Phytochemicals and cognitive/behavioral function in patients with Alzheimer's disease: a scoping review protocol : JBI Evidence Synthesis

Secondary Logo

Journal Logo


Phytochemicals and cognitive/behavioral function in patients with Alzheimer's disease: a scoping review protocol

Brown, Darla Rose1,2; Martin, Tina1,2

Author Information
JBI Database of Systematic Reviews and Implementation Reports 16(2):p 297-302, February 2018. | DOI: 10.11124/JBISRIR-2016-003312
  • Free



Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive deterioration in cognitive and behavioral function.1-3 In Western countries, AD accounts for more than half of all dementia cases.2,4,5 Autopsy is considered necessary for definitive diagnosis, however clinical diagnosis is often made through measurements of physical and cognitive function such as the Mini Mental Status Examination (MMSE).6 It is estimated that there are currently over 25 million people living with AD worldwide and that this number will increase to over 100 million by 2050,2-8 with roughly one in eighty-five people throughout the world living with AD.8 Approximately US$100 billion is spent annually to provide care for AD patients including adult day programs, residential care communities, home health agencies hospice and nursing homes.7 Risk factors for AD include age, nutrition and exposure to toxins in our food and environment.3,4

The symptoms of AD include impaired cognitive, visuospatial and language abilities as well as changes in behavior and personality.9 These are manifestations of the pathophysiologic changes occurring within the body due to toxins present in our food and environment.2,3,5 Exposure to toxins induces a stress response throughout the body's tissues which results in mitochondrial dysfunction, protein misfolding and aggregation as well as synapse loss.5,10 As protein clusters form, they inhibit the body's abilities for cellular signalling and neuronal function, leading to eventual neuron loss through apoptosis.10 Physical changes can be seen in MRI scans showing medial temporal lobe (MTL) atrophy as well as in positron emission tomography (PET) scans showing hypoperfusion in temporoparietal areas.11 Recent research has focused on dietary factors and their ability to modify or inhibit inflammatory pathways to slow or halt disease progression.7

Although interest in holistic treatments is not entirely new to the medical world, the mechanism of action of these therapies has not been well understood, resulting in more recent research into therapies such as herbal medicine and phytochemicals for AD.12,13 Phytochemicals or the non-nutrient plant compounds in fruits, vegetables other plant foods show promise in the treatment of many chronic conditions.14 Studies focusing on plant phytochemicals have shown that they act as antioxidants by scavenging free radicals that have been induced through stress.2,3,5,15 This leads to neuronal cell regeneration, neuroprotection and neurorescue activities in the brain that support improved neuronal survival, differentiation, long-term potentiation and memory enhancement.5,10,16 Regular intake of phytochemicals through a diet high in fruits and vegetables has been shown to improve mental and physical function, increase neuron cell survival and boost the antioxidant system.2,3,5,7,16,17

The brain requires a large, constant source of energy which is provided by nutrients found in our diets, making personal food choices important.7,18 A diet high in saturated fats, red meat and other processed meats has been linked to the development of iron-induced free radicals which contribute to insoluble deposits in the brain typically seen in AD.19 Conversely, diets consisting of mostly fruits, vegetables and nuts provide a natural source of bioactive phytochemicals that are thought to play a pivotal role in the prevention and slowed progression of chronic conditions.7,17 Fatty acids, sterols, alkaloids, flavonoids, glycosides, saponins, tannins and terpenes are some of the phytochemicals known to be found in these food sources.13,14 Researchers are beginning to understand their mode of action, however, it is unclear whether their benefit is due to a combined action as a whole food or if it could be replicated with supplementation of individual phytochemicals.14

