Copy of article written by Denise Melton which was published in Avena Magazine, Summer 2015, Vol 15 (4), quarterly magazine of the New Zealand Association of Medical Herbalists
Alzheimer’s Disease (AD) is the most common neurodegenerative disease and the fourth leading cause of death in developed countries, with the incidence set to rise dramatically over the next thirty years at huge cost due to the fact that medium to late stage AD requires full time care. AD can be familial, caused by gene mutation with early onset or related to environmental factors, with age being one of the biggest risk factors, along with type 2 diabetes and obesity. AD is characterised by progressive memory loss and lowered memory recall; death of neuronal tissue, shown as a decrease in size of the hippocampus and cerebral cortex; diminished ability to function, lowered mood and aggressive behaviour. At this time there is no known cause or cure for AD, and a definitive diagnosis is only possible postmortem by the presence of neurofibrillary tangles and senile plaques in the neural tissue, however the presence of tangles and plaques does not always result in AD. It appears that AD is extremely complex resulting from a combination of factors including aggregated amyloid-ß protein, inflammation, oxidative stress, lowered cerebral glucose uptake and insulin resistance (Craft et al, 2011). There are few treatments for AD and none that can stop the advance of the disease once the clinical manifestations are seen, however some natural therapies have been shown to slow the progression of the disease; which can reduce the incidence of AD by half, and also modify or alleviate the symptoms (Sezgin & Dincer, 2014). In this review we will look three natural treatments, these being; 1) improve brain metabolism through the use of diet, 2) reduce inflammation and oxidative stress with plant phytochemicals such as curcumin and resveratrol 3) exercise, an important factor in improving overall brain health.
Brain metabolism and cognitive decline
AD has a progressive onset with years before any clinical symptoms appear and the pathology appears to have a strong metabolic correlation, with impaired glucose metabolism being an early predictor of cognitive decline (Mosconi et al, 2006). The brain consumes a fifth of blood glucose and oxygen, which is used by the mitochondria to drive cellular processes. The brain also uses ketones efficiently when glucose levels are low, as when you are asleep, however a decrease in glucose uptake alters metabolism, resulting in oxidative stress which disrupts synaptic activity (Mosconi, Pupi & De Leon, 2008). High glucose levels in the blood have a negative effect on cognition, learning and memory in non diabetics as shown in this study of 141 persons between the ages of 50 to 80 years. Blood glucose, glycosylated haemoglobin (HbA1c) and insulin levels were measured after a 10 hour fast, then participants were tested on delayed recall, learning ability, and memory, as well as scanned with an MRI to assess hippocampal volume. Lower memory performance in all tasks was shown as well as smaller hippocampal volume for higher levels of both HbA1c and blood glucose, indicating that high blood glucose levels effects the learning centres of the brain (Kerti et al, 2013). High levels of dietary carbohydrate increase the risk of mild cognitive impairment even without any other risks for brain degeneration, as shown by this study in which elderly participants where followed for a period of 3.7yrs, their macronutrient intake assessed using a questionnaire and cognition abilities tested (Roberts et al, 2012). In a population study of 737 participants between the ages of 45-75 years, which looked at dietary information from the past year, as well as education, lifestyle information and cognitive abilities indicated that high sugar intake contributed to lower memory and learning scores when tested and those that had a high intake of fructose showed the higher rates of decline in cognition function (Ye et al, 2011).
Glucose is transported across the blood brain barrier via glucose transmitters (GLUTs) and into astrocytes (GLUT1) and neurons (GLUT3), these are not insulin dependent. GLUT4 involved in glucose transport in areas such as the hippocampus, an area responsible for memory and learning involve insulin-regulation, therefore these areas are susceptible to insulin-resistance. Lack of glucose to these areas due to insulin-resistance in a state of hyperglycaemia means that the neurons are unable to obtain fuel from glucose or ketones, (ketones are only made available if glucose levels are low) resulting in a decline in memory and learning abilities (Watson & Craft, 2004). Studies involving the relationship between Type 2 Diabetes Mellitus (T2DM) and AD showed that T2DM and impaired fasting glucose could enhance the progression of AD due to hyperglycaemia, hyperlipidaemia and insulin resistance, however it may not contribute to AD (Janson, 2004, Schrijvers et al, 2010). In a postmortem study of AD brain tissue, AD pathologies was linked to impaired insulin and insulin-like growth factor expression which affects mitochondrial function and energy metabolism, increasing pro-inflammatory cytokines and oxidative stress (Steen et al, 2005).
