Concord grape juice supplementation improves memory function in older
adults with mild cognitive impairment
*, Tiffany A. Nash
, Marcelle D. Shidler
, Barbara Shukitt-Hale
and James A. Joseph
Department of Psychiatry, University of Cincinnati Academic Health Center, Cincinnati, OH, USA
USDA Human Nutrition Research Center on Aging and Tufts University, Boston, MA, USA
(Received 1 May 2009 – Revised 3 September 2009 – Accepted 4 September 2009 – First published online 23 December 2009)
Concord grape juice contains polyphenol compounds, which have antioxidant and anti-inﬂammatory properties and inﬂuence neuronal signalling.
Concord grape juice supplementation has been shown to reduce inﬂammation, blood pressure and vascular pathology in individuals with CVD,
and consumption of such ﬂavonoid-containing foods is associated with a reduced risk for dementia. In addition, preliminary animal data have
indicated improvement in memory and motor function with grape juice supplementation, suggesting potential for cognitive beneﬁt in ageing
humans. In this initial investigation of neurocognitive effects, we enrolled twelve older adults with memory decline but not dementia in a ran-
domised, placebo-controlled, double-blind trial with Concord grape juice supplementation for 12 weeks. We observed signiﬁcant improvement in
a measure of verbal learning and non-signiﬁcant enhancement of verbal and spatial recall. There was no appreciable effect of the intervention on
depressive symptoms and no effect on weight or waist circumference. A small increase in fasting insulin was observed for those consuming grape
juice. These preliminary ﬁndings suggest that supplementation with Concord grape juice may enhance cognitive function for older adults with
early memory decline and establish a basis for more comprehensive investigations to evaluate potential beneﬁt and assess mechanisms of action.
Memory: Cognitive impairment: Elderly: Grape juice: Polyphenols
Worldwide dementia prevalence is almost 25 million cases
and is projected to reach more than 81 million cases by the
. Alzheimer’s disease comprises 60 to 80 % of
cases of dementia
. The construct mild cognitive impair-
identiﬁes individuals with elevated risk for demen-
, and progression from mild cognitive impairment to
Alzheimer’s disease can be as high as 10 % per year
Further, there are indications that even age-associated
memory impairment, originally conceptualised as benign
, can reﬂect very early neurodegeneration.
Older adult samples with subjective memory complaints
who meet criteria for age-associated memory impairment
show degradation in the medial temporal lobe that is similar,
albeit not as extensive, as that observed in subjects with
mild cognitive impairment and Alzheimer’s disease
longitudinal investigation has shown a trebling of risk for
those categorised as having age-associated memory impair-
. Such ﬁndings imply that memory complaints and
associated manifestations in everyday functioning can be
meaningful indicators of neurodegeneration. Preventive inter-
ventions initiated when early memory decline is evident have
the potential to forestall progression, most likely at the ﬁnal
stage when such treatment might be effective
Regulation of inﬂammation generally is reduced with
, and accelerated inﬂammation is implicated in
neurodegenerative disorders such as Alzheimer’s disease
Berry fruits contain polyphenol compounds, which have
anti-inﬂammatory and antioxidant properties
also induce neuroprotective effects and inﬂuence neuronal
signalling involved in memory function
(14 – 16)
, and speciﬁc
constituents of grape juice have exhibited neuroprotective
Concord grape juice contains a variety of ﬂavonoids and
antioxidants, among them anthocyanins and proanthocyani-
and comparatively high levels of total phenolics
Information concerning ﬂavonoid transport into the central
nervous system and absorption into brain tissue is emerging.