There are currently several pharmaceutical options marketed for the treatment of AD symptoms, such as cholinergic drugs, cholinesterase inhibitors, stimulants and vasodilators.13 However, they have only provided modest benefits to patients suffering from the disease.2 This has led to an interest in alternative therapies within the Western medical community, but there is still limited data available in humans regarding the effects of phytochemicals on the progression of AD.5 Both in vitro and in vivo studies representing the effects of supplementation with phytochemicals on the brain function of animal models who have been modified to represent brains affected with AD are more widely available.2,3,5,7,16 These studies have cited significant reversal of age related deficits in neuronal and behavior parameters as well as decreased neuron damage and oxidative stress.5,7,17 Other studies, also using rat models, have shown improved locomotor activity and neuronal protection mechanisms.5,7 Most interestingly, one study even showed that certain phytochemicals found in berberine can cross the blood brain barrier in rats with positive effects on brain function.16 Considering the lack of proven treatment for AD, a review of dietary changes to include phytochemicals is of extreme importance.

There are systematic reviews investigating diet and vitamin consumption in the setting of AD. However, the existing systematic reviews focus on interventions to increase food consumption, increase vitamin/mineral supplementation and dietary interventions in older dementia patients or people who have not yet been diagnosed with AD.20-23 This review does not aim to find strategies to increase food consumption in late stage AD patients or to review literature relating to vitamin deficiency. This review aims to explore the topic of phytochemicals and the progression of AD. A preliminary search for systematic and scoping reviews has been conducted and none have been identified. The following sources were searched for scoping reviews: JBI Database of Systematic Reviews and Implementation Reports, PROSPERO, Campbell Systematic Reviews and Database of Abstracts of Reviews and Effects.

A review of this subject is vital to the future of healthcare as around the world, the population is aging and millions of people are living with a diagnosis of AD.8 Current pharmaceutical treatment options are not providing sufficient relief from the burden of disease and current projections show the number of people living with AD continuously growing until at least 2050.1 Nurses, providers and caregivers everywhere will need to understand how to best care for these patients and what options they have for symptom management. As AD patients develop obvious deficits, their disease process is already advanced and even the most proven medical therapies will be less effective.11 This creates a sense of urgency to find an intervention that could be applied easily in the early stages of disease, such as a dietary intervention with phytochemicals. The purpose of this scoping review is therefore to find what is known about phytochemicals and cognitive/behavioral function in patients with AD. The JBI methodology for scoping reviews will be used for this review.24

Inclusion criteria


This scoping review will consider studies that include both male and female patients who have been diagnosed with AD. Participants of any age of onset and level of cognitive or physical decline will be included. Studies involving participants taking any type of medication for their AD will also be included as long as they are represented in both control and treatment groups treated with phytochemicals. If patients and/or their caregivers are unable to document phytochemical intake, the study will be excluded.


The concepts examined by this scoping review are phytochemicals found in dietary choices and supplementation such as pills and liquids. Any dosage or form of administration of phytochemicals will be considered for inclusion. Phytochemicals such as fatty acids, sterols, alkaloids, flavonoids, glycosides, saponins, tannins and terpenes can be found in plants, fruits, nuts and spices. Measurement of cognitive/behavioral function may include the use of approved scales such as the MMSE and/or imaging such as MRI or PET.


This scoping review will consider studies conducted in any care setting. This may include, but is not limited to, acute care settings, nursing homes, long-term care facilities and in-home care.

Types of studies

This scoping review will consider both experimental and quasi-experimental study designs including randomized controlled trials, non-randomized controlled trials, before and after studies and interrupted time-series studies. In addition, analytical observational studies including prospective and retrospective cohort studies, case-control studies and analytical cross-sectional studies will be considered for inclusion. This review will also consider descriptive observational study designs including case series, individual case reports and descriptive cross-sectional studies for inclusion.

Qualitative studies will also be considered that focus on qualitative data including, but not limited to, designs such as phenomenology, grounded theory, ethnography and qualitative description.

Text and opinion papers will also be considered for inclusion in this scoping review.


Search strategy

The search strategy will aim to find both published and unpublished studies. Studies published in English will be included. Since there has been so much growth in the field of AD research in recent years, studies completed between 2007 and present will be included in this review to ensure the most current information is represented. An initial limited search of MEDLINE (via PubMed) and CINAHL has been undertaken to identify articles on this topic, followed by analysis of the text words contained in the titles and abstracts, and of the index terms used to describe these articles. This informed the development of a search strategy including identified keywords and index terms, which will be tailored for each information source. An initial search strategy is presented in Appendix I. The reference list of all included studies will be screened for additional studies.

