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Tea for Alzheimer Prevention
L. Feng, M.-S. Chong, W.-S. Lim, T.-S. Lee, E.-H. Kua, T.-P. Ng
Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore and National University Health System, Singapore;
the Department of Geriatric Medicine, Tan Tock Seng Hospital, Singapore; Institute of Geriatrics and Active Ageing, Tan Tock Seng Hospital, Singapore; the
Neurobehavioral Disorders Program, Duke-NUS Graduate Medical School, Singapore.
Corresponding Author: Lei Feng ( pcmfl@nus.edu.sg ), Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore (NUS) and
National University Health System (NUHS), Tel: +65 67723491 Fax: +65 67772191
J Prev Alz Dis 2015;2(2):136-141
Published online April 8, 2015, http://dx.doi.org/10.14283/jpad.2015.57
Abstract
The availability of empirical data from human studies in recent
years have lend credence to the old axiomatic wisdom that
health benefits of tea drinking extend to the area of cognition.
Specifically, there is increasing interest as to whether tea
drinking can delay or even prevent the onset of Alzheimer’s
disease (AD). Data from several cross-sectional studies have
consistently shown that tea drinking is associated with better
performance on cognitive tests. This association is supported
by longitudinal data from the Singapore Longitudinal Aging
Study, the Chinese Longitudinal Healthy Longevity Survey
and the Cardiovascular Health Study. The only two published
longitudinal analyses on clinical outcome reported conflicting
results: one study reported that mid-life tea drinking was not
associated with risk reduction of Alzheimer’s disease in late life
while the other one found that green tea consumption reduced
the incidence of dementia or mild cognitive impairment. Two
small trials from Korea and Japan reported encouraging but
preliminary results. While the existing evidence precludes
a definite conclusion as to whether tea drinking can be an
effective and simple lifestyle preventive measure for AD,
further research involving longer-term longitudinal studies
and randomized controlled trials is clearly warranted to shed
light on this topic of immense public health interest. Biological
markers of tea consumption and Alzheimer diseases should be
employed in future research to better delineate the underlying
mechanisms of tea drinking’s protective effect on cognition.
Key words: Tea, aging, Alzheimer’s disease, dementia, cognitive
decline, prevention.
Background
It was written by Lu Yu (han yu pinyin: Lù Yǔ; 733-
804) in his famous book “The Classic of Tea” that
“tea as a beverage was started by Shen Nong”. This
dated the history of tea drinking to about 5000 years ago,
when She Nong ruled China as a legendary emperor.
Today, tea is one of the most widely consumed beverages
in many countries with many well recognized health
benefits.
The effects of tea drinking on cognitive function in the
elderly and the potential of tea as a simple yet effective
lifestyle preventive measure for Alzheimer’s disease (AD)
is now attracting immense research interest. Because tea
is easily available, cheap and has no side effects at usual
levels of consumption, the potential of reducing disease
burden at the population level is considerable. There
are currently 35 millions people with AD worldwide;
since the principal risk factor of AD is age with its
incidence doubling every 5 years after 65 years of age, the
number of Alzheimer patients is expected to rise sharply
with the rapidly aging demographic trend worldwide.
Since AD is akin to a chronic condition with relatively
prolonged survival after diagnosis at the mild stage, even
a moderate reduction of incidence rate at the population
level would have a huge impact on reducing burden of
health to the healthcare system and society at large.
The urgency of establishing prevention strategy for
AD lies in the fact that none of the currently approved
drug therapies (namely cholinesterase inhibitors and
N-methyl-D-aspartate receptor antagonist) can reverse
disease progression; the condition of patients who are
taking these drugs remains stable for a year or more and
then may decline, though at a rate that is slower than that
among untreated patients (1). The search for a disease
modifying agent has proved equally elusive. Results
from recent large scale phase 3 trials involving disease
modifying agents such as the anti-amyloid-β monoclonal
antibody drugs solanezumab (2) and bapineuzumab
(3) were essentially negative. The disappointing results
from these studies have provided the impetus for the
increasing shift in attention to non-pharmacological
preventive lifestyle measures in the battle against AD.
