Association between tea consumption and risk of cognitive disorders: A dose-response meta-analysis of observational studies

Abstract

Background:
The epidemiological evidence for a dose-response relationship between tea consumption and risk of cognitive disorders is sparse. The aim of the study was to summarize the evidence for the association of tea consumption with risk of cognitive disorders and assess the dose-response relationship.

Methods:
We searched electronic databases of Pubmed, Embase, and Cochrane Library (from 1965 to Jan 19, 2017) for eligible studies that published in the international journals. A random-effects model was used to pool the most adjusted odds ratios (ORs) and the corresponding 95% confidence intervals (CIs).

Results:
Seventeen studies involving 48,435 participants were included in our study. The meta-analysis showed that a higher tea consumption was associated with a significant reduction in the risk of cognitive disorders (OR=0.73, 95% CI: 0.65-0.82). When considering the specific types of tea consumption, the significantly inverse association is only found in green tea consumption (OR=0.64, 95% CI: 0.53-0.77) but not in black/oolong tea consumption (OR=0.75, 95% CI: 0.55-1.01). Dose-response meta-analysis indicated that tea consumption is linearly associated with a reduced risk of cognitive disorders. An increment of 100 ml/day, 300 ml/day, and 500 ml/day of tea consumption was associated with a 6% (OR=0.94, 95% CI: 0.92-0.96), 19% (OR=0.81, 95% CI: 0.74-0.88), and 29% (OR=0.71, 95% CI: 0.62-0.82) lower risk of cognitive disorders.

Conclusions:
Tea consumption is inversely and linearly related to the risk of cognitive disorders. More studies are needed to further confirm our findings.

Full text

Oncotarget43306
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Association between tea consumption and risk of cognitive
disorders: A dose-response meta-analysis of observational
studies
Xueying Liu1,2, Xiaoyuan Du3, Guanying Han4 and Wenyuan Gao1
1School of Pharmaceutical Science and Technology, Tianjin University, Nankai District, Tianjin 300072, China
2Department of Pharmacy, The Third Aliated Hospital of Jinzhou Medical University, Jinzhou 121001, China
3Department of Pathology, The First Aliated Hospital of Jinzhou Medical University, Jinzhou 121001, China
4Department of Pharmacy, The First Aliated Hospital of Jinzhou Medical University, Jinzhou 121001, China
Correspondence to: Wenyuan Gao, email: gaowenyvip@163.com
Keywords: tea consumption, cognitive disorders, dose-response, meta-analysis
Received: February 15, 2017 Accepted: March 29, 2017 Published: April 26, 2017
Copyright: Liu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0
(CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source
are credited.
ABSTRACT
Background: The epidemiological evidence for a dose-response relationship
between tea consumption and risk of cognitive disorders is sparse. The aim of the
study was to summarize the evidence for the association of tea consumption with risk
of cognitive disorders and assess the dose-response relationship.
Methods: We searched electronic databases of Pubmed, Embase, and Cochrane
Library (from 1965 to Jan 19, 2017) for eligible studies that published in the
international journals. A random-eects model was used to pool the most adjusted
odds ratios (ORs) and the corresponding 95% condence intervals (CIs).
Results: Seventeen studies involving 48,435 participants were included in our
study. The meta-analysis showed that a higher tea consumption was associated with a
signicant reduction in the risk of cognitive disorders (OR=0.73, 95% CI: 0.65-0.82).
When considering the specic types of tea consumption, the signicantly inverse
association is only found in green tea consumption (OR=0.64, 95% CI: 0.53-0.77) but
not in black/oolong tea consumption (OR=0.75, 95% CI: 0.55-1.01). Dose-response
meta-analysis indicated that tea consumption is linearly associated with a reduced
risk of cognitive disorders. An increment of 100 ml/day, 300 ml/day, and 500 ml/
day of tea consumption was associated with a 6% (OR=0.94, 95% CI: 0.92-0.96),
19% (OR=0.81, 95% CI: 0.74-0.88), and 29% (OR=0.71, 95% CI: 0.62-0.82) lower
risk of cognitive disorders.
Conclusions: Tea consumption is inversely and linearly related to the risk of
cognitive disorders. More studies are needed to further conrm our ndings.
INTRODUCTION
In the rapidly aging societies around the world,
cognition-related diseases, such as mild cognitive
impairment, cognitive decline, dementia and Alzheimer’s
disease (AD), are gradually increasing [1, 2]. The number
of people with dementia worldwide is about 35.6 million
as announced by WHO and this number will be doubled
by 2030, tripled by 2050 [3]. Interventions against early
cognitive disorders may be particularly effective to reduce
the social burden of AD and other types of dementia. It has
been indicated that the intake of certain diet and nutrients,
such as fruit and vegetable [4], Mediterranean diet [5],
omega-3 fatty acids [6], vitamin C [7], vitamin E [8], milk
[9], coffee [10], and light to moderate amounts of alcohol
[11], is related to the reduced risk of cognitive disorders
and dementia.
A number of epidemiological studies have found that
tea consumption may also improve mental performance
[12] and reduce the progression of cognitive dysfunction
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Meta-Analysis

