 2014), it does not appear to be protective against progression from mild cognitive impairment to AD (Evans, Morris & Rajan, 2014). In otherwise healthy older adults, intervention trials have failed to find any improvement in cognition from vitamin E supplementation (Kang et al., 2006; Kang et al., 2009).
The evidence is inconsistent in epidemiology in respect of vitamin C from diet and/or supplements. In the CHAP Study vitamin C supplementation was associated with attenuated cognitive decline, but not vitamin C from food sources alone (Morris et al., 2002). In the Rotterdam Study dietary vitamin C was associated with lower risk of dementia, after controlling for supplementary antioxidant intake (Engelhart et al., 2002). However, at 9-years follow-up in the Rotterdam cohort the effect of vitamin C was no longer evident and, consistent with the CHAP Study, only high vitamin E intake was associated with a lower risk for dementia (Devore et al., 2010). While inverse associations have been noted between serum ascorbate and dementia risk (Chang et al., 2014), there is currently a lack of controlled human data in respect of vitamin C intake and cognitive decline.
A high intake of dietary flavonoids, the diverse group of phytonutrients found in vegetables and fruit, has been associated with reduced risk of dementia (Letteneur et al., 2007), and reduced risk of AD in smokers (Engelhart et al., 2002). This association is not always evident, and a feature of populations with high flavonoid intake is the fact that they also tend to have higher intakes of fish (Devore et al., 2012), making an assessment of flavonoid intake alone difficult.
In human intervention trials, daily anthocyanin supplementation has been shown to improve cognitive function in elderly adults with mild cognitive impairment over 12-weeks (Krikorian et al., 2009; Krikorian et al., 2010). Controlled trials in adults with mild cognitive impairment are thus promising, albeit limited.
Due to their collective role in various neurological processes, B-vitamins have been implicated in neurological disease (Morris, Schneider & Tangney, 2006). In particular, vitamins B6, B9 and B12 are all essential co-factors in the methylation of homocysteine to methionine, and high homocysteine levels have previously been associated with an increased risk of AD (Morris et al., 2006).
This makes a connection between B-vitamin deficiency plausible on a mechanistic level, yet the CHAP Study failed to find any association between B6, B9 or B12 and risk of AD over a 4-year period (Morris et al., 2006). There are some potential anomalies in the epidemiological research. For example, greater cognitive decline was observed with high supplemental folic acid and dietary folate intake (Morris et al., 2005).
While the epidemiology is inconsistent (Morris, Schneider & Tangney, 2006), a randomised controlled trial of high dose B6, B9 and B12 in elderly adults with mild cognitive impairment reduced brain atrophy by 29.6% over 2-years compared with controls (Smith et al., 2010). The suggested mechanism was reduced homocysteine, which decreased 22.5% in the treatment group (Smith et al., 2010). Another notable feature of this study was that the rate of brain atrophy in the placebo group was independent of the MTHFR 677C>T polymorphism, which genetically predisposes an individual to elevated homocysteine unless higher levels of B9 are consumed to overcome reduced enzymatic function (Smith et al., 2010).
In an almost identical trial, which used the same doses of B6 (20mg/d), B9 (800mg/d) and B12 (500mg/d), homocysteine levels decreased by 30% and attenuated cognitive decline in elderly adults with mild cognitive impairment (Jager et al., 2012). It has been noted that the inconsistencies in epidemiological research may be due to study design limitations (Morris, Schneider & Tangney, 2006). The limited evidence from RCT’s does suggest a potential protective effect of high dose B-vitamins in adults with mild cognitive impairment (Smith et al., 2010; Jager et al., 2012).
The food sources associated with attenuated cognitive decline, and prevention of dementia and AD, are consistent with the nutrients identified: green leafy vegetables, berries and fish providing vitamin E, folate and essential fatty acids (Morris, 2016). Particular diet patterns associated with overall health have primarily been investigated for prevention of cardiovascular disease, including the Mediterranean diet or Dietary Approaches to Stop Hypertension [DASH] but some recent data supports these dietary patterns in preventing cognitive decline (Morris et al., 2015).
These diet patterns do not, however, specifically encompass the food types and servings identified for dementia prevention, leading to the formulation by venerated dementia research Martha Clare Morris and colleagues, of the Mediterranean-DASH Intervention for Neurodegenerative Delay [the MIND diet] (Morris et al., 2015). The MIND diet encompasses specific intake of green leafy vegetables and berries, one or more servings of fish per week, but makes no recommendations for high fruit, dairy, potato or fish intake >6 per week that are characteristic of the Mediterranean and DASH diets (Morris et al., 2015).
In assessing the impact of the more specific MIND diet recommendations in a elderly community-dwelling adults, the effect of high adherence was a delayed cognitive ageing equivalent to 7.5-years (Morris et al., 2014). For perspective, this means that an 80-year old had the cognition of a 73-year old when assessed 5-years after baseline. A really interesting feature of this particular study is the comparison of the MIND to Mediterranean and DASH diets. Health-promoting as they may be, they only appear to be protective against AD with high adherence (Morris et al., 2014). In contrast, the MIND diet afforded substantially reduced risk at the highest tertile, but even moderate reduction of risk for AD with intermittent compliance (Morris et al., 2014).
The food-based recommendations to prevent dementia are currently strongest for green leafy vegetables, berries, and fish (Morris, 2016). This list will most likely expand over the next few years, as scientific advances are made in a field that is currently underdeveloped (Morris, 2016).
For now, this is my twist on the state of the evidence for best food-based approach:
1: Green leafy vegetables (kale, spinach, chard, lettuce etc.): 1 serving (1-2 cups dry measure minimum) per day
2: Other veg (peppers, squash, carrots, broccoli, celery, tomatoes, beets, zucchini, aubergine): 1 cup serving per day
3: Oily fish (salmon, mackerel, sardines, herrings, anchovies): 3 90-120g servings per week
4: Dark-skinned berries (strawberries and blueberries in particular): 100g daily (or at least 4-5 times per week)
5: Nuts (nut butters count): 30g serving daily (or every other day)
6: Dark chocolate (min.85%): 10-20g serving daily (or every other day)
7: Beans/legumes: 1/2 cup or 80-100g serving 3-4 meals per week
8: Extra virgin olive oil: 1 tablespoon (15ml) daily
9: Red wine (no joke): 1 glass (5 fl oz or 150ml) daily (obviously optional, but the evidence supports it)
Most of the foods are reflected in the MIND diet, but I’ve tinkered with serving frequency with some because, for example, its not hard to eat a 100g of blueberries every day. These foods collective reflect the nutrients with the strongest evidence for protecting brain health: vitamin E, omega-3 fatty acids, antioxidants – in particular flavonoids, B-vitamins and, potentially vitamin C.
However, it bears noting that assessing the healthfulness of any particular diet pattern is difficult, due to the complexity of diet and the interactions between micronutrients and phytonutrients. For this reason, we can expect to continue to uncover other contributing factors, and the above list is not intended to be definitive or exhaustive; this field is only emerging, and subject to change as the evidence evolves.
For now, I think it is important to re-emphasise: when it comes to your brain health, prevention is currently the only option. Start insuring consistent intake of the foods listed above, and keep your brain sharp.