The disease processes of AD in the brain starts at
least a decade before clinical symptoms become
apparent. It is well accepted that AD is a chronic and
complex disease and many researchers in the field
now believe that prevention may be a more promising
target than treatment of established disease. With
better understanding of contributing factors through
previous observational studies, there has been a surge
in recent years in primary prevention trials, such as the
Multi-Domain Alzheimer’s Prevention Trial (MAPT),
the Prevention of Dementia by Intensive Vascular Care
study (PreDIVA) and the Finnish Geriatric Intervention
Study to Prevent Cognitive Impairment and Disability
(FINGER). In Singapore, an early Dementia Prevention
Program (DPP) has been initiated by a group of clinicians,
136
Received February 12, 2015
Accepted for publication March 4, 2015
The Journal of Prevention of Alzheimer’s Disease - JPAD©
Volume 2, Number 2, 2015
researchers and volunteers at the Training and Research
Academy at Jurong Point (TaRA@JP) (4, 5). Since
multiple factors across the life span contribute to disease
outcomes in late life, it is premature to postulate that
targeting any single factor in isolation would significantly
reduce disease incidence, hence the rationale for the
multiple-domain approach in most of prevention studies.
Nevertheless, for scientific clarity, each of the candidate
preventive measures should be examined in isolation
with well designed observational and interventional
studies. Tea is one such promising candidates.
There is strong biological basis that supports the
assertion that tea drinking may be an effective preventive
measure for AD. Many molecular lesions have been
detected in AD, but the overarching theme that emerge
from the data is that an accumulation of misfolded
proteins in the aging brain results in oxidative and
inflammatory damage, which in turn leads to energy
failure and synaptic dysfunction (6). Tea contains various
bioactive compounds such as the catechins, theaflavins,
thearubigins and L-theanine. Those compounds may
protect the brain from AD through multiple mechanisms
including the actions on upstream events such as
amyloid formation (7, 8) and downstream events such
as oxidative stress and inflammation (9). In this paper,
we provide a brief summary of key studies that supports
the role of tea in Alzheimer prevention, along with our
recommendations for future research directions.
Tea for AD: evidence from observational
studies
Information and main findings from observational
studies are organized according to data sources. In
situations where there are multiple papers from the same
cohort, these are summarized under a single section. Key
findings from the longitudinal studies are summarized in
Table 1.
The Tsurugaya Project 1: cross-sectional
analysis (10)
The Tsurugaya Project 1 is a community-based study
among elderly Japanese living in a defined geographical
location namely the Tsurugaya district, a suburban
area of Sendai City in northern Japan. In this study,
information on the frequency of tea consumption was
collected through items in a comprehensive geriatric
assessment questionnaire. Subjects were grouped into
3 categories according to their green tea consumption
frequency: ≤3 cups/week, 4–6 cups/week or 1 cup/
day, and ≥2 cups/day; the volume of a typical cup of
green tea in Japan is 100 milliliters. Cognitive function
was assessed using the Japanese language version of
the Mini-Mental State Examination (MMSE). Cognitive
impairment was defined as MMSE total score <26. Based
on data from 1,003 subjects aged 70 years or above, the
authors reported that higher consumption of green tea
was associated with a lower prevalence of cognitive
impairment. Using < or =3 cups/week as the reference
group, the odds ratio (OR) was 0.62 (95% CI: 0.33, 1.19)
for 4-6 cups/week or 1 cup/day, and 0.46 (95% CI: 0.30,
0.72) for > or =2 cups/day.
The Hordaland Health Study: cross-sectional
analysis (11)
The Hordaland Health Study was conducted from
1997 to 1999 as a collaboration between the University
of Bergen, University of Oslo, local health services and
the Norwegian Institute of Public Health. The Cognitive
Sub-study of the project recruited and assessed 2,197
participants who were born in 1925-1927 using a
cognitive test battery that includes the Kendrick Object
Learning Test, Trail Making Test, part A (TMT-A),
modified versions of the Digit Symbol Test, Block Design,
MMSE, and Controlled Oral Word Association Test.
Information on habitual tea intake was collected using
a Food Frequency Questionnaire (FFQ). A standard cup
of tea was defined as 200 milliliters and the frequency of
consumption was given per day, week, or month. Data
from a total of 2,031 study participants aged between
70-74 years were used in the analysis on the association
between tea consumption and cognitive function. It was
found that study participants who consumed tea had
significantly better mean test scores and lower prevalence
of poor cognitive performance (defined as a score in the
highest decile for the TMT-A and in the lowest decile for
all other tests) than those who did not. The association
was dose dependent and approximately linear.
The sharpest dose-response effect of tea on cognitive
performance was up to ~200 milliliter/day.