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[13, 14]. An animal study has shown that oolong and
green teas could reduce the deteriorations of cognitive
ability, brain degenerative changes and aging process in
senescence accelerated-prone mice P8 [15]. Experimental
studies indicated that the anti-oxidative and anti-
inammatory effects of tea and its components, such as
catechins and theanine, may contribute to neuroprotection
[16–20].
The strength of the association between tea
consumption and the risk of cognitive disorders remains
uncertain due to the differences in participants and
methodological methods used in the previous studies.
In the current study, we conducted a systematic review
and dose-response meta-analysis to quantitatively assess
the association between tea consumption and the risk of
cognitive disorders.
RESULTS
Description of the included studies
Of the 407 citations identied from the database
searches, 17 studies met the inclusion criteria and were
nally included in the meta-analysis, including six
cohort studies [21–26], three case-control studies [27–
29] and eight cross-sectional studies [3, 30–36]. The
study selection process is shown in Figure 1. Among the
included studies, twelve were from Asia, two were from
Europe, two were from North America, and one was from
Australia, involving a total of 48,435 participants. The
characteristics of these studies are summarized in Table
1. All included studies measured tea consumption by self-
administered questionnaire or self-reported food frequency
questionnaire. The diagnosis of cognitive disorders was
based on standard criterion in all the articles. Most of
the included studies adjusted for potential confounding
factors. We recorded relative risks of cognitive disorders
according to the highest vs. the lowest category of
tea consumption. The results of quality evaluation for
each study are presented in detail in the Supplementary
Materials (Supplementary Tables 3-5).
All types of tea consumption and risk of
cognitive disorders
Figure 2 shows the results of meta-analysis of
relative risk according to the highest vs. lowest category of
all types of tea consumption. The summary result showed
that high tea consumption was associated with a reduced
risk of cognitive disorders (OR=0.73, 95% CI: 0.65-
0.82), with some heterogeneity (I2=51.4%, p=0.001). In
the stratied analysis by the type of outcome, the pooled
ORs and 95% CIs of higher tea consumption were 0.66
(0.58-0.76) for cognitive impairment, 0.67 (0.43-1.03) for
cognitive decline, 0.80 (0.59-1.09) for dementia, and 1.12
(0.87-1.45) for Alzheimer’s disease. Subgroup analyses by
study design showed that the inverse association between
tea consumption and risk of cognitive disorders was found
in both cohort studies (OR=0.84, 95% CI: 0.74-0.95) and
cross-sectional studies (OR=0.66, 95% CI: 0.58-0.75)
(Table 2). Sensitive analysis showed that the inverse
association was not materially changed in the leave-one-
out analyses by omitting one study in turn, with pooled
ORs range from 0.71 (95% CI: 0.63-0.80) to 0.0.75 (95
CI: 0.66-0.84) (Supplementary Figure 1).
Four estimates from two individual studies were
available for assessing the relative risk for men and
women, separately. The pooled results also showed a
trend of reduced risk of cognitive disorders in both men
and women by higher tea consumption, but did not
reach statistical signicances (OR=0.65, 95% CI: 0.38-
1.11 and OR=0.63, 95% CI: 0.38-1.07, respectively)
(Supplementary Figure 2).
Different types of tea consumption and risk of
cognitive disorders
Eleven estimates from seven individual studies
were available for analysis of green tea consumption
and the risk of cognitive disorders and seven estimates
from four individual studies were available for analysis
of black/oolong tea consumption and risk of cognitive
disorders. The pooled analyses showed that higher green
tea consumption was associated with a reduced risk
of cognitive disorders (OR=0.64, 95% CI: 0.53-0.77)
(Figure 3A); however, there was no signicant association
between higher black/oolong tea consumption and risk of
cognitive disorders (OR=0.75, 95% CI: 0.55-1.01) (Figure
3B). Subgroup analyses by study design showed that the
inverse association between green tea consumption and
risk of cognitive disorders was found in both cohort
studies (OR=0.46, 95% CI: 0.23-0.95) and cross-sectional
studies (OR=0.66, 95% CI: 0.53-0.83); higher black/
oolong tea consumption was associated with a reduced
risk of cognitive disorders in cross-sectional studies
(OR=0.61, 95% CI: 0.49-0.75) (Table 2).
Dose-response analyses
Fifteen estimates from eight individual studies
were included in the dose-response meta-analyses. Other
studies were not included because there were only two
categories of tea consumption in these studies, and dose-
response meta-analysis requires data for the distribution
of cases and person-time across at least three categories
of exposure [37]. As shown in Figure 4, there was a
linear relationship between tea consumption and risk of
cognitive disorders (p for linear trend=0.042; p for non-
linear trend=0.236). The dose-response meta-analyses
showed that an increment of 100 ml/day, 300 ml/day, and
500 ml/day of tea consumption was associated with a 6%
(OR=0.94, 95% CI: 0.92-0.96), 19% (OR=0.81, 95%
CI: 0.74-0.88), and 29% (OR=0.71, 95% CI: 0.62-0.82)
lower risk of cognitive disorders, respectively (Figure 5).

