The Associations of Plasma/Serum Carotenoids with Alzheimer’s Disease: A Systematic Review and Meta-Analysis

Abstract

Background:

Multiple lines of evidence indicate protective effects of carotenoids in Alzheimer’s disease (AD). However, previous epidemiological studies reported inconsistent results regarding the associations between carotenoids levels and the risk of AD.

Objective:

Our study aims to evaluate the associations of six major members of carotenoids with the occurrence of AD by conducting a systematic review and meta-analysis.

Methods:

Following PRISMA guidelines, a comprehensive literature search of PubMed, Web of Science, Ebsco, and PsycINFO databases was conducted, and the quality of each included studies was evaluated by a validated scoring systems. Standardized mean differences (SMD) with 95% confidence intervals (CI) were determined by using a random effects model. Heterogeneity was evaluated by I² statistics. Publication bias was detected using funnel plots and Egger’s test.

Results:

Sixteen studies, with 10,633 participants were included. Pooled analysis showed significantly lower plasma/serum levels of lutein (SMD = –0.86, 95% CI: –1.67 to –0.05, p = 0.04) and zeaxanthin (SMD = –0.59; 95% CI: –1.12 to –0.06, p = 0.03) in patients with AD versus cognitively intact controls, while α-carotene (SMD = 0.21, 95% CI: –0.68 to 0.26, p = 0.39), β-carotene (SMD = 0.04, 95% CI: –0.57 to 0.65, p = 0.9), lycopene (SMD = –0.12, 95% CI: –0.96 to 0.72, p = 0.78), and β-cryptoxanthin (SMD = –0.09, 95% CI: –0.83 to 0.65, p = 0.81) did not achieve significant differences.

Conclusion:

Of six major members of carotenoids, only lutein and zeaxanthin concentrations in plasma/serum were inversely related to the risk of AD. More high-quality longitudinal studies are needed to verify these findings.

Keywords

Alzheimer’s disease carotenes carotenoids xanthophylls

INTRODUCTION

Alzheimer’s disease (AD) is the most common neurodegenerative disease in the elderly. It has caused considerable morbidity and mortality worldwide and has imposed tremendous financial burden on public health systems in the past decades [1]. It is estimated that the number of people affected by AD-related dementia will increase to 81.1 million by 2040 [2]. The clinical features of AD include progressively impaired cognition, loss of memory, and behavioral abnormalities, and two major pathological hallmarks of AD are the deposition of senile plaque and formation of neurofibrillary tangles [3]. Although the underlying mechanism of AD has not yet been comprehensively elucidated, oxidative stress is commonly regarded as a crucial factor in the pathogenesis and pathology of this disease [4, 5]. Thus, identifying a way to reduce oxidative damage would be beneficial for AD treatment.

Carotenoids are a group of phytochemicals richly present in deep green, yellow, orange, or red fruits and vegetables. There are more than 750 structurally defined carotenoids identified in nature [6]. A dietary intake of fruits and vegetables provides most of the 40 to 50 carotenoids [7]. Based on their chemical composition and structure, carotenoids are broadly classified into two main groups: carotenes (without oxygen) and the oxygenated derivatives xanthophylls [8]. Meanwhile, six major carotenoids found in considerable concentrations in human serum are α-carotene, β-carotene, β-cryptoxanthin, lutein, zeaxanthin, and lycopene, which are considered essential in human nutrition [9]. Therefore, a greater attention needs to be devoted to evaluate the health effects of these 6 carotenoids on human. Recently, carotenoids have been unveiled as promising candidates for AD prevention and treatment, by its antioxidant properties [10 –12].

Several previous clinical and epidemiological studies have been conducted to explore the association between plasma/serum carotenoids and AD [13, 14], but the findings were inconsistent. A recently published meta-analysis addressed the epidemiological evidence on this issue and reported that carotenoids seemed to describe an inverse relationship between plasma/serum levels of carotenoids and AD [15]. There was still no satisfactory evidence to make a clinical recommendation due to the pooled results based on case-control studies only. Another meta-analysis assessing single β-carotene for AD involving dietary intake trials shared similar inefficient conclusions [16]. Therefore, it would be necessary to further analyze the associations between carotenoids and AD by incorporating recent epidemiological studies.