JPAD - Volume 2, Number 2, 2015 Review Article
137
Table 1. Longitudinal studies on the association between
tea and cognitive outcome
Cohort Main ndings
SLAS Total tea consumption was signicantly associated
with a lower risk of cognitive decline
CAIDE Mid-life tea drinking was not associated with the
risk of dementia and Alzheimer’s disease in late
life.
CLHLS Tea drinkers had higher verbal uency scores
throughout the follow-up period.
CHS Tea drinking was associated with an attenuated
rate of cognitive decline in women but not in men.
Nakajima Green tea consumption was associated with
reduced incidence of overall cognitive decline
(dementia or MCI).
138
The Singapore Longitudinal Aging Study
(SLAS): cross-sectional and longitudinal
analysis
The Singapore Longitudinal Ageing Study (SLAS) is
a community-based study on health and health-related
conditions in aging. The project recruited 2,808 older
adults aged 55 and above in the southeast region of
Singapore from 2003 to 2005 and conducted regular
follow-up assessment at a time interval of approximately
2.5 years. In the SLAS cohort, global cognitive function
was assessed using a modified version of the MMSE
(12). Neuropsychological assessment was conducted
for approximately one third of the study participants
at baseline; details of the battery have been described
elsewhere (13, 14). Information on tea consumption was
collected about the habitual intake of common types of
teas among local elderly using indigenous references and
terms.
Analysis based on baseline data from 2,501 SLAS
participants showed an inverse relationship between
tea consumption and the odds of having cognitive
impairment defined as a MMSE total score of less than
24 (15). Compared with the reference group of rare or
no tea intake, the ORs for low, medium, and high levels
of tea intake were 0.56, 0.45, and 0.37 respectively (P
for linear trend < 0.001). The protective effects were
most evident for black (fermented) and oolong (semi-
fermented) teas, the predominant types consumed by
this population. Analysis based on data from 716 SLAS
subjects who had neuropsychological test data showed
that tea consumption was independently associated
with better performances on global cognition (B=0.055,
P=0.03), memory (B=0.031, P=0.01), executive function
(B=0.032, P=0.009), and information processing speed
(B=0.04, P=0.001) (16). Both black/oolong tea and green
tea consumption were associated with better cognitive
performance. Analysis based on 1,438 SLAS subjects
who had complete MMSE data at baseline and repeated
MMSE at follow-up revealed reverse association between
tea drinking and the odds of having cognitive decline
defined as a MMSE total score drop of 1 point or greater
during the follow-up period (15). Compared with the
OR for rare or no tea intake, the ORs for low, medium,
and high levels of tea intake were 0.74, 0.78, and 0.57
respectively (P for linear trend = 0.042).
The Chinese Longitudinal Healthy Longevity
Survey (CLHLS): longitudinal analysis and
gene-environment (G×E) interaction
The CLHLS is a population based cohort study of
oldest-old and comparative sub-sample of younger elders
in China. In the CLHLS cohort, cognitive function was
measured by the verbal fluency test at baseline (n=7,139),
year 2000 (n=4,081), year 2002 (n=2,288) and year 2005
(n=913) for oldest-old participants (80-115 years old) (17).
Self-reported information on tea consumption habits at
the age of 60 and year 1999 was collected through face-to-
face interviews. The frequency was recorded as “almost
every day” or “occasionally” or “rarely or never”. In the
linear mixed effects model that adjusted for age, gender,
years of schooling, physical exercise and activities score,
the regression coefficient for daily drinking (at age
60) and occasional drinking was 0.72 (P<0.0001) and
0.41(P=0.01) respectively. Tea drinkers had higher verbal
fluency scores throughout the follow-up period . Similar
results were found for current tea drinking status at the
study baseline year (1998) as a predictor variable.
An interesting GxE interactions between FOXO
genotypes and tea drinking was revealed in cross-
sectional analysis that involved 822 CLHLS participants
who were aged 92 and above (18). Associations between
tea drinking and reduced cognitive disability defined
using MMSE cutoffs were much stronger among
carriers of the genotypes of FOXO1A-266 or FOXO3-310
or FOXO3-292 compared with noncarriers, and it was
reconfirmed by analysis of three-way interactions across
FOXO genotypes, tea drinking at around age 60, and at
present time.