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Figure 1: Flowchart for the selection of eligible studies.
The inverse association was not materially changed when
subgrouped by study design (Table 2).
Publication bias
Visual assessment of funnel plot (Figure 6) showed
that the studies were distributed fairly symmetrically
about the combined effect size in the meta-analysis
of all types of tea consumption and risk of cognitive
disorders, which suggests little publication bias. Egger’s
regression test (p=0.678) and Begg-Mazumdar test
(p=0.747) further conrmed that there was no potential
publication bias.
DISCUSSION
Tea is a commonly consumed beverage not only
in Asia but also in other parts of the world and has
been reported to have unlimited health benets. To our
knowledge, this study is the rst dose-response meta-
analysis to evaluate the effect of tea consumption on
the risk of cognitive disorders. The ndings from our
meta-analysis indicated that tea consumption is inversely
associated with the risk of cognitive disorders. However,
when considering the specic types of tea consumption,
the signicantly inverse association is only found in green
tea consumption but not in black/oolong tea consumption.

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Table 1: Characteristics of included studies in the systematic review and meta-analysis
Study Country Study design Sample
size
Mean
age
(years)
Follow-up
duration
(years)
Exposure
variable Disease type Disease
ascertainment Adjustment
Broe et al,
1990 Australia Case-control 340 77.5 - All tea AD NINCDS-
ADRDA
Age, sex and the general
practice of origin
Chen et
al, 2012 China
Prospective
nested case-
control study
5691 89.2 3 All tea Cognitive
decline MMSE None
Dai et al,
2006
The
United
States
Cohort 1589 71.8 6.4 All tea AD NINCDS-
ADRDA
Years of education,
gender, regular physical
activity, BMI, baseline
CASI score, olfaction
diagnostic group,
total energy intake,
intake of saturated,
monounsaturated,
and polyunsaturated
fatty acids, ApoE
genotype, smoking
status, alcohol drinking,
supplementation of
vitamin C, vitamin
E, and multivitamin,
tea drinking, fruit and
vegetable juice drinking,
dietary intake of vitamin
C, vitamin E, and
β-carotene.
Eskelinen
et al, 2009 Finland Cohort 1409 50.2 21 All tea Dementia, AD
MMSE,
DSM-IV and
NINCDS-
ADRDA
Age, sex, education,
follow-up time,
community of residence,
midlife smoking, systolic
blood pressure, serum
total cholesterol, BMI,
and physical activity.
Forster et
al, 1995
The
United
Kingdom
Case-control 218 55.9 - All tea AD NINCDS-
ADRDA None.
Huang et
al, 2009 China Cross-
sectional 681 93.5 - All tea Cognitive
impairment MMSE
Age, sex, sleep habits,
educational level, religion
habits, and temperament.
Kitamura
et al, 2016 Japan Cross-
sectional 1143 68.9 - All tea;
green tea
Cognitive
impairment MMSE
Age, BMI, history
of stroke, history of
myocardial infarction,
walking time, alcohol
intake, and fruit
consumption.
Kuriyama
et al, 2006 Japan Cross-
sectional 1003 74.7 - All tea and
green tea
Cognitive
impairment MMSE
Age, sex, energy intake,
intake of nondietary
vitamin C or E, sh
consumption, green
or yellow vegetable
consumption, mild
leisure-time physical
activity, vigorous leisure-
time physical activity,
smoking, and alcohol use.
(Continued )

