Dietary interventions as a neuroprotective therapy for the delay of the onset of cognitive decline in older adults: an umbrella review protocol

Review question and Objective Are individual dietary interventions effective in delaying the onset of cognitive decline in older adults? The objective of this umbrella review is to determine the effectiveness of individual dietary interventions in delaying the onset of cognitive decline in older adults. Background Nutrition is one of the lifestyle factors that may contribute to the development and progression of chronic diseases such as atherosclerosis, cancer, cardiovascular disease, diabetes and neurodegenerative diseases. Increasing life expectancies have seen an increasing number of people affected by chronic diseases associated with ageing such as dementia. Neurodegenerative diseases such as Alzheimer's Disease (AD) are the most common cause of dementia, thought to be responsible for up to 70% of cases. Dementia broadly refers to a large group of illnesses which cause a progressive decline in a person's cognitive functioning. It is a broad term used to describe a loss of memory, intellect, rationality, social skills and normal emotional reactions. The major risk factor for AD is age with the prevalence doubling every 5 years after the age of 65. Other risk factors include the epsilon 4 allele of the apoliprotein E gene (APOE &egr;4), smoking, depression and diabetes.1 Mild cognitive impairment (MCI) can be associated with normal ageing or early dementia and is characterized by a measurable decline in cognitive abilities, including memory and thinking skills. The changes are generally not severe enough to interfere with daily life or independent function, but it does represent a higher risk for the development of AD.2–4 The clinical diagnosis of AD is challenging with multiple sets of well‐established criteria aiming to establish if there is evidence of cognitive and functional decline that impacts on an individual's ability to carry out routine daily activities. Variations among the range of cognitive tests used to characterize cognitive domains can make comparison across studies challenging.5 The possible mechanisms associated with neurodegeneration have been hypothesized with a view to determining the cause of abnormalities in the transport, degradation and aggregation of proteins including amyloid ‐&bgr; peptides, apolipoprotein E (APOE) and tau, a microtubule‐associated protein in the brain. Free radicals and neuroinflammation processes are thought to underlie many of the neurodegenerative conditions.6 Natural compounds such as curcumin, carotenoids, acetyl‐L‐carnitine, vitamin D, polyphenols and other nutraceuticals have been studied for their potential to target multiple pathways in AD.7 Many of these natural compounds are widely available as nutritional supplements and have been studied for their potential role in neuroprotection. Acetyl‐L‐carnitine (ALC) is an acetylated form of L‐carnitine that is naturally produced by the body, although it is often taken as a dietary supplement. ALC has been reported to protect peripheral and nervous system synapses in neurodegenerative and ageing models.8 This has led to the study of the effect of ALC on cognitive decline in a series of clinical trials with conflicting outcomes. Alpha lipoic acid (ALA) has been shown to have a variety of properties which can interfere with the pathogenesis or progression of AD.9 ALA is an endogenous antioxidant that interrupts cellular oxidative processes in both its oxidized and reduced forms. ALA increases acetylcholine production by activation of choline acetyltransferase and has the ability to chelate redox‐active transition metals, thus inhibiting the formation of hydroxyl radicals, and also scavenges reactive oxygen species (ROS). 10 ALA has therefore been postulated as a potential therapeutic in AD. Further studies have reported that AD sufferers lack the enzyme responsible for converting choline into acetylcholine within the brain. It has been proposed that lecithin, the major dietary source of choline, may accelerate synthesis of acetylcholine in the brain via increased availability of choline which has been the subject of several clinical trials.11 Inositol, also known as vitamin B8, is a simple polyol with eight naturally occurring stereoisomers. It is not an essential nutrient and nuts, seeds, beans, whole grains, cantaloupe and citrus fruits are a source of phytic acid (inositol hexaphosphate, IP6), which releases inositol when acted on by bacteria in the digestive tract. Clinical trials have been undertaken using varying doses of inositol or scyllo‐inositoll.12–14 Scyllo‐inositol has been shown to inhibit cognitive deficits in mice and can significantly decrease insoluble amyloid ‐&bgr; 40 peptide, amyloid ‐&bgr; 42 peptide and plaque accumulation in the brains of mice. However it does not incorporate into the phosphatidylinositol family of lipids and does not interfere with phosphatidylinositol lipid production.15 Polyphenols are a large group of naturally occurring secondary metabolites of plants and are characterized by the presence of at least one phenolic unit per molecule. There are several classes of polyphenols that have been studied for their potential anti‐ageing and brain protective properties. These include flavonoids such as the anthocyanins which are typically found in berries, grapes and red wine and catechins often found in tea. Curcumin from turmeric and resveratrol from grapes and red wine are examples of bioactive species of the non‐flavonoids chemical class.16 Curcumin has been reported to have effects such as decreased beta‐amyloid plaques, delayed degradation of neurons, metal‐chelation, anti‐inflammatory, antioxidant and decreased microglia formation and to improve the overall memory in patients with AD.17 Resveratrol has been reported to have effects in in vitro models of AD and in in vivo animal studies and moderate red wine consumption has been associated with a lower incidence of dementia and AD in epidemiological studies;18 however clinical studies in humans are lacking. Grape seed polyphenolic extracts have been reported to provide beneficial disease‐modifying bioactivities in tau‐associated neurodegenerative disorders by modulating tau‐mediated neuropathologic mechanisms in in vitro studies.19 Similarly, epidemiological studies have reported that consumption of up to three servings of wine daily is associated with a lower risk of AD in elderly individuals without the APOE &egr;4 allele.20 Moderate drinkers with mild cognitive impairment who consumed less than one drink of wine per day showed a significantly lower rate of progression to dementia than abstainers.21 Omega 3 polyunsaturated fatty acids (PUFA) are essential fatty acids with docosahexanoic acid (DHA) being a major component of membrane phospholipids in the brain. Evidence from observational and epidemiological studies has suggested a possible inverse relationship between high dietary intake of PUFA and risk of dementia.22–24 Postulated mechanisms that might qualify omega 3 PUFA as an interventional target for the primary prevention of dementia include its anti‐atherogenic, anti‐inflammatory, anti‐oxidant, anti‐amyloid and neuroprotective properties. In vitro and/or in vivo animal studies utilizing several of these compounds have demonstrated some success in slowing neurodegeneration and have led to further investigation in clinical trials of their likely role in preventing cognitive decline in humans. However, the relationship between nutrition and cognitive functioning, particularly in elderly populations, is unclear, as many elderly people with cognitive impairment have low blood levels of some nutrients even in the absence of malnourishment.25 These findings have been reported in cross‐sectional and longitudinal studies and further assessed in systematic reviews and meta‐analyses with a view to pooling results to achieve some definitive conclusions. A preliminary search of Medline on PubMed, Web of Science and Cochrane Central (Database of Systematic Reviews and Cochrane Collaboration Central Register of Controlled Trials), has not identified any umbrella reviews on the topic.