The Cardiovascular Health Study (CHS):
longitudinal analysis
The CHS is a prospective longitudinal study of
cardiovascular disease in participants aged 65 years
and older. In this study, 5,201 men and women were
enrolled in 1989 and 1990 from a random sample of
Medicare-eligible residents in four U.S. communities
(19). In the CHS, cognitive performance was assessed
using the Modified Mini-Mental State (3MS) examination
which was administered annually up to 9 times. The
relationship of tea consumption on changes in cognitive
function was analyzed for 4,809 CHS participants using
Linear Mixed Models. The authors reported modestly
Review Article TEA FOR ALZHEIMER PREVENTION
Table 2. Interventional studies on tea and cognitive outcome
Country, City Study design Sample size Main nding
Korea, Daejeon RCT 91 Green tea extract and L-theanine led to improvements in memory
but the changes were not signicant at an alpha level of 0.05.
Japan, Higashi-Murayama Single-arm trial 12 Green tea improved cognitive function in a group of Japanese
elderly with diagnosis of Alzheimer disease, Vascular dementia or
Dementia with Lewy bodies.
JPAD - Volume 2, Number 2, 2015
139
Review Article
reduced rates of cognitive decline for levels of tea
consumption among women, with no such effect for men.
The adjusted mean rate of decline for the reference group
(women who drank less than 5 cups of tea per year) was
1.30 standard 3MS points per year. Compared with the
reference group, female participants drinking tea 5-10
times/year, 1-3 times/month, 1-4 times/week, and 5+
times/ week had average annual rates of decline (95%
CI) of 3MSE scores that were 0.23 (-0.14-0.60), 0.44 (0.13-
0.75), 0.53 (0.24-0.82), and 0.29 (0.01-0.57) points lower,
respectively.
The Cardiovascular risk factors, Aging and
Dementia (CAIDE) study: longitudinal analysis
The CAIDE study is the first study that examined
the association between midlife tea consumption and
dementia status in late life. The investigators selected
a random sample from survivors of population-based
random samples rstly studied within the North Karelia
Project and the FINMONICA study in 1972, 1977, 1982
or 1987 and completed follow-up assessments in 1998
for 1,409 individuals who were living in the study area
in Eastern Finland (in Joensuu or Kuopio) (20). A total of
61 person were identified as demented, out of which 48
had AD. Midlife tea consumption status of CAIDE study
subjects was dichotomized into those not drinking tea (0
cup/day) versus those drinking tea (at least 1 cup/day).
In the logistic regression model, the OR of dementia and
AD for tea drinkers was 1.04 (95% CI 0.59–1.84) and 0.91
(95% CI 0.48–1.71) respectively. There was no association
between midlife tea consumption and the risk of AD in
late life.
The Nakajima Project: longitudinal analysis
(21)
The Nakajima Project is the first longitudinal study
that examined the association between green tea and the
incidence of dementia and MCI. It is a population-based
cohort study that examined the correlations between
lifestyle factors and dementia in elderly Japanese. The
study was conducted in Nakajima, in the Nanao district
of Ishikawa Prefecture, Japan. Among 490 Nakajima
Project participants who were assessed as cognitively
normal in 2007-2008 (baseline); 26 incident dementia
cases and 64 mild cognitive impairment (MCI) cases were
ascertained at the follow-up survey in 2011-2013. The OR
for combined incidence of dementia and MCI was 0.32
for daily green tea consumers and 0.47 for participants
who consumed green tea 1-6 days per week compared
with participants who did not consume green tea at
baseline. There was no association between black tea
and the incidence of dementia and MCI but the number
of black tea consumers was very small: only 86 (17.6%)
of the participants consumed black tea at least 1 day per
week, and the number of daily tea consumers was only 6
(in contrast, the number of daily green tea consumer was
157).
Tea for AD: evidence from interventional
studies
Two interventional studies exist in the literature,
one from Korea and the other from Japan. The studies
targeted individuals who had self-reported cognitive
deficits or were previously diagnosed with dementia,
and hence strictly speaking, should not be considered
as primary prevention trials. Nevertheless, the results
from those two trials provide important insights from
the preliminary evidence and are hence included in this
discussion.
The Daejeon University Oriental Hospital
study: Randomized Controlled Trial (22)
This is a randomized, double-blind, placebo-controlled
study that tests the potential of LGNC-07, a nutraceutical
ingredient containing green tea extract (GTE) and
L-theanine, as an intervention for cognitive improvement
among individual with subjective cognitive impairment.