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Study Country Study design Sample
size
Mean
age
(years)
Follow-up
duration
(years)
Exposure
variable Disease type Disease
ascertainment Adjustment
Lindsay et
al, 2002 Canada Cohort 4088 73.3 5 All tea AD DSM-IV Age, sex, and education.
Ng et al,
2008 Singapore Cross-
sectional 2607 66 -
All tea;
green tea;
black and
oolong tea
Cognitive
impairment,
cognitive
decline
MMSE
Age, sex, education,
smoking, alcohol
consumption, BMI,
hypertension, diabetes,
heart disease, stroke,
depression, APOEε4,
physical activities,
social and productive
activities, vegetable and
fruit consumption, sh
consumption, and coffee
consumption.
Noguchi-
Shinohara
et al, 2014
Japan Cohort 490 71.2 4.9 Green tea;
black tea
Dementia,
cognitive
decline
MMSE, CDR
and DSM-III-R
Age, sex, history of
hypertension, diabetes
mellitus, typerlipidemia,
education, APOE ε4
carrier status, alcohol
drinking, smoking,
physical activities and/
or hobbies, and coffee
consumption.
Shen et al,
2015 China Cross-
sectional 9375 70 - All tea;
green tea
Cognitive
impairment
CCM and
MMSE
Age, sex, race,
education, marriage,
tea concentration, tea
categories, physical
examinations, family
status, disease situation,
behavioral risk factors,
dietary intake, nutrition
supplement, depression
and ADL.
Tomata et
al, 2016 Japan Cohort 13645 73.8 5.7
Green tea;
black tea;
oolong tea
Dementia
LTCI system
and cognitive
function score
Age, sex, history of
disease, educational
level, smoking,
alcohol drinking,
BMI, psychological
distress score, time
spent walking, social
support, participation in
community activities,
motor function score,
consumption volume
of specic foods coffee
consumption, and energy
intake.
Wang et
al, 2014 China Cohort 223 70.9 2 Green tea Cognitive
decline MMSE Age and gender.
Wang et
al. 2016 China Cross-
sectional 1005 72.7 - All tea Cognitive
impairment
Clinical
diagnosis and
MMSE
Not mention.
(Continued )

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Study Country Study design Sample
size
Mean
age
(years)
Follow-up
duration
(years)
Exposure
variable Disease type Disease
ascertainment Adjustment
Wu et al,
2011 Taiwan Cross-
sectional 2119 73.3 - All tea Cognitive
impairment MMSE
Age, gender, educational
level, marital status,
social support,
hyperlipidemia, stroke,
physical function,
depressive symptoms,
self-rated health, cigarette
smoking, leisure-time
physical activity,
fruits and vegetables
consumption, coffee
intake, multivitamin
intake, and BMI.
Yao et al,
2010 China Cross-
sectional 2809 70.6 - All tea Cognitive
impairment MMSE None.
Abbreviations: AD, Alzheimer’s disease; ADL, Activities of Daily Living; BMI: body mass index; CASI, Cognitive
Abilities Screening Instrument; CDR, Clinical Dementia Rating Scale; DSM-III-R, Diagnostic and Statistical Manual of
Mental Disorders, Third Edition, Revised; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition;
LTCI, Long-term Care Insurance; MMSE, Mini-Mental State Examination; NINCDS-ADRDA, National Institute of
Neurological and Communicative Diseases and Stroke-Alzheimer Disease and Related Disorders Association.
Figure 2: Relative risk of cognitive disorders according to the highest vs. lowest category of all types of tea consumption.