Information sources

The databases to be searched include: CINAHL; PubMed; DynaMed; Embase; Scopus; Alt Healthwatch; Cochrane Database of Clinical Trials

The search for unpublished studies will include:; OAIster; ProQuest Theses and Dissertations; Natural Medicines Comprehensive Database; National Center for Complimentary and Integrative Care; Medline Plus

Data extraction

Data will be extracted from papers included in the scoping review using the draft data extraction tool listed in Appendix II by two independent reviewers. The data extracted will include specific details about the populations, concept, context and study methods of significance to the scoping review question and specific objectives. Any disagreements that arise between the reviewers will be resolved through discussion, or with a third reviewer. Authors of papers will be contacted to request missing or additional data where required. The draft data extraction tool will be modified and revised as necessary during the process of extracting data from each included study. Modifications will be detailed in the full scoping review report.

Data mapping

The extracted data will be presented in diagrammatic or tabular form in a manner that aligns with the objective/s and scope of this scoping review. The tables and charts will report on: distribution of studies by year or period of publication, countries of origin, area of practice (facility, in-home, etc.), and research methods. A qualitative thematic analysis will be undertaken to provide an overview of the literature. A narrative summary will accompany the tabulated and/or charted results and will describe how the results relate to the reviews objective and question/s. The findings will be discussed as they relate to practice and research.

Appendix I: Initial search strategy

  • 1. “Alzheimer's” OR “Alzheimer's Disease” OR “Alzheimer's Dementia” OR “Dementia
  • 2. “Phytochemical” OR “Phytochemicals
  • 3. “Diet” OR “Food”
  • 4. “Fruits” OR “Vegetables” OR “Nuts” OR “Grains” OR “Seeds”
  • 5. “Flavanoids” OR “Fatty acids” OR “Sterols” OR “Glycosides” OR “Saponins” OR “Tannins” OR “Terpenes”
  • 6. “Measurement” OR “Measurement tools” OR “Scales” OR “Measurement Scales”
  • 7. “Imaging” OR “MRI” OR “PET” OR “Diagnostic”
  • 8. #2 OR #3 OR #4 OR #5
  • 9. #6 OR #7
  • 10. #1 AND #8 AND #9

Appendix II: Data extraction tool



This review is to contribute towards the degree award of Doctorate of Nursing Practice (DNP) from University of Mississippi Medical Center School of Nursing for DRB.