The investigators recruited ninety-one participants (25
men and 66 women, MMSE total scores ranging from
21 to 26) from Daejeon University Oriental Hospital and
randomly allocated them into LGNC-07 treatment or
placebo arms. Participants took two 430-mg capsules of
treatment or placebo twice a day 30 minutes after meals
for 16 weeks. Treatment capsules contained 360 mg of
GTE, 60 mg of L-theanine, 5.7 mg of silicone dioxide,
and 4.3 mg of magnesium stearate. Neuropsychological
tests and electroencephalography were conducted to
evaluate the effect of LGNC-07 on memory and attention.
Electroencephalograms were recorded in 24 randomly
selected subjects hourly for 3 hours in eye-open, eye-
closed, and reading states after a single dose (LGNC-07,
n = 12; placebo, n = 12).
The investigators reported that LGNC-07 led to
improvement in memory by marginally increasing
delayed recognition in the Rey-Kim memory test
(P = 0.057). Stratified analyses showed that LGNC-07
improved memory and selective attention by significantly
increasing the Rey-Kim memory quotient and word
reading in the subjects with MMSE (Korean version)
scores of 21-23 (LGNC-07, n = 11; placebo, n = 9). Brain
theta waves, an indicator of cognitive alertness, were
increased significantly in the temporal, frontal, parietal,
and occipital areas after 3 hours in the eye-open and
reading states.
140
Review Article
The White Cross Nursing Home study: single
arm trial
This is a small study that was conducted from July
to September 2012 at the White Cross Nursing Home in
Higashi-Murayama, Japan. Study participants were asked
to consume green tea powder (2 grams /day, containing
227 milligrams catechins and 42 milligrams theanine)
during meals for a period of 3 months. The consumption
of other supplements that could have antioxidant effects
was prohibited during the intervention period and for
a seven-day washout period prior to the start of the
intervention. Participants were advised to maintain
their customary intake of home-brewed green tea or tea
beverages during the study period.
Analysis based on twelve participants (2 men, 10
women; 3 AD, 8 Vascular Dementia, 1 Dementia with
Lewy bodies; mean age 88 years) who had complete data
for the trial showed significant improvement in MMSE
(Japanese version): the mean score improved from 15.3
± 7.7 before intervention to 17.0 ± 8.2 (P = 0.03). The
study demonstrates that green tea improves cognitive
function even at relatively low catechin and theanine
concentrations which can be obtained from ordinary
levels of daily green tea intake. It should be noted that the
concentration of bioactive compounds in the daily dose of
green tea powder employed in this study approximately
equates to two to four cups of bottled or home-brewed
green tea.
Conclusions and recommendations
Take together, the body of evidence as summarized
above appears to support the role of tea as an effective
yet simple lifestyle preventive measure for AD. Future
research involving more robust study designs are
warranted, especially longitudinal studies that examine
clinical outcomes and interventional studies that target
individuals at high risk of developing AD. Given that tea
drinking is relatively safe and have many concomitant
health benefits, practitioners can generally recommend
tea drinking as a simple lifestyle measure for overall
cognitive health and possible benefit in AD prevention,
especially in populations with an established tea-drinking
culture. As for types of tea, current observational data
do not support the superiority of any type of tea (such as
green tea) over others (such as black tea).
It should be noted that although the neuroprotective
role of tea consumption is biologically plausible, there
is a lack of good data on underlying neural mechanisms
from human studies. Recently, Schmidt and colleagues
demonstrated that green tea extract enhanced parieto-
frontal connectivity during working memory, and that
the magnitude of increased connectivity was positively
correlated with improvement in task performance (23). It
is unknown whether long-term tea consumption would
induce functional and structural changes in the brain.
We therefore recommend that future studies should
include biomarkers of Alzheimer pathophysiology such
as structural and functional imaging modalities involving
Magnetic Resonance Imaging (MRI) and Positron
Emission Tomography (PET), as well as cerebrospinal
fluid based biomarkers involving tau and amyloid.
Biomarkers of tea intake such as catechin and theanine
(24, 25) should also be monitored.
Lastly, we recommend that a large prevention trial that
is adequately powered akin to the Ginkgo Evaluation of
Memory (GEM) study (26, 27) be conducted to examine
the preventative effect of tea drinking among subjects
with normal cognition at baseline. The authors look
forward to data from such a trial to confirm or reject the
notion of tea in the prevention of Alzheimer’s disease.
Dr Feng received conference travel support from Amore Pacific, Republic of Korea.
He is currently planning grant application on the role of tea as a preventive for dementia.
Conflict of interests: None of the co-authors reported potential conflict of
interests.
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