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Overall, the risk decreases by 6%, 19%, and 29% for every
100 ml/day, 300ml/day, and 500ml/day increase in tea
consumption, respectively.
A previous meta-analysis from Kim et al. [38] found
that caffeine intake from coffee or tea was not associated
with the risk of cognitive disorders. When subgrouped by
caffeine source, caffeine intake from tea also showed no
association with cognitive disorders. However, in their
study, they used caffeine intake from tea as the exposure
variable of interest, while our study used the overall
tea consumption as the exposure. Systematic reviews
from Arab et al. [39] and Panza et al. [40] assessed
epidemiologic evidence of the relationship between tea,
coffee, or caffeine consumption and cognitive decline.
However, the included studies that specically for tea
consumption were rare and pooled analyses were not
conducted in these two reviews. In addition, although they
found the estimates of cognitive decline were lower among
consumers, there is a lack of a distinct dose response.
The ndings of our study extend the results of a previous
cohort study [41], which found that tea consumption is
signicantly associated with a lower risk of incident
functional disability, such as stroke, cognitive impairment,
and osteoporosis. In Feng et al’s study [14], verbal uency
test was used as measure of cognitive function. This
study found that daily and occasional tea drinkers had
signicantly higher verbal uency scores compared with
non-drinkers, and regular tea drinking was associated with
better cognitive function in oldest-old Chinese. In Ide et
al.’s study [13], they found that green tea consumption
was not only effective in improving cognitive function,
but also effective in reducing the progression of cognitive
dysfunction.
Arab et al.’s study [42] found that some levels of
tea consumption modestly reduced rates of cognitive
decline among the women but not men. Thus, sex may be
an important factor that impacts the association between
tea consumption and risk of cognitive disorders. However,
Table 2: Results of subgroup analyses by study design
Exposure variable Study design Number of estimates
Pooled OR (95% CI), I2
statistics (%), and P-value for
the heterogeneity Q test
All types of tea consumption Cohort 12 0.84 (0.74-0.95); I2=56.6%,
P=0.01
Cross-sectional 16 0.66 (0.58-0.75); I2=43.4%,
P=0.03
Green tea consumption Cohort 3 0.46 (0.23-0.95); I2=70.9%,
P=0.03
Cross-sectional 8 0.66 (0.53-0.83); I2=60.6%,
P=0.01
Black/oolong tea consumption Cohort 4 1.08 (0.63-1.84); I2=41.2%,
P=0.16
Cross-sectional 3 0.61 (0.49-0.75); I2=0.0%,
P=0.52
An increment of 100 ml/day
of tea consumption Cohort 6 0.96 (0.93-0.99); I2=34.8%,
P=0.18
Cross-sectional 9 0.92 (0.89-0.95); I2=50.9%,
P=0.04
An increment of 300 ml/day
of tea consumption Cohort 6 0.91 (0.84-0.99); I2=63.2%,
P=0.02
Cross-sectional 9 0.77 (0.72-0.83); I2=27.1%,
P=0.20
An increment of 500 ml/day
of tea consumption Cohort 6 0.84 (0.61-0.98); I2=67.8%,
P=0.01
Cross-sectional 9 0.69 (0.63-0.75); I2=0.0%,
P=0.45

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Figure 3: Relative risk of cognitive disorders according to the highest vs. lowest category of green tea (A) and black/oolong tea
(B) consumption.

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there were very limited studies that focused on this
association for men and women separately. In the current
meta-analysis, only four estimates from two individual
studies were available for assessing the relative risks
for men and women, separately; and our results showed
that neither male nor female tea consumers showed a
signicant association with the risk of cognitive disorders.
This may be due to the very limited studies included in
the meta-analyses, which led to low statistical powers.
Therefore, more studies are needed to further assess the
association between tea consumption and risk of cognitive
disorders in difference sexes.
There are several plausible mechanisms to explain
the protective effect of tea consumption against cognitive
disorders. Many studies have shown that oxidative
stress, which occurs by oxidizing macromolecules such
as proteins, lipids, and DNA, is an important pathogenic
factor in cognitive diseases including AD [43–46]. Tea
is enriched in polyphenols and the major tea-related
polyphenols present in green tea are catechins, which
are polyphenolic compounds with high antioxidant
capacities [47], and they have shown effects on anti-
aging [48], anti-diabetic [49, 50], anti-stroke [51],
and anti-cancer [52] in various studies. Polyphenols
contained in green tea have also been reported to have
anti-amyloidogenic effects, and could be a key molecule
for the development of preventives and therapeutics for
AD [53, 54]. Coimbra et al.’s study [20] showed that
green tea can signicantly reduce the serum levels of
malonyldialdehyde and malonyldialdehyde+4-hydroxy-
2(E)-nonenal, the lipid peroxidation products, and
reduce the oxidative stress within the erythrocyte.
L-theanine, a free amino acid naturally found in tea, can
also play a neuroprotective role [55]. Caffeine, another
important component of tea leaf, has been known for
its refreshing effect and is benecial for performance
improvement on attention tasks when combined with
L-theanine [56, 57]. Chen et al. [58] demonstrated
that one mechanism implicated in the pathogenesis
of AD is blood-brain barrier dysfunction and caffeine
exerts protective effects against AD at least in part by
keeping the blood-brain barrier intact. Furthermore,
previous studies supported the biological effects of
caffeine on brain function [59], including modulation
Figure 4: Dose-response relationship between tea consumption and risk of cognitive disorders.