In the present study, we conducted a systematic review and meta-analysis of published epidemiological studies (cohort, case-control or cross-sectional studies) to evaluate the relation of plasma/serum levels of six carotenoids (α-carotene, β-carotene, β-cryptoxanthin, lutein, zeaxanthin, and lycopene) with the occurrence of AD.

METHODS

Literature search strategy and sources

This systematic review was performed in accordance with PRISMA guidelines [17]. We conducted a systematic review of the literatures reporting the relationship of carotenoids and AD in the databases of PubMed, Web of Science, Ebsco, and PsycINFO. A hand search of reference lists of review studies was conducted and experts in this field were contacted if necessary. The range of searching time was from inception to December 2020. January of 1998 was chosen as the beginning point due to lack of carotenoids studied prior to 1998. The MeSH terms and key words used for searching were as follows: “carotenoid”, “carotene”, “xanthophyll”, “α-carotene”, “β-carotene”, “lutein”, “zeaxanthin”, “lycopene”, “β-cryptoxanthin”, “Alzheimer’s disease”. More details can be found in Part I of Supplementary Material. Key information, such as study design, contextual setting, sample size, and key findings, was retrieved from the studies selected for review.

Study selection criteria

Two authors examined whether literatures were included for review and meta-analysis in accordance with the specific inclusion and exclusion criteria: studies were included if they a) focused on investigating the relationship between concentration of carotenoid outcomes in plasma/serum and AD; b) reported a measure of concentration of carotenoids in plasma/serum as study outcome; c) were original research, either an experimental study or an observational study; studies were excluded if they: a) used only non-AD patients as the study sample, unless the results for the AD subjects and the non-AD subjects were presented separately; b) failed to report sufficient quantitative data to measure the outcome of interest; c) articles from newspaper, magazines, technical reports, commentaries, editorials, literature reviews, conference proceeding and other ‘grey’ literatures; d) Non-English language. The flow chart in Fig. 1 detailed the process of the study selection.

Fig. 1

Flow chart of the literature search and screening process.

Data extraction and quality assessment

Two authors extracted the data from the included studies in accordance with a data extraction form, including basic information (author/year, country, study design, participant ages, sample size, plasma/serum exposure measures, quality score; Table 1). A predefined quality score is a modified version of prior scoring systems which we used to assess the quality of each included study [18]. A score of 0 to 2 points was allocated to each of the following 5 items: study objective, study design, sample size, outcome assessment, and confounder adjustment. A total score of 10 points represented the highest quality. On the contrary, the lowest quality of study was expressed as 0 score. Any discrepancies between the two authors were resolved by discussion or by consultation of a third reviewer. More details can be found in Part II of Supplementary Material.

Table 1

Summary of the 16 included studies in this review with investigation of plasma/serum carotenoids in Alzheimer’s disease

