There are more than 40 million individuals with Alzheimer's disease and related dementias (ADRD) around the world and these numbers are expected to approximately double every 20 years (Prince, Comas-Herrera, Knapp, Guerchet, & Karagiannidou, 2016). ADRD is the leading chronic condition among older adults. It is progressive and terminal, leaving individuals with increasingly complex needs for treatment and care. In the absence of any effective disease-modifying treatment and with currently licensed drugs providing an average of only 6 months of symptomatic benefit, ADRD exerts an enormous financial burden on health care services, particularly when individuals reach later stages of the condition and may require specialized care (Shea, Rogers, & Remington, 2012; Wimo, Jonsson, Bond, Prince, & Winblad, 2013).
Persons with ADRD are at particular risk of malnutrition and weight loss. These issues frequently arise in the initial stages of the condition and persist as cognitive impairment progresses. In part, this progression is thought to be related to diminishing appetite during aging resulting from slowing metabolic function in older adults. Several studies have reported significant nutritional deficiencies in persons with early ADRD, raising the question of the possible role of nutrition in the development of prodromal ADRD and overall brain health in old age (Eskelinen et al., 2008; Laitinen et al., 2006). As ADRD develops, malnutrition is likely exacerbated by the practical impact of cognitive and functional decline, which leads to difficulties with storing and preparing food, as well as recalling mealtimes and daily routines. Literature indicates that poor nutrition is closely associated with increased cognitive and functional decline in persons with ADRD (Spaccavento, Del Prete, Craca & Fiore, 2009). As ADRD progresses, it is common for nutritional status to deteriorate further through a cycle of decreased nutritional intake and deterioration of nutritional status.
In addition to the association of nutrition with the progression of ADRD, it is also an important factor in overall brain health. Nutrients play complex roles within neuronal development, replacement, and function. Particularly, omega-3 fatty acids, antioxidants, and B vitamins have essential neuroprotective functions, including production and maintenance of membrane lipids and neurotransmitters, closely linked to synaptic plasticity (Kamphuis & Scheltens, 2010). It also has been suggested that the bio-availability of nutrients is altered in persons with ADRD, meaning that their nutritional needs are different from their healthy counterparts (van der Beek & Kamphuis, 2008). Non-nutritive bioactive food components, in particular flavonoids such as anthocyanin (Spencer, 2008), have demonstrated antioxidant and anti-inflammatory activity that may protect against neurodegenerative diseases and improve cognition in older adults (Spencer, 2010; Spencer, Vauzour, & Rendeiro, 2009). These flavonoids are found in high concentrations in darkly colored fruits and vegetables, wine, tea, and cocoa (Somerset & Johannot, 2008). The majority of these findings come from preclinical studies (Spencer et al., 2009), which have found suppressive effects on Ab production in vitro (Gezen-Ak et al., 2013) and improvement of memory loss in vivo (Nakagawa et al., 2016). In addition to these phytochemicals, B vitamins, particularly folate, are of interest given that insufficient levels of folate, which have been observed in persons with ADRD (Chen et al., 2015), can impair absorption of vitamin B12, resulting in an inflammatory state (Chen et al., 2016).
Overall, malnutrition and weight loss affect the person's quality of life as it contributes to an increased risk of frailty, premature morbidity, and reduces autonomy (Lopez & Molony, 2018). Improvement of nutrition and associated behaviors is therefore an important focus in persons with ADRD. Nonpharmacological treatment approaches offer a low-risk, potentially effective means of influencing behaviors such as those related to nutrition (Volkert et al., 2015). Several studies have reported benefits to persons with ADRD following psychosocial treatments tailored to other behaviors and quality of life indicators, including agitation, mood, and social interaction (Testad et al., 2014). Numerous studies have also examined the impact on factors related to nutrition, but the landscape and key issues within this evidence base have not been collated and defined. The literature has focused particularly on the role of diet and nutrition in prevention of ADRD given that inflammatory processes are implicated in the pathophysiology of ADRD (Gezen-Ak et al., 2013).