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Figure 5: Relative risk of cognitive disorders for an increment of 100 ml/day (A), 300 ml/day (B), and 500 ml/day
(C) of tea consumption.

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of white matter lesions and/or microvascular ischemic
lesions [60]. Another potential mechanism for long-
term neuroprotective effect of caffeine may involve
blockade of adenosine A2A receptors [61], which may
attenuate injury caused by β-amyloid, the toxic peptide
that accumulates in the brain of patients with AD [62,
63]. In fact, both acute and long-term caffeine intake
were shown to suppress β-amyloid levels in plasma
and brain of AD transgenic mice [64, 65] and memory
restoration and reversal of AD pathology in mice with
preexisting β-amyloid burden [66]. In addition, tea
consumption has shown to reduce the hypertension
risk [67] and decrease the serum concentrations of total
cholesterol (TC) and low density lipoprotein cholesterol
(LDL-C) [68]; hypertension and dyslipidemia are well
known to be the risk factors for atherosclerosis [69, 70],
and atherosclerosis is in turn associated with cognitive
dysfunction. Thus, tea consumption may reduce the risk
of cognitive disorders indirectly by reducing the relevant
health problems on atherosclerosis.
In our study, green tea consumption but not in black/
oolong tea consumption was associated with reduced risk
of cognitive disorders. This may be due to the fact that
the nutritional and functional components are not quite
the same between green tea and black/oolong tea. For
example, the levels of catechin (epigallocatechin gallate
[ECGC]) are highest in green tea, followed in order
by oolong tea and black tea [71]. Moreover, green tea
contains ascorbic acid and high intake of ascorbic acid is
related to the reduced risk of AD [72]; however, black tea
do not contain ascorbic acid [22]. The differences in the
protective effects of cognitive function between green tea
and black/oolong tea need to be further claried by more
mechanistic studies.
Figure 6: Funnel plot to explore publication bias. The vertical line is at the mean effect size.

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The strengths of the present meta-analysis include
less inuence exerted by small-study bias, greatest
extent of control for confounding factors, a moderate-
to-high quality of studies included in the meta-analysis,
and no evidence of publication bias. Moreover, we
performed dose-response meta-analysis and found a
linear relationship between tea consumption and risk of
cognitive disorders.
However, our study has several limitations.
First, we found a mild heterogeneity within the studies,
which could be explained by the difference in study
designs, study populations, measure methods of tea and
cognitive disorders, and analytical strategies. Second,
the association was evaluated by using the most adjusted
model in each included study; however, some important
confounding factors, such as lifestyle (diets, hobbies,
physical activities, etc.), cultural differences, lifestyle-
related diseases (diabetes mellitus, hypertension,
dyslipiedemia, etc.) and ApoE status were not adjusted
in some of the included studies. In addition, we cannot
exclude chance, residual or unmeasured confounding
as the alternative explanation of our results. Thus, our
results must be explained with caution. Third, in most
of the included studies, the consumption of tea was
measured using a self-administered questionnaire; and
thus, misclassication is inevitable. Fourth, although the
overall analysis was based on a large number of studies,
few studies were available according to tea subtypes,
study populations from Europe and US, and genders,
which have led to unstable results in or restriction to
secondary analysis. Finally, our conclusions are based
on results from observational studies. Especially, as the
number of available cohort studies was limited, we also
included cross-sectional studies in our meta-analysis to
increase the statistical power. Thus, a causal association
between tea consumption and cognitive disorders cannot
be determined with the present data alone.
In conclusion, the results of our meta-analysis,
involving 17 independent observational studies, provide
signicant evidence of an inverse and a linear relationship
of tea consumption with the occurrence of cognitive
disorders. A greater increment of tea drinking led to a
greater magnitude in risk reduction. Further well-designed
long-term randomized controlled trials (RCTs) are needed
to conrm our ndings.
MATERIALS AND METHODS
Search strategy and eligibility criteria
The guidelines published by the Meta-analysis
of Observational Studies in Epidemiology (MOOSE)
group was followed to complete the meta-analysis
(Supplementary Table 1) [73]. Eligible studies that
published in the international journals were searched
in electronic databases of Pubmed, Embase, and
Cochrane Library (from 1965 to Jan 19, 2017) by two
investigators. We used the following MeSH and free-text
terms in the search strategy: “Tea [Mesh]”, “Cognitive
Dysfunction [Mesh]”, “Alzheimer Disease [Mesh]”,
“Dementia [Mesh]”, “tea consumption”, “tea intake”,
“tea”, “cognitive decline”, “cognitive impairment”,
“cognitive disorder”, “dementia”, “Alzheimer disease”,
and “Alzheimer’s disease”. The search was restricted
to studies in human beings and publications in English
language. The reference lists of identied articles and
relevant reviews were also checked for potentially eligible
studies.
Studies that met the following criteria were included
in our meta-analysis: (1) examination of tea consumption
as the variable of interest; (2) determination of incidence
of cognitive impairment, cognitive decline, dementia, or
Alzheimer’s disease as the outcome of interest; and (3)
reporting the relative risks (RR) or odds ratios (OR) of
cognitive disorders, and 95% condence intervals (CI),
or sufcient data with which to calculate these, according
to the different levels of tea consumption. Studies about
animal experiment, mechanistic research and review
research were excluded.
Data extraction and study quality evaluation
The following data from each included study
were extracted by two investigators: rst author,
publication year, country, study design, sample size,
mean age of the participants, follow-up duration of
cohort studies, disease type of the outcome (cognitive
impairment, cognitive decline, dementia, or Alzheimer’s
disease), exposure variable (tea type), exposure variable
ascertainment method, disease ascertainment methods,
categories of tea consumption, risk estimates with CIs,
and confounding factors adjusted for. We included the
most adjusted estimate when a study reported more than
one risk estimate. Two investigators assessed the quality
of each study, using the Newcastle-Ottawa Scale (NOS)
recommended by Wells and colleagues [74]. The NOS
score of each included study ranges from 1 to 9 stars for
cohort and case-control studies and 1 to 5 stars for cross-
sectional studies.
Statistical analyses
We performed meta-analyses of risk estimates for
cognitive disorders comparing the highest category of
exposure to tea consumption with the lowest category.
The results of studies using cognitive impairment,
cognitive decline, dementia and Alzheimer’s disease
as the outcomes are presented separately. If a single
study reported results for different populations (men
and women), different types of tea consumption (green
tea and black tea) or different assessment methods of
cognitive disorders but did not report the overall results,

Oncotarget43318
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the results for each population, type of tea consumption
and assessment method of cognitive disorders were
calculated as a different study [75]. We rst conducted
a meta-analysis of all types of tea consumption and
the risk of cognitive disorders, and then we conducted
meta-analyses for this association in different sexes and
types of tea consumption, respectively. Subsequently,
we conducted a dose-response meta-analysis from
the correlated natural log of ORs across categories of
tea consumption [76, 77], to estimate linear trends of
OR for cognitive disorders per 100, 300, and 500 ml/
day increment in tea consumption. As studies reported
results for tea consumption in cups, we derived milliliter
by assuming that the average cup equals to 215 ml
[32]. We converted the level of consumption category
based on the calculated midpoint of tea consumption
if the study did not report the median of exposure
category. If the maximum dose was xed unlimitedly
(e.g. ≥2 cups/d), we assumed that the mean was 25%
larger than the lower level of the specic category [78].
Supplementary Table 2 summaries the denition of tea
consumption and the means of conversion of categories
within each study.
We used a random effects model to estimate
the pooled ORs and 95% CIs to take into account the
heterogeneities between studies. χ2 test and I2 statistic
were used to evaluate the heterogeneity between studies.
Sensitivity analysis was performed for the main meta-
analysis by removing each individual study from the meta-
analysis [79]. We visually assessed publication bias for the
main meta-analysis by using funnel plots. Then we used
Egger’s regression test [80] and Begg-Mazumdar test [81]
to further assess publication bias. All statistical analyses
were performed using Stata Version 12.0 software (Stata
Corp, College Station, TX).
CONFLICTS OF INTEREST
No conicts of interest was declared by the authors.
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