References	Study design	Age(years)	Country	Sample size	Plasma/Serum exposure measures	Quality score
Boccardi et al. [14], 2020	Cross-sectional study	Total:79.2±4.8	Italy	Total: n = 68	Plasma: β-carotene	8
		AD:79.3±4.6		AD: n = 31
		Control: 79.1±5.1		Control: n = 37
Nolan et al. [11], 2018	Cohort study	AD-Trial 1:78.5±8.75	Ireland	Total: n = 30	Serum: Lutein Zeaxanthin	7
		AD-Trial 2:78.77±7.65		AD-Trial 1: n = 12
		Control: 77±7.4		AD-Trial 2: n = 13
				Control: n = 15
Mullan et al. [13], 2017	Case-control study	Total:78.1±7.4	UK	Total: n = 559	Serum: α-carotene	10
		AD: 80.2±7.7		AD: n = 251	β-carotene
		Control: 76.5±6.7		Control: n = 308	β-cryptoxanthin Lutein
					Lycopene zeaxanthin
Amadieu et al. [20], 2017	Cohort study	AD: 75.9±4.2	France	Total: n = 666	Serum:α-carotene	10
		Control: 72.8±4.4		AD: n = 110	β-carotene
				Control: n = 556	β-cryptoxanthin Lutein
					Lycopene zeaxanthin
Feart et al. [21], 2016	Cohort study	Total: 74.4	France	Total: n = 1092	Plasma: α-carotene	10
				AD: n = 199	β-Carotene Lycopene
				Control: n = 893	β-cryptoxanthin
					Lutein Zeaxanthin
Nolan et al. [26], 2014	Case-control study	AD: 80±7.8	Ireland	Total: n = 69	Serum: Lutein Zeaxanthin	7
		Control: 76±6.6		AD: n = 36
				Control: n = 33
Min et al. [25], 2014	Cohort study	AD:≥50	USA	Total: n = 6958	Serum: α-carotene	9
		Control:≥50		AD: n = 75	β-carotene
				Control: n = 6883	β-cryptoxanthin Lycopene
					Lutein Zeaxanthin
Giavarotti et al. [22], 2014	Case-control study	Total: 82	Brazil	Total: n = 65	Plasma: β-carotene Lycopene	6
				AD: n = 23
				Control: n = 42
Mangialasche et al. [24], 2012	Case-control study	AD: 77.4±6.3	Italy	Total: n = 521	Plasma: β-carotene	9
		Controls: 74.7±5.3		AD: n = 168
				Controls: n = 187
Kiko et al. [23], 2012	Cross-sectional study	AD: 72.5±1.4	Japan	Total: n = 58	Plasma: Lutein	8
		Controls: 74.1±1.3		AD: n = 30	Zeaxanthin Lycopene
				Controls: n = 28	β-cryptoxanthin
					α-carotene,
					β-carotene
Wang et al. [32], 2008	Case-control study	AD-group 1:75.46±8.75	USA	Total: n = 46	Plasma: Lutein	9
		AD-group 2:74.87±10.00		AD-group 1: n = 10	Zeaxanthin Lycopene
		AD-group 3:76.50±10.69		AD-group 2: n = 13	β-cryptoxanthin
		Control: 70.17±11.18		AD-group 3: n = 13	α-carotene,
				Control: n = 10	β-carotene
Polidori et al. [27], 2004	Cross-sectional study.	AD: 76.8±6.9	Italy	Total: n = 141	Plasma: Lutein	8
		Controls: 75.7±7.3		AD: n = 63	Zeaxanthin Lycopene
				Control: n = 55	β-cryptoxanthin
					α-carotene
					β-carotene
Rinaldi et al. [29],2003	Case-control study.	Total: 75.8±4.8	Italy	Total: n = 144	Plasma: Lutein	9
		AD: 76.8±6.9		AD: n = 63	Zeaxanthin Lycopene
		Controls: 75.8±7.2		Control: n = 56	β-cryptoxanthin
					α-carotene
					β-carotene
Polidori et al. [28], 2002	Case-control study	Total: 85.9±5.5	Italy	Total: n = 75	Plasma: Lutein Zeaxanthin	8
				AD: n = 35	β-cryptoxanthin Lycopene
				Control: n = 40	α-carotene
					β-Carotene
Schippling et al. [30], 2000	Case-control study	AD: 71.7±10.1	Germany	Total: n = 58	Plasma: α-carotene	7
		Controls: 55.1±18.8		AD: n = 29	β-Carotene
				Control: n = 29
Sinclair et al. [31], 1998	Cross-sectional study	AD: 74.3±8.1	UK	Total: n = 83	Plasma: β-carotene	7
		Controls: 73.4±7.2		AD: n = 25
				Control: n = 41

AD, Alzheimer’s disease.

Meta-analysis

We conducted a meta-analysis which concentrating on incident or prevalent AD subjects to determine the strength of the relationship of AD outcomes with specific plasma/serum carotenoids (α-Carotene, β-Carotene, β-cryptoxanthin, lutein, lycopene, zeaxanthin). Because the units of measurement for plasma/serum carotenoids levels in each study were not consistent, the standardized mean difference (SMD) with 95% confidence intervals (CI) was used to estimate the size of the effect in the present study and the Cohen’s d method was used to interpret the calculated pooled estimates. A random effects model was applied for all analyses. Heterogeneity between studies was evaluated by using I² statistics. Potential publication bias was detected by funnel plots and Egger’s test [19]. Furthermore, the sensitivity test was conducted by omitting each study in turn to evaluate the stability of the overall results. All statistical analyses were performed by using STATA SE 16.