Proteins in the blood become glycated due to high levels of glucose which impairs their function and creates advanced glycation endproducts (AGEs). Apolipoproteins are particularly prone to glycation and ApoB, the main apolipoprotein in LDL, is especially susceptible as it is rich in the amino acid lysine (Younis, 2008). There are three types of genes that code for Apolipoprotein, and the Apolipoprotein E (APOE) gene is a risk factor for AD, although not everyone with this gene will develop AD. Glycation effects the uptake of apoE-containing lipoproteins by the astrocytes which means they need to make cholesterol for the neurons which is an energy intensive process which leads to oxidative stress in the astrocyte and oxidation of the lipoprotein which can lead to arterial plaques forming (Laffont, 2002). Oligodendrocytes also require cholesterol from ApoB in order to create the myelin that surrounds the axons protecting them from oxidation damage therefore glycation of ApoB lipoproteins could result in damage to the axons and affect the transmission of nerve impulses as shown in an animal study (Saher et al, 2005). The amyloid plaque deposition associated with AD is largely due to AGEs and evidence shows that the interaction of AGEs with a receptor for AGEs (RAGE) bring about oxidation and inflammation of the blood vessels, altering cell gene expressions contributing to the pathology and characteristics of AD (Takeuchi & Yamagishi, 2008).
Given that the mechanisms described above for the development of AD are similar in other metabolic diseases such as diabetes and metabolic syndrome, it would follow that a calorie restrictive diet especially low carbohydrate would reduce AD neuropathology. In a small study of 23 adults, an average age of 70 years with mild cognitive impairment, half of which were placed on a high carbohydrate diet, 50% of calories from carbohydrates and half on a low carbohydrate diet, 5-10% of calories from carbohydrates, to assess whether diet effected their memory performance. These adults all had normal levels of fasting glucose however their fasting insulin levels was in the upper limits of the normal range and they all were sightly overweight. The trial was over a 6 week period with the results showing that low carbohydrate diets, forces the brain to use ketones for energy and lowers fasting insulin levels resulting in enhanced cognition (Krikorian et al, 2012). A similar study of 937 elderly persons that looked at the macronutrients in participants’ diet and how this impacted their rate of cognitive decline, this study also showed that high carbohydrate was a risk factor for neurodegeneration (Roberts et al., 2012). In another study done on mice, dietary ketosis brought about through low carbohydrate diet was shown to reduce soluble beta-amyloid (Aß) thought to be brought about by lowered brain insulin levels, this reduction in Aß did not correlate with memory improvement (Van der Auwera et al, 2005).
The Mediterranean diet which is defined by the consumption of manly plant food with high intake of monounsaturated oil, inclusion of fish and seafood with low intake of dairy, meat and saturated fat, and regular moderate consumption of red wine, is thought to be beneficial for most chronic disease (Martínez-Lapiscina et al, 2013). In a population-based cohort study done to investigate whether the Mediterranean diet improved risk for dementia it was found that higher adherence to the Mediterranean diet principals may slow cognitive decline (Féart et al., 2009) The Mediterranean diet was tested as an option for maintaining brain health in a study of 194 brain healthy 70 year old adults. Participants where asked to keep a weeks diary of their food intake, and given a score based on adherence to the Mediterranean diet. Five years later participants took tests to measure dementia and cognitive decline and correlation with high meat consumption and lower performance was shown (Titovaa et al., 2013). Omega 3 polyunsaturated fatty acids (PUFA) found in fish are part of what makes the Mediterranean diet so protective, these fats maintain membrane fluidity, modulate neuronal function and regulate oxidative stress processes. In 2003 Morris and colleagues analysed data from a questionnaire given to 815 subjects analysing their dietary intake after which they where followed for up to 3.7yrs for signs of AD (Morris et al., 2003). Out of the 815, 131 developed AD, however a significantly reduced risk was seen by those who ate fish once a week compared to those who rarely or didn’t ever eat fish. Using omega 3 as a supplement on it’s own or combined with alpha lipoic acid was assessed in a small study of 39 people with AD, both supplements were found to slow cognitive decline (Shinto et al, 2014). The Framingham Heart Study looked at levels of Docosahexaenoic Acid (DHA) in the brain of 899 people, median age of 76yrs who showed no signs of cognitive decline, for a period of 9.1years. Over this period 99 cases of dementia, of which 71 where AD, was seen, and it was shown that those with higher plasma levels of DHA and who consumed fish up to 3 times per week had less risk for cognitive decline (Schaefer et al., 2006).