1. Brookmeyer R, Johnson E, Ziegler-Graham K, Arrighi HM. Forecasting the global burden of Alzheimer's disease. Alzheimers Dement 2007; 3 3:186–191.
2. Kim J, Lee HJ, Lee KW. Naturally occurring phytochemicals for the prevention of Alzheimer's disease. J Neurochem 2010; 112 6:1415–1430.
3. Venkatesan R, Ji E, Kim SY. Phytochemicals that regulate neurodegenerative disease by targeting neurotrophins: a comprehensive review. Biomed Res Int 2015; 2015:814068.
4. Solfrizzi V, Panza F, Frisardi V, Seripa D, Logroscino G, Imbimbo BP, et al. Diet and Alzheimer's disease risk factors or prevention: the current evidence. Expert Rev Neurother 2011; 11 5:677–708.
5. Goozee K, Shah T, Sohrabi H, Rainey-Smith S, Brown B, Verdile G, et al. Examining the potential clinical value of curcumin in the prevention and diagnosis of Alzheimer's disease. Br J Nutr 2016; 115 3:17.
6. Lacy M, Kaemmerer T, Czipri S. Standardized mini-mental state examination scores and verbal memory performance at a memory center: implications for cognitive screening. Am J Alzheimers Dis Other Demen 2015; 30 2:8.
7. Essa M, Vijayan R, Castellano-Gonzalez G, Memon M, Braidy N, Guillemin G. Neuroprotective effect of natural products against Alzheimer's disease. Neurochem Res 2012; 37 9:14.
8. Brookmeyer R, Johnson E, Ziegler-Graham K, Arrighi M. Forecasting the global burden of Alzheimer's disease. Alzheimers Dement 2007; 3 3:6.
9. McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR, Kawas CH, et al. The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement 2011; 7 3:263–269.
10. Nakamura T, Lipton S. S-Nitrosylation and uncompetitive//fast off-rate (UFO) drug therapy in neurodegenerative disorders of protein misfolding. Cell Death Differ 2007; 14 7:10.
11. Dubois B, Feldman HF, Jacova C, Dekosky ST, Barberger-Gateau P, Cummings J, et al. Research criteria for the diagnosis of Alzheimer's disease: revising the NINCDS-ADRDA criteria. Lancet Neurol 2007; 6 8:12.
12. Dong L, May BH, Feng M, Hyde AJ, Tan HY, Guo X, et al. Chinese Herbal Medicine for Mild Cognitive Impairment: A Systematic Review and Meta-Analysis of Cognitive Outcomes. Phytother Res 2016; 30 10:1592–1604.
13. Kumar GP, Khanum F. Neuroprotective potential of phytochemicals. Pharmacogn Rev 2012; 6 12:81–90.
14. Liu RH. Health benefits of fruit and vegetables are from additive and synergistic combinations of phytochemicals. Am J Clin Nutr 2003; 78 (3 Suppl):517S–520S.
15. Huang H, Zheng B, Guo Y, Zhao J, Zhao J, Ma XW, et al. Antioxidative and Nneuroprotective effects of curcumin in an Alzheimer's disease rat model co-treated with intracerebroventricular streptozotocin and subcutaneous D-galactose. J Alzheimers Dis 2016; 52 3:899–911. 5.
16. Jiang W, Li S, Li X. Therapeutic potential of berberine against neurodegenerative diseases. Sci China Life Sci 2015; 58 6:6.
17. Joseph JA, Shukitt-Hale B, Denisova NA, Bielinski D, Martin A, McEwen JJ, et al. Reversals of age-related declines in neuronal signal transduction, cognitive, and motor behavioral deficits with blueberry, spinach, or strawberry dietary supplementation. J Neurosci 1999; 19 18:8114–8121.
18. Mattson M. Lifelong brain health is a lifelong challenge: From evolutionary principles to empirical evidence. Ageing Res Rev 2015; 20:37–45.
19. Lipinski B, Pretorius E. The role of iron-induced fibrin in the pathogenesis of Alzheimer's disease and the protective role of magnesium. Front Hum Neurosci 2013; 7:11.
20. Krause DRP. Dietary interventions as a neuroprotective therapy for the delay of the onset of cognitive decline in older adults: an umbrella review. JBI Database System Rev Implement Rep 2015; 13 2:74–83.
21. Jackson J, Currie K, Graham C, Robb Y. The effectiveness of interventions to reduce undernutrition and promote eating in older adults with dementia: a systematic review. JBI Database System Rev Implement Rep 2011; 9 37:1509–1550.
22. Hines SW, Wilson J, McCrow J, Abbey J, Sacrea S. Oral liquid nutritional supplements for people with dementia in residential aged care facilites: a systematic review. JBI Database System Rev Implement Rep 2010; 8 1:1–52.
23. Moola S. Evidence Summary. Advanced Dementia: Clinical Care with Eating and Drinking. The Joanna Briggs Institute EBP Database, [email protected] 2016. JBI7972.
24. Peters MDJ, Godfrey C, Khalil H, Mclnerney P, Baldini Soares C, Parker D. Methodology for JBI Scoping reviews. Joanna Briggs Institute Reviewers Manual. Adelaide: Joanna Briggs Institute; 2015.

Alzheimer's disease; Alzheimer's; dementia; diet; phytochemicals