By Sarah Belton
Bachelor of Human Nutrition,
University of Canberra
Dementia is defined as an insidious and progressive neurodegenerative disease that slowly reduces memory, higher intellectual function, and cognitive performance in general. Dementia is an umbrella term used to describe a range of symptoms caused by structural and chemical alterations in the brain, closely linked to a number of physical diseases such as hypertension, obesity, Type 2 diabetes, and cardiovascular diseases. Alzheimer’s disease is the most prevalent of the dementias, closely followed by vascular dementia. Risk factors associated with dementia include both genetic and environmental elements. The following discussion will focus on the modifiable dietary risk factors associated with serum cholesterol and homocysteine, with recommendations for preventative strategies and dietary advice.
The most prominent structural change in the brain, that has been labelled the characteristic hallmark associated with Alzheimer’s, is the over accumulation of b-amyloid protein deposits in neurons and extracellular brain space (1-3). Normal b-amyloid protein levels facilitate in modulation of synaptic activity and neuronal growth (4). However, the consequence of b-amyloid protein accumulation and aggregation is the unregulated buildup of neuritic plaques, which in turn compromise the structural integrity of cerebral blood vessels, and hence the nutrient transport to essential brain tissues (5). Recent studies have examined the generation and regulation of these plaques, with conclusions directing responsibility largely to cholesterol levels (6-8). Although the relationship is supported by evidence, there are very few scientific conclusions that can explain the exact interaction between increased cholesterol levels and the enhanced formation of b-amyloid plaques in the brain. However, the impact that cholesterol claims over the b-amyloid metabolic pathway can be directly observed through both genetic and dietary connections (2).
Evidence has established a specific allele variant of the apolipoprotein gene that is essential for cholesterol synthesis and transport in the brain, as a major genetic risk factor for dementia and Alzheimer’s disease (9-12).This allele is presumed to be highly influential on the accelerated formation of b-amyloid plaques, although the direct interaction remains highly controversial (6, 13).
Despite the consistent support for their biological relationship, the specific mechanisms of dietary cholesterol and b-amyloid regulation remain elusive (7, 13-16). One possible hypothesis postulates that the secondary vascular effects of elevated serum cholesterol may have a negative effect on the cerebrovascular system, which would cause alterations to the mechanisms of cerebral cholesterol synthesis and transport, as well as b-amyloid regulation and clearance (17).
A diet high in saturated fat has been shown to elevate serum cholesterol levels (18). Over time, high serum cholesterol levels have been associated with cardiovascular disorders such as high blood pressure (18), blood clots, cholesterol plaques within blood vessels (19), and consequent changes in blood circulation. The resulting physiological effect of blood clots, plaques, and b-amyloid deposits within blood vessels and tissues involves altered or restricted blood flow throughout the body, in addition to reduced nutrient transport. Both of these factors result in limited delivery of important nutrients such as oxygen and glucose through the cerebrovascular system, therefore affecting cognitive function (20, 21).
High cholesterol has also been associated with obesity (22, 23) and Type 2 diabetes (1, 24), which are both known risk factors for the development of dementia (25, 26). Furthermore, high serum cholesterol profiles have been shown to encourage b-amyloid deposits within neurons and surrounding cerebral tissue, which lead to the hallmark clusters associated with dementia (27). Thus, it is reasonable to assume that individuals with a diet high in saturated fat are at high risk of developing cardiovascular diseases and cognitive decline (2, 17, 27).
In contrast to the effect of saturated fats, intake of polyunsaturated dietary fats can act as a protective measure against the above mentioned physiological implications and risk factors linked to elevated cholesterol levels (28, 29). Unsaturated fat derivatives are key components of the highly synaptic myelin sheaths located in the brain (30). They have important roles in maintaining the structural integrity of the neuronal membranes (31) and establishing fluidity of the synaptosomal membranes, hence monitoring the plasticity, speed and effectiveness of neuronal communication (28).
Polyunsaturated fats promote positive reactions within the vascular system such as anti-arrhythmic, anti-thrombotic, anti-atherogenic and anti-inflammatory effects (32). More specifically, omega 3 polyunsaturated fats lower blood pressure, serum triglyceride levels, and improve endothelial functioning (29). As previously discussed, the knowledge that these factors decrease cardiovascular disease risk implies that they will also indirectly decrease dementia risk (2, 27).These fats could also have a direct protective impact against dementia by limiting the synthesis of pro-inflammatory cytokines. Cytokines are considered a strong pathological component to Alzheimer’s disease and cognitive decline (32). As an additional cerebral benefit to maintaining neuronal membrane function, unsaturated fat derivatives may have a role in regulating amyloid precursor protein (APP), thus limiting b-amyloid production (29).
The initial report from the Italian Longitudinal Study on Ageing established a distinct connection between high polyunsaturated fat intake and a decrease in cognitive decline. After a median follow up time of 8.5 years there was still a significant linear correlation between unsaturated dietary fat consumption and cognitive performance (28). The importance of unsaturated dietary fats can be supported further by the substantial field of evidence that directly relates fish intake to increased cognitive function and performance during old age. Multiple studies have shown a 40-60% reduced risk of dementia and Alzheimer’s with a high fish, and hence high polyunsaturated fat, diet (33-35).