RESULTS

Study selection and study characteristics

A flow chart of the literature search process with the specific reasons for exclusion is shown in Fig. 1. A total of 349 unduplicated records were identified from four databases and other sources (i.e., citations). Of these, 122 studies were excluded after screening the titles and abstracts. We further reviewed the full text of the remaining 227 studies and excluded 197 studies based on the exclusion criteria. From 30 studies remaining, 14 were excluded due to not reporting concentration of plasma/serum carotenoids or not regarding plasma/serum carotenoids as the final outcome. Finally, 16 studies were included for meta-analysis [11 , 20–32].

The baseline characteristics of the 16 included articles were summarized in Table 1. The majority of these included studies (15 records) were published after the year of 2000. All studies predominantly concentrated on middle-aged and elderly populations, of which 4 were longitudinal cohort studies, 4 were case-control, and 8 were cross-sectional. There were 12 studies conducted in Europe. The other articles were from Japan, USA, and Brazil. The range of quality score was assigned from 0 to 10 points. Of the 16 studies, 11 studies gained the points more than 8 or equal 8, and the rest 5 studies had points less than 8.

Associations of plasma/serum carotenes versus AD

Of the 14 studies investigating the association of plasma/serum β-carotene levels with AD, 4 studies reported significantly lower levels in AD groups compared with controls [13 , 24], whereas 2 studies showed significantly higher levels in AD patients compared with controls [23, 25]. Overall, pooled analysis demonstrated that there was no significant difference in levels of plasma/serum β-carotene between AD patients and controls (SMD = 0.04, 95% CI: –0.57 to 0.65, p = 0.9; Fig. 2A; n = 14 studies). In addition, significant heterogeneity was found (I² = 98.33%; Fig. 2A). However, sensitivity analysis indicated that no single study took the responsibility for the heterogeneity, as showed in Fig. 3A.

Fig. 2

Cohen’s d in plasma/serum levels of β-carotene (A), α-carotene(B), lycopene (C), lutein (D), β-cryptoxanthin(E), and zeaxanthin (F) in AD group and control group (random-effect model). The diamond indicates the pooled SMD with corresponding 95% CI. Treatment means AD group, control means cognitively-intact controls group.

Fig. 3

Sensitivity tests for plasma/serum β-carotene (A), α-carotene (B), lycopene (C), lutein (D), β-cryptoxanthin (E), and zeaxanthin (F). Sensitivity analysis was performed by repeating the meta-analysis sequentially excluding one study at a time. The vertical lines indicate the overall SMD with 95% CI. Hollow circles represent the pooled SMD when the remaining study is omitted from the meta-analysis. The two ends of each broken line represent the 95% CI.

Of the 10 studies detecting the relation between plasma/serum α-carotene levels and AD, 5 studies indicated lower plasma/serum α-carotene levels in AD patients compared with controls [13 , 27–30], whereas two studies reported significantly higher levels in AD patients compared with controls [23, 25], and the other 3 studies reported no significant difference between the two groups [20 , 32]. Pooled analysis showed no significant statistically difference in plasma/serum α-carotene levels observed between two groups (SMD = 0.21, 95% CI: –0.68 to 0.26, p = 0.39; Fig. 2B; n = 10 studies). Significant heterogeneity was observed between studies (I² = 96.38%; Fig. 2B). However, sensitivity test failed to detect the source of the heterogeneity (Fig. 3B).

Pooled analysis of 10 studies indicated that no significant difference in plasma/serum lycopene concentration levels between AD patients and controls (SMD = –0.12, 95% CI: –0.96 to 0.72, p = 0.78; Fig. 2C). Of these 10 studies, 7 studies reported lower levels of plasma/serum lycopene [13 , 27–29], one study showed a significantly higher level in AD patients compared with controls [25], and the other 2 studies reported no difference between two groups [21, 32]. Significant heterogeneity was detected (I² = 98.91%; Fig. 2C), but no single publication was identified by sensitivity analysis to account for the heterogeneity (Fig. 3C).