In people with medium to advanced stage AD there is a risk of malnutrition and weight loss, due to difficulty chewing and swallowing, and loss of enjoyment from food, this contributes to hastening their decline, therefore it is important to address diet on an ongoing basis (Grundman, 2005). Supplementation of vitamins and minerals therefore may be necessary, niacin (B3) has been shown to have a beneficial effect on patients with dementia and a preventative effect on AD (Morris et al, 2004). Vitamin B12 is essential to brain health and in reducing homocystine which is often high in AD, although homocystine contributes to vascular disease it is not shown to be responsible for the pathologies in AD (Kivipelto et al, 2009), B1, B6 & folate are also needed by the brain and insufficiences can result in metabolic dysfunction adding to mitochondrial stress (Clarke et al, 2014).
Oxidative stress and neuroinflammation are a feature of the AD brain (Zhou et al, 2014), polyphenols which are a phytochemical found in plant food that can cross the blood brain barrier, have been shown to preserve and improve both memory and cognition by targeting specific signalling pathways associated with protein folding and neuroinflammation (Williams et al, 2008). Curcuminoids found in turmeric and resveratrol found in grapes have been shown to protect brain cells against toxicity from aggregated amyloid-ß and oxidative stress (Feng et al, 2013; Taylor et al, 2011). Most Flavonoids exhibit anti-inflammatory and antioxidant properties so a diet rich in plant foods would be beneficial in combating some of the pathology of AD (Ross, 2002; Joseph, 2005). In one study done in vitro to ascertain the protective effects merlot, a red wine, it was shown that many of the phytochemicals have a neuroprotective property with quercetin and procyanidins being the most powerful, in their ability to reduce reactive oxygen species production and scavenge free radicals (Martín et al, 2011).
Protective Role of Exercise
Physical exercise, even in moderate amounts, is beneficial for the brain in many ways as it promotes brain-derived neurotrophic factor (BDNF), activates antioxidant pathways, improves brain plasticity and improves learning (Marques-Aleixo, 2012). In older persons their level of physical activity declines due to a decrease in social interactions, lack of exercise opportunities and a general sense of what physical activity is appropriate for them given that they may have some other handicap (Miller, 2012). In a study of 1740 participants as part of a broader study on aging and dementia, physical exercise was monitored and it was shown that regular exercise, at least three times per week, regardless of the type decreased or delayed risk for development of AD (Larson, 2006). In California a study was done with persons diagnosed with mild through to moderate AD, who agreed to be monitored over a period of a year for their level of physical exercise, as well as their mood, apathy levels and other behavioural symptoms associated with AD. The results showed that even small amounts of exercise, and walking was the preferred option for most of the participants, improved mood and other behavioural symptoms and stabilised cognition, whereas those who were sedentary showed no improvement and even decline (Winchester, 2013).
Mindful exercise, which includes body awareness exercises, learning sequences, breathing and looking inwards, incorporating dance movement, physical therapy, yoga and Tai Chi improves the daily lives of those living with dementia, and overall sense of self. This is evident in a small qualitative study of 11 people, mostly women, who took part in a programme of mindful exercise and their movements were observed and recorded by the instructors. Overall it was shown that participants not only improved in their physical movements but showed significant behavioural and social improvements (Wu et al, 2014). A recent study on individuals over 65 who had mild cognitive impairment looked at the effectiveness of Tai Chi verses just stretching and toning on cognitive decline, Tai Chi was more preventative to further decline (Lam, 2014).
AD is a debilitating disease with a set outcome once diagnosis has been confirmed, reducing the incidence and slowing the progression should be our aim. High sugar diets are consistently shown to be implicated in the formation of AD and ongoing cognitive decline, with high blood glucose and insulin-resistance contributing to the formation of free radicals, and the death of neurons in the memory and learning areas of the brain. As a natural health practitioner we can offer some help in educating our clients to the beneficial effects of a high plant based diet, such as the Mediterranean diet with emphasis on those foods which contain large amounts of medicinal polyphenols such as blueberries, grapes and turmeric. The inclusion of omega 3 PUFA in the form of fish and seafood or supplemented along with supplementation with B vitamins reduces risk of AD. Regular physical exercise regardless of genetic predisposition and even at low intensity such as walking or Tai Chi improves cognition and protects against early development of AD. Mindful exercise also has a vital role to play in the psychological aspects of AD, such as mood and social behaviours.
This review has only looked at three areas in which we can help with prevention of AD, however other avenues of interest include looking at education, heavy metal toxicity, HDL cholesterol, herbal remedies, the microbiome, and their respective contributions to AD.
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