In addition to polyunsaturated fats, fruits and vegetables should be considered a determinant for a healthy and protective diet. These two low saturated fat food groups are recognised for the high amounts of antioxidant micronutrients that they provide, with the added benefit of synergistically improved bioavailability (36). Antioxidants have the ability to neutralise free radicals, and reduce oxidative stress, which is defined as an imbalance between oxidants and antioxidants. This imbalance is a pathogenic mediator for Alzheimer’s, responsible for damaged DNA, proteins and lipids in both the brain and peripheral tissues of sufferers (37). A diet high in antioxidants has been associated with a slower rate of cognitive decline, illustrating a strong inverse linear relationship (38).
Taking into account the last two dietary components discussed, the Mediterranean diet is considered one of the best preventative measures to lower the risk of both cardiovascular and cognitive diseases (35). The Mediterranean diet consists primarily of vegetables, fruits, nuts, legumes, and fish, with moderate intake of wine, and low intake of meat and dairy products (18). This diet displays great benefit to blood lipid concentrations, decreased oxidative stress, and the overall function of the vascular system (18, 39-41). It is worth noting for the following discussion that vitamins B6, B12, and folate are all included in the Mediterranean diet. Vitamin B6 and folate are found in legumes, bananas, nuts and leafy green vegetables (25), while B12 is found in animal products such as meat, eggs and dairy (25). These vitamins are important regulators responsible for preventing the second structural change of the brain tissue observed in dementia sufferers; the shrinkage of vulnerable cerebral regions that are critical to learning and memory (42, 43).
One of the key biological components that influences this progressive atrophy is homocysteine (Hcy), a toxic by-product of amino acid metabolism (44). Total plasma Hcy concentrations are regulated and monitored by B vitamins. However, a deficiency in these essential nutrients can lead to high levels of Hcy in circulation, which may be responsible for various pathological changes in the brain including vascular damage, oxidative stress, promotion of apoptosis, and an increased generation and accumulation of b-amyloid plaques (45-47). In relation to atrophy of the brain, elevated Hcy levels have been held accountable for the reduction in hippocampal volume (48), total brain volume (49), medial temporal lobe volume, (44, 43, 48), and the ventrile-to-brain ratios (50), observed in dementia sufferers, although the causal pathway has yet to be defined. Further evidence regarding the detrimental side effects associated with the unregulated biomarker include carotid, coronary and cerebral atherosclerosis, thrombosis, stroke, cardiovascular mortality (27) and cognitive diseases (51-53).
The concept that this modifiable risk factor could be prevented by vitamin B intake has raised some promising research, although most of the longitudinal research does not have a sufficient number of participants. Regarding B6, B12, and folate, studies have been controversial but the general consensus appears to be that B6 and folate demonstrate a linear correlation between plasma concentrations and higher memory or cognitive performance tests (52, 53, 42). B12 however poses difficulty for research in the sense that serum concentrations do not accurately reflect the intracellular concentrations (54), leading to conflicting data across the field. Epidemiological evidence has established hyperhomocysteinemia as a strong prognostic marker for poor cognitive performance and future decline. Excessive Hcy concentrations and B vitamin deficiencies are considered to be modifiable risk factors with regard to dementia (42, 44). The preventative nature of vitamin B in relation to neurodegenerative diseases could be demonstrated by larger observational or random control trials.
Vitamin D is also considered essential for the prevention of cognitive decline, as it has the positive effects of stimulating phagocytosis and clearance of b-amyloid plaques, whilst additionally protecting against glucocorticoid-induced apoptosis in hippocampal cells that would otherwise result in atrophy, a characteristic component of Alzheimer’s development (55). Vitamin D can be obtained by sun exposure, oily fish intake, and is fortified in all margarine and some milks in Australia (56). However, the question of reverse causation is still unanswered, as many elderly people have restricted physical access to direct sunlight, possibly due to other ailments (55). Many of the studies surrounding vitamin D and dementia have been cross-sectional or case-control, with little observation into the disease progression related to physical mobility and sun exposure.
Dementia is physically characterised by the over production and accumulation of b-amyloid proteins in vulnerable cerebral tissue. Hippocampal and lobular atrophy are often also observed. The two most common modifiable risk factors for b-amyloid dysfunction are elevated cholesterol levels and plasma homocysteine concentrations. The Mediterranean diet has been highly recommended as a preventative diet. Evidence suggests that the high polyunsaturated fat intake can counteract the saturated fat risk factor associated with high cholesterol profiles. Elevated circulating cholesterol levels are considered to be directly linked to cognitive decline and cardiovascular diseases. In addition, the high concentration of fibre, antioxidants, and B vitamins found in the Mediterranean diet may aid in regulating and monitoring the plasma homocysteine levels. This may in turn prevent the over accumulation of the b-amyloid proteins in the cerebral tissue. Due to the strong association between dementia and other physical diseases such as obesity, Type 2 diabetes, hypertension, and cardiovascular risk, the healthy and balanced nature of the Mediterranean diet will also greatly decrease cognitive decline simply by decreasing the risk of developing metabolic disorders.
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