Associations of plasma/serum xanthophylls versus AD

The plasma/serum lutein levels were estimated in AD patients and cognitively intact controls in 10 studies. 7 studies (including the study of Nolan et al.: trial 2) described a significant decline lutein level in AD patients [11 , 26–29], whereas 4 studies (including the study of Nolan et al.: trial 1) reported no significant variations [11 , 32]. Collectively, the level of plasma/serum lutein concentration in AD group was significantly lower than those in controls (SMD = –0.86, 95% CI: –1.67 to –0.05, p = 0.04; Fig. 2D). Heterogeneity across these 10 studies achieved a high percentage (I² = 98.58%; Fig. 2D). However, sensitivity analysis failed to detect a specific publication to account for the heterogeneity (Fig. 3D).

Of the 9 studies analyzing levels of plasma/serum β-cryptoxanthin in AD group and normal cognitive controls, 4 studies reported the dramatic lower levels in AD group when comparing controls [13 , 29]. Collectively, there was no significant difference in plasma/serum β-cryptoxanthin between groups of AD and control (SMD = –0.09, 95% CI: –0.83 to 0.65, p = 0.81; Fig. 2E). Statistically significant heterogeneity was observed between studies (I² = 98.54%; Fig. 2E), but sensitivity analysis failed to attribute this to an individual study (Fig. 3E).

Pooled analysis of 10 publications indicated a significant reduction of plasma/serum zeaxanthin in AD group compared with controls (SMD = –0.59; 95% CI: –1.12 to –0.06, p = 0.03; Fig. 2F). 5 studies/trials reported the considerable lower levels of plasma/serum zeaxanthin in AD [13 , 29], while other 5 studies/trials showed no significant difference between these two groups [11 , 32]. A significant heterogeneity was detected (I² = 96.59%; Fig. 2F). However, sensitivity analysis was unable to attribute this to any specific study (Fig. 3F).

Publication bias

The funnel plot and Egger’s test were performed to evaluate the potential publication bias in this meta-analysis. As shown in Fig. 4, most of the funnel plots showed a relatively asymmetric distribution, indicating the presence of significant publication bias. Furthermore, publication bias was confirmed by using Egger’s test in most of the analyses (β-carotene, α-carotene, lutein, β-cryptoxanthin, zeaxanthin), except in the analysis of lycopene (Table 2).

Fig. 4

Funnel plots for plasma/serum β-carotene (A), α-carotene (B), lycopene (C), lutein (D), β-cryptoxanthin (E), and zeaxanthin (F). The standardized mean difference (Cohen’s d) from each study is plotted on the x-axis, and the standard error is plotted on the y-axis. In the absence of publication bias, the plot should be symmetrically distributed on either side of the meta-analytic estimate of effect side.

Table 2

Assessment of publication bias with corresponding z points and associated p value across six types of carotenoids

Types of Carotenoids	Z score	p
plasma/serum β-carotene	–4.27	< 0.001
plasma/serum α-carotene	–3.33	< 0.001
plasma/serum lycopene	0.31	=0.758
plasma/serum lutein	–4.21	< 0.001
plasma/serum β-cryptoxanthin	–5.07	< 0.001
plasma/serum zeaxanthin	–5.54	< 0.001

4 DISCUSSION

Carotenoids are an extensively distributed class of natural pigments that play pivotal roles in multiple physiological functions in human body [6]. Given the antioxidant and anti-inflammatory activities, carotenoids draw much attention as promising candidates for prevention or treatment of various neurodegenerative diseases (i.e., AD). Although some observational studies reported the associations between carotenoids and AD, the findings are conflicting on this issue. In the present study, we conducted a systematic review and meta-analysis to comprehensively evaluate the relationship of six major members of carotenoids with the risk of AD. The pooled analysis showed that the plasma/serum levels of lutein and zeaxanthin were significantly lower in patients with AD versus cognitively intact controls, while α-carotene, β-carotene, lycopene, and β-cryptoxanthin did not achieve significant statistical differences. The findings of our meta-analysis showed that the lutein and zeaxanthin concentrations in plasma/serum were inversely associated with the risk of AD, indicating that higher plasma/serum levels of carotenoids, especially lutein and zeaxanthin may be beneficial in reducing the AD risk.