A number of recent studies have indicated that certain of
these compounds, in particular anthocyanins, cross the
blood–brain barrier, although speciﬁc mechanisms have not
(21 – 23)
. In addition, anthocyanins have been
identiﬁed in brain regions that mediate cognition, including
the medial temporal lobe and cortex
, and hippocampal dis-
tribution has been associated with behavioural enhancement in
animal supplementation studies
Human trials have shown that short- and moderate-term
supplementation with grape juice produces beneﬁt in individ-
uals with CVD, including increased serum antioxidant
capacity and reduced LDL oxidation
, improved endothelial
and reduced platelet aggregation
. Such ﬁndings
are pertinent with respect to age-related cognitive decline
because of the strong relationship between CVD and neurode-
(28 – 31)
. Epidemiological studies indicate that con-
sumption of fruits and vegetables is associated with lower
risk of neurodegenerative disorders and better cognitive per-
formance in the elderly
(32 – 34)
, and these effects have been
*Corresponding author: Dr Robert Krikorian, fax þ1 513 558 0877, email email@example.com
British Journal of Nutrition (2010), 103, 730–734 doi:10.1017/S0007114509992364
qThe Authors 2009
British Journal of Nutrition
attributed to the intake of a variety of ﬂavonoid compounds
with antioxidant and anti-inﬂammatory properties. Recently,
a preliminary animal study demonstrated that ingestion of
Concord grape juice for 6 – 8 weeks induced enhancement of
cognitive performance in aged rodents
We sought to assess the effect of supplementation with
Concord grape juice on memory performance in older adults
with early age-related memory decline in a controlled trial
as an initial assessment of potential beneﬁt in an at-risk
sample. We also obtained data on mood, anthropometrics
and metabolic parameters.
Participants were recruited from the general community with
newspaper advertising soliciting older adults with early
memory decline but not dementia for a dietary intervention
study. We enrolled twelve participants (eight men, four
women) with acquired memory changes such as forgetfulness
and prospective memory lapses. The mean age of the entire
sample was 78·2 (SD 5·0) years and the mean educational
level was 14·1 (SD 2·9) years.
Prospective participants were assessed with structured inter-
view instruments to determine eligibility for study inclusion.
The Academic and Medical History Questionnaire
used to obtain demographic information and information
regarding academic attainment, current and past medical
conditions, and medication and substance use. Those with dia-
betes, substance-abuse disorder, or diagnosed psychiatric or
neurological condition were excluded. The level of memory
impairment was determined with the Clinical Dementia
, which elicits information from the participant and
an informant (typically, spouse or adult child) about the
nature and extent of cognitive decline as manifested in activi-
ties at home and in the community. The domains memory,
orientation, problem solving, community affairs, home activi-
ties and personal care were evaluated to determine a dementia
staging classiﬁcation. Scores for each domain contributed to a
global Clinical Dementia Rating classiﬁcation with the
memory domain weighted most heavily. Clinical Dementia
Rating classiﬁcations include no impairment, mild decline,
and mild, moderate and severe dementia. We enrolled individ-
uals with mild decline and excluded those with Clinical
Dementia Rating classiﬁcations indicating no impairment
and those with mild, moderate and severe dementia. A sum
of boxes score also was derived
. This score represented
the arithmetic sum of the category scores across the six
domains of functioning and served to quantify level of func-
Seven subjects were randomly assigned to receive the
placebo beverage and ﬁve were assigned to receive 100 %
Concord grape juice. Placebo and juice were provided for
the research by Welch Foods, Inc. (Concord, MA, USA).
The placebo beverage contained no juice or natural poly-
phenol but was formulated to look and taste like grape juice
and to have the same carbohydrate composition and energy
load (3·0 kJ/ml). The intervention involved 12 weeks of
daily consumption of juice or placebo with assessments at
pre-treatment baseline and during the ﬁnal week of the inter-
vention. Previous human trials examining antioxidant effects,
endothelial function and cardioprotection in healthy subjects
and those with CVD used briefer interventions, of the order
of 2–4 weeks
(17,20 – 21)
. We chose a longer intervention
period because our outcomes concerned cognitive – cerebral
function in older adults, and there are indications in pre-
clinical studies with other berry fruits that several weeks may
be required for accumulation in brain regions
. We instituted
a dosing schedule determined by body weight to maintain
daily consumption between 6 and 9 ml/kg, a range consistent
with other human grape juice trials
(17,20 – 