The role and impact of nutritional intervention in early-stage ADRD, specifically on cognition and key symptoms such as behavior, is less straightforward. The current integrative review sought to examine the literature pertaining to nutritional interventions for persons with ADRD and to make recommendations for priority areas for future research and practice.
The current integrative literature review was conducted from January 2007 through February 2018. These dates were chosen to update a previous review of nutritional interventions (Burgener et al., 2008) published from a white paper summarizing the state of the science relating to nonpharmacological strategies to address symptoms of early-stage dementia (Burgener et al., 2007).
Search and Inclusion Criteria
Databases interrogated in the search were PubMed, EBSCO, Medline, CINAHL, and PsycINFO, with the following search terms applied: dementia, nutrition, intervention, and Alzheimer's disease. Combined search terms were then developed: dementia OR Alzheimer's disease AND nutrition AND intervention. In addition, a historical search of the citations of retrieved articles was performed. Studies included in this review were written in English and focused on nutritional interventions for persons with early-stage ADRD living in the community. Articles were excluded if the study sample did not include persons with ADRD, a nutritional intervention (e.g., nutritional supplementation, nutrition education), focused on individuals living in nursing or care homes, evaluated a medical food, involved in vitro or in vivo methods, or if the article did not report research findings.
Review Process and Evaluation
The current review used the method for an integrative review as described by Whittemore and Knafl (2005). Integrative reviews allow for a more complete understanding of a subject area by summarizing the empirical and theoretical literature. This type of review informs research, health care practice, and policy given that integrative reviews provide an overview of the state of the science, describing the depth and breadth of an area of research. Given that systematic reviews often only include randomized controlled trials (RCT), an integrative approach was taken given that the majority of literature reporting potentially efficacious results from nonpharmacological interventions might be excluded (Cohen-Mansfield et al., 2014). By taking an integrative approach, the available literature is put to its best use by including findings from studies of all types of design.
The grading scheme used to make recommendations is shown in Table 1. The reviewed studies were evaluated based on the type and strength of evidence using a grading scheme for making recommendations consistent with previous reviews (Anderson, Rogers, Bossen, Testad, & Rose, 2017; Burgener, Jao, Anderson, & Bossen, 2015) that was developed by the University of Iowa College of Nursing.
Grading Scheme Used to Make Recommendations Regarding Reviewed Studies
The literature search resulted in 101 articles that were assessed for eligibility. Ninety-five studies were excluded. Reasons for exclusion were that the studies focused on residents living in nursing or care homes (n = 5), did not involve persons with ADRD (n = 22), evaluated medical foods (n = 6), did not examine an intervention (n = 44), used an animal model (n = 6), or was an in vitro study (n = 12). Six studies were included in the review (Table 2). The flow of studies through the review process is shown in Figure 1. Two main types of interventions were identified in the six studies included in this review: nutritional supplementation with a vitamin or food (n = 4) and educational interventions (n = 2). Both types of interventions were graded as A2 level evidence according to the quality scoring process (Table 1).
Summary of Findings From Included Studies
Flow diagram of study selection process.
Nutritional Supplementation Interventions
A study by Remington et al. (2015) aimed to determine whether nutritional intervention with a nutraceutical formulation (NF) could have a positive impact on cognitive performance and behavioral symptoms of distress in 106 persons with ADRD. Participants were randomly allocated to receive a NF containing folate, alpha-tocopherol, vitamin B12, S-adenosyl methioinine (SAM), N-acetyl cysteine, and acetyl-L-carnitine (n = 62) or a placebo control (n = 44). The intervention lasted for 3 or 6 months, followed by an open-label extension phase during which all participants received the NF for 6 additional months. Outcome measures included cognitive impairment (Dementia Rating Scale [DRS]), neuropsychiatric symptoms (Neuropsychiatric Inventory), and activities of daily living (ADLs). The authors reported that the intervention group receiving the NF showed significant improvements in cognition compared with controls within 3 months (Clox-1 [executive clock drawing test], p = 0.0083, 95% confidence interval [CI] [0.4481, 2.9343]; DRS, p = 0.0266, 95% CI [0.1722, 2.7171]). Specifically, improvements at 3 months were statistically and clinically significant in terms of the memory domain (p = 0.0131, standardized effect size = 0.5) and total age-adjusted DRS score (p = 0.0026). For participants receiving the NF, the impact varied according to stage of ADRD, with a greater impact among participants classified as cognitively intact or in mild to moderate stages of ADRD. Participants receiving the placebo did not display any change in DRS domains. The study showed no significant difference in neuropsychiatric symptoms or ADLs. The intervention and control groups improved or maintained baseline performance during the open-label extension phase (Remington et al., 2015).
Kent et al. (2017) conducted a 12-week RCT to examine the impact of anthocyanin-rich cherry juice on cognitive performance in older adults (age >70 years) with mild to moderate ADRD (N = 49). Participants in the intervention group (n = 24) consumed 200 mL/day of cherry juice, whereas participants in the control group (n = 25) consumed an equal amount of apple juice with negligible anthocyanin content. Outcome measures comprised a battery of cognitive tests, including the Rey Auditory Verbal Learning Test (RAVLT), self-ordered pointing test, Boston naming test, trail making test, digit span backwards task, and category and letter verbal fluency. Additional outcomes included anthropometric measures, handgrip strength, blood pressure, instrumental ADLs (IADLs), and serum levels of C-reactive protein (CRP), interleukin-6 (IL-6), and vitamin C. No differences were observed between groups at baseline in terms of age, body mass index (BMI), anthropometric measures, or total flavonoid intake. However, there were significant differences at baseline in terms of malnutrition, IADLs, and handgrip strength, and habitual intake of several flavonoid subclasses, with habitual intake higher in the intervention group. Following the intervention, significant improvements in cognitive performance were observed in the intervention group at 6 and 12 weeks for category verbal fluency task (p = 0.014, standardized effect size = 0.711), RAVLT total scores (p = 0.014, standardized effect size = 0.713), RAVLT delayed recall (p = 0.005, standardized effect size = 0.433), and RAVLT 20-minute delayed recall (p < 0.001, standardized effect size = 0.242) compared with controls. Significant decreases in systolic blood pressure (p = 0.038) were found in the intervention group following the intervention. There were no significant differences between groups in serum levels of vitamin C, IL-6, or CRP at baseline or 12 weeks.
In a study by Chen et al. (2016), the effects of folate supplementation were investigated in 121 individuals newly diagnosed with ADRD being treated with donepezil. Participants were randomly assigned to receive either supplemental treatment with folate (1.25 mg/day; n = 61) or no additional supplement (n = 60) for 6 months. Outcome measures included cognitive performance using the Mini-Mental State Examination (MMSE); functional status (i.e., ADLs); and serum levels of Aβ40, Aβ42, the Aβ42/Aβ40 ratio, amyloid precursor protein mRNA, presenilin-1 (PS1) mRNA, PS2 mRNA, IL-6 mRNA, tumor necrosis factor-alpha (TNF-α) mRNA, folate, vitamin B12, homocysteine (Hcy), S-adenosylmethionine (SAM), S-adenosyl homocysteine (SAH), and the SAM/SAH ratio. MMSE scores were higher in the intervention group compared with controls (p = 0.041, standardized effect size = 0.538), although there was no change in ADLs. Serum levels of folate (p = 0.001, standardized effect size = 0.937), SAM (p = 0.012, standardized effect size = 0.712), and the SAM/SAH ratio (p < 0.001, standardized effect size = 0.999) increased in the intervention group versus controls following the intervention. No change was observed regarding serum concentrations of vitamin B12, Hcy, or SAH. A significant decrease in Aβ40 protein levels was found in the intervention group versus controls (p = 0.003, standardized effect size = 0.843), whereas the Aβ42/Aβ40 ratio increased in the intervention group (p = 0.029, standardized effect size = 0.594). Protein (p = 0.021, standardized effect size = 0.638) and mRNA levels (p = 0.044, standardized effect size = 0.527) of TNF-α and mRNA levels of PS1 mRNA (p = 0.017, standardized effect size = 0.676) significantly decreased in the intervention group compared with controls. No change was observed in mRNA levels of PS2 or IL-6.
Nakagawa et al. (2016) tested the effects of a 4-week intervention of quercetin-rich onion powder (18 g/day) on cognitive performance (MMSE, Revised Hasegawa Dementia Scale [HDS-R]) using a cohort study design. Although average MMSE and total HDS-R scores did not change over the duration of the intervention, there were significantly higher scores on the memory recall component of HDS-R following quercetin intake (p < 0.03).
Two studies examined the impact of educational interventions on nutritional status in persons with ADRD. A study by Salva et al. (2011) compared the impact of the NutriAlz program, a standardized protocol for feeding and nutrition directed to the physician and primary caregiver, as well as persons with ADRD, with usual care on functional level and the effectiveness in improving clinical practice related to nutrition and caregiver burden. Home-dwelling individuals (n = 946) with mild to moderate ADRD were included in the study, with 448 participants in the intervention group and 498 participants in the control group. The length of the intervention was 12 months with 6- and 12-month follow up. The study showed no significant difference between the two groups regarding reduction in the loss of autonomy as measured by ADLs. The authors also reported no differences in weight change between the control and intervention groups, mainly because participants' weights remained stable throughout the study period. No difference in caregiver burden, as evaluated by the Zarit Caregiver Burden Scale, was observed. However, nutritional status, assessed using the Mini Nutritional Assessment, showed a significant improvement of 0.46 points (range = 0.09 to 0.83) in the intervention group, suggesting an improvement in nutritional behaviors, whereas the control group showed a worsening in the risk for malnutrition of −0.66 points (range = −0.80 to −0.21), with p = 0.028 for the group effect (Salva et al., 2011).
Suominen et al. (2015) examined the effects of tailored nutritional guidance on nutritional status, health-related quality of life (HRQoL) and falls. A 12-month intervention was delivered to 78 home-dwelling individuals with ADRD living with a spouse. Forty couples were included in the intervention group and 38 couples in the control group. Couples in the intervention group received home visits from a nutritionist four to eight times during the intervention period. During the visits, couples received tailored nutritional guidance based on food diaries, which they kept for 3 days. Protein- and nutrient-enriched drinks were provided as needed. Participants in the control group received a written guide about nutrition for older adults in addition to normal community care. No significant difference in changes in body weight were observed between the two groups (p = 0.68). However, there were statistically significant changes in HRQoL between groups (p = 0.007, adjusted for age, sex, baseline MMSE scores, and BMI), as well as a statistically significant difference in the incidence of falls (incidence rate ratio = 0.55; 95% CI [2.16, 6.46]; p < 0.001, adjusted for age, sex, and MMSE). The authors noted that during the study, it became clear that weight gain may not be a relevant aim for this type of intervention. Only one half of participants included in the study were at risk for malnutrition, with none classified as malnourished. The study also revealed that male caregivers benefitted from guidance for food-related activities (Suominen et al., 2015).
The current review focused on exploring the literature related to nonpharmacological approaches to improve nutritional status in persons with ADRD living in the community. The six studies meeting the inclusion criteria for the review demonstrated a range of benefits resulting from interventions designed to address nutritional needs (Remington et al., 2015; Salva et al., 2011; Suominen et al., 2015). Direct nutritional supplementation led to benefits in cognition. Educational approaches also improved nutritional status, HRQoL, and incidence of falls. Interestingly, none of the studies reported weight gain. The breadth of benefit across the literature highlights the need for a multidisciplinary approach to nutrition in ADRD to confer broad benefits to patients and their caregivers.
Nutritional status in ADRD is central to overall health and has a direct impact on nutrient intake, hydration, weight maintenance, resistance to infection, overall resilience, and optimal brain health. In addition, nutritional status is also likely a key player in longer-term outcomes, such as institutionalization, hospital admission, and mental health and well-being (Volkert et al., 2015). The evidence related to the specific nutritional needs of persons with ADRD is limited, although there are indications of unique requirements in this patient group that may have implications for health and progression of cognitive decline. Given the public health agenda to promote good care and health in persons with ADRD, nutrition is a key aspect to consider within overall care planning (World Health Organization, 2003).
The literature reviewed in the current study highlights several potential opportunities for improving nutritional status and support for persons with ADRD living in the community. Despite the small amount of evidence, the six studies identified suggest a broad benefit may be conferred through educational approaches and nutritional s upplementation. The indication of benefit to cognition through nutritional supplementation is particularly key and might form the basis of a multi-component approach to address cognitive and associated outcomes. It is noteworthy that the cognitive benefits reported with nutritional supplementation were most impactful in persons with mild cognitive impairment at baseline, indicating a possible differential, or threshold, effect in those with more severe impairment. One complication to understanding the relationship between folate status and cognitive decline is the widespread use of folate fortification in Western countries (Chen et al., 2016). It also is important to consider the feasibility and bioavailability of nutritional supplementation interventions. For example, in the study by Kent et al. (2017), a feasible and acceptable serving of cherry juice was used that represented an achievable daily intervention. This serving provided an additional 138 mg/day of anthocyanins, representing 46 times the average consumption of anthocyanin (Kent et al., 2017).
The findings of the nutritional supplementation intervention studies reviewed are consistent with other human studies, as well as in vivo research, demonstrating improvement in cognitive performance with dietary supplementation with foods rich in flavonoids (Krikorian et al., 2012; Krikorian, Nash, Shidler, Shukitt-Hale, & Joseph, 2010; Krikorian et al., 2010; Shukitt-Hale, Cheng, & Joseph, 2009). How flavonoids might moderate the pathophysiology of ADRD remains unclear. Findings from preclinical research suggest that flavonoids and other phytochemicals most likely play a role in improving cognitive performance through the modulation of cellular and molecular activities in the brain rather than abrogating the actual disease process, such as by upregulating signaling cascades in regions of the brain involved in memory (Spencer, 2010). The specific benefits seen in early ADRD may also provide further rationale for exploring the value of these interventions for preventive approaches to reduce cognitive decline and conversion to dementia in at-risk groups. Nutraceuticals have been raised as a potential risk reduction avenue and warrants further investigation.
The supplements investigated in these studies are not directly comparable, which leaves unanswered questions related to the specific contents and associated value of dietary supplements. This warrants further examination to understand fully the potential impact of different approaches to dietary supplementation and in which patient groups these approaches might be of value. Future research should assess the effects of manufacturing processes on the content of flavonoids in food products. In addition, dose-response studies of flavonoids and folate are needed to establish the optimal dose of these nutritional supplements for improving cognitive performance.
The broader benefits conferred by guidance and education indicate that these approaches might be suitable for integration into usual care and support frameworks for caregivers and persons with ADRD to ensure widespread adoption. Furthermore, it is important to also focus on supporting caregivers of persons with ADRD when tailoring nutritional interventions. Typically, spousal caregivers are old themselves and are responsible for providing nutrition for the household. Given that caring for a person with ADRD is highly stressful, and is associated with physical and emotional burden, caregivers themselves are at risk for poor nutrition (Beattie, McCrow, Dyce, Fielding, & Isenring 2014). Given the potential benefit to global outcomes such as mental health, nutritional status, and incidence of falls, it is possible that these educational elements could play a role in helping caregivers and persons with ADRD to live independently at home for longer. Remaining at home for as long as possible is a major public health goal given the detrimental health outcomes associated with moving individuals into long-term residential care settings.
The limitations in the current study relate to the paucity of literature available, which prevents a wider scope for discussion. However, this is a major finding from the review. The review was also limited to considering interventions for earlier-stage ADRD by virtue of focusing on community-dwelling individuals. As discussed above, this approach is appropriate given the considerable differences in needs and clinical issues pertaining to these two care settings. Further work is warranted to explore this topic in long-term and acute care settings, in addition to use of nutritional approaches in preventive studies and evaluate the longitudinal effect of nutrition on functional outcomes. Finally, selection bias of participants in all studies reviewed should be considered given that those individuals with an interest in diet and nutrition are more likely to participate. These individuals may already consume healthier foods and higher levels of bioactive food components (Kent et al., 2017).
The work reviewed has implications for research on nutritional interventions and dementia. The initial indications of benefit to persons with ADRD, particularly the impact on cognition with nutritional supplementation, warrants further investigation. The findings suggest that a complex intervention combining educational, psychosocial, and nutritional interventions aiming at persons in the earlier stages of ADRD and mild cognitive impairment might be of value to establish the most impactful approach to improving nutritional status.
There also are important questions related to the most meaningful measures of benefit for this field of research. The review data indicate that weight gain as an outcome is not necessarily of great value, particularly in persons in the earlier stages of ADRD. More global outcomes, such as mental health and quality of life, may be of more relevance. It is likely that research focusing on later-stage ADRD and in care home settings, when weight loss and basic hydration are of clinical concern, would require a different approach, in intervention type and research design.
Overall, the current review provides a valuable perspective on the literature pertaining to nonpharmacological approaches to improve nutritional status in dementia.
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Grading Scheme Used to Make Recommendations Regarding Reviewed Studies
|A1||Evidence from well-designed meta-analysis or well-done systematic review with results that consistently support a specific action (e.g., assessment, intervention, or treatment)|
|A2||Evidence from one or more randomized controlled trials (RCTs) with consistent results|
|B1||Evidence from high-quality, evidence-based practice guideline|
|B2||Evidence from one or more quasi experimental studies with consistent results|
|C1||Evidence from observational studies with consistent results (e.g., correlational, descriptive studies)|
|C2||Inconsistent evidence from observational studies or RCTs|
|D||Evidence from expert opinion, multiple case reports, or national consensus reports|
Summary of Findings From Included Studies
|Study (Year)||Intervention||Objective||Duration||Design||Sample Size||Outcomes||Measures||Findings|
|Chen et al. (2016)||Folate supplement||Determine the effects of folate supplementation on cognitive function in persons with AD||6 months||RCT||N = 121
Intervention, n = 1
Control, n = 60||Cognitive performanceDaily functionSerum markers of AßSerum markers of inflammation||MMSE
Vitamin B12||Positive impact of nutritional intervention on cognitive performanceDecreased serum markers of Aß and inflammation|
|Kent et al. (2017)||Cherry juice||Assess whether daily consumption of cherry juice improved cognitive function in older adults with ADRD||12 weeks||RCT||N = 49
Intervention, n = 24
Control, n = 25||Cognitive performanceBlood pressureSerum markers of inflammation||RAVLT
Boston naming test
Digit span backwards task
IL-6||Positive impact of nutritional intervention on cognitive performance (verbal fluency, short- and long-term memory)Decreased systolic blood pressure|
|Nakagawa et al. (2016)||Onion powder||Examine the effects of intake of quercetin-rich onion powder on memory recall in persons with early-stage AD||4 weeks||Cohort study||N = 5||Cognitive performanceNeuroimaging||HDS-R
PET||No change in MMSE or overall HDS-R scoresImproved scores on HDS-R memory recall component|
|Remington et al. (2015)||Nutraceutical formulation||Determine whether nutritional intervention could positively impact cognitive performance and behavioral difficulties for persons with AD||3 to 6 months||Double-blind, multi-site, phase II study||N = 106
Intervention, n = 62
Control, n = 44||Cognitive performanceBPSDDaily function||Clox-1
ADLs||Positive impact of nutritional intervention on cognitive performance
No improvement in NPI
ADLs did not change for either group|
|Salvà et al. (2011)||Educational nutrition program (NutriAlz)||Assess the effectiveness of health and nutrition program (NutriAlz) versus usual care on functional level in persons with dementia living at home, as well as on clinical practice related to nutrition and caregiver burden||12 months||Cluster randomized multi-center study||N = 946
Intervention, n = 448
Control, n = 498||Loss of autonomyNutritional statusCaregiver burden||Charlson Index
RUD||No difference in loss of autonomy, nutritional status, or caregiver burden|
|Suominen et al. (2015)||Tailored guidance with home visits||Examine the effects of tailored nutritional guidance on nutritional status, HRQoL, and incidence of falls||12 months||RCT||N = 78
Intervention, n = 40
Control, n = 38||Weight changeProtein intakeNutrient intakeHealth-related QoLIncidence of falls||HRQoL
BMI||No effect on weight
Improved nutritional status and HRQoL
Reduced frequency of falls|