The xanthophylls lutein and zeaxanthin are oxygenated carotenoids that preferentially concentrated in the brain and macular region of the retina [33]. Our study found negative relations between serum/plasma levels of lutein, zeaxanthin, and AD. As proved by laboratory studies, these two predominant carotenoids provide neuroprotective effects through their antioxidant properties and anti-inflammatory functions [34, 35]. The low levels of lutein and zeaxanthin may result from depletion of oxidative stress and inflammation, which could explain why AD patients often accompanied by low macular pigment optical density and poor vision [36]. Our findings are also supported by a community-based cohort study by Yuan et al. in 2020 [37], which reported that total carotenoids consumption, in particular lutein and zeaxanthin, showed inverse associations with AD incidence. The cohort study also revealed that the beneficial effects of lutein and zeaxanthin may relate to the inhibition of the amyloid plaque severity and neurofibrillary tangle formation, providing a deeper insight into the possible mechanism underlying beneficial effects of carotenoids [37]. Moreover, a previously published meta-analysis by Mullan et al. [15] evaluated the associations of serum levels of ten dietary antioxidants (α-carotene, β -carotene, lycopene, β-cryptoxanthin, lutein, zeaxanthin, vitamin A, vitamin C, vitamin E, uric acid) with AD. It is found that AD patients had significantly lower plasma levels of α-carotene, β-carotene, lycopene, and lutein. No significant difference was observed for plasma levels of β-cryptoxanthin and zeaxanthin. The results of Mullan et al.’s analysis were limited by the selection of case-control studies, whereas our research included three main types of observational studies (longitudinal cohort studies, case-control studies, cross-sectional studies). In addition, five more newly-published studies [11 , 21] over the last five years were included in our meta-analysis compared with those included in the analysis of Mullan et al. Thus, we believe that our study is an update and expanded study of previous meta-analysis and should provide additional evidence for understanding the associations between plasma/serum carotenoids and AD.

This systematic review and meta-analysis compromised several strengths. First, the current study is, to the authors’ knowledge, one of the rare studies to determine the relationships between a wide range of carotenoid levels in plasma/serum and AD through meta-analysis. Second, this review included literatures with a relative high-level quality by using a validated scoring system tool (Part II Supplementary Material). Third, various indexes of carotenoids used in the searching process, allowing for a comprehensive overview and understanding of the studies. In addition, the assessment of plasma/serum levels could reflect the absorption and utilization rate of nutrients more efficiently than a simple assessment of dietary intakes of carotenoids. Thus, our meta-analysis was restricted to the included studies focusing on the assessment of plasma/serum carotenoids levels.

Nevertheless, the findings in this review should be interpreted with cautions, in accordance with a few limitations. First, because our results were primarily generated from observational studies, we could not conclude a causal relationship between carotenoids and AD. Second, significant heterogeneity was observed between the included studies. The observed heterogeneity may be a result of differences in study designs, research methods, sample sizes, and so on. Third, the confounding variables (i.e., other carotenoids, nutrients, lifestyles) were not precluded, which may result in a spurious association of plasma/serum carotenoids with AD occurrence. Fourth, one of the included studies [25] used a different grouping method. It divided participants into two groups: subjects with AD mortality and subjects without AD mortality. However, subjects without AD mortality can be regarded as subjects without AD (cognitively-intact controls) in our analysis. This issue did not appear to affect our results, since all participants were selected from the institutionalized civilian US populations in their study [25].

CONCLUSION

This meta-analysis summarized the accumulating evidence that plasma/serum levels of lutein and zeaxanthin were inversely associated with AD. Despite failure to reach statistical significance, a trend toward decreased serum/plasma levels of α-carotene, β-carotene, lycopene, and β-cryptoxanthin in AD patients was observed. Given the results obtained from observational studies, further well-designed intervention studies will be merited to determine an adequate recommended daily intake and optimum plasma/serum levels of carotenoids for the prevention or treatment of AD.

Footnotes

ACKNOWLEDGMENTS

This research was supported by National Natural Science Foundation of China (No.81871464).

Authors’ disclosures available online ().

The supplementary material is available in the electronic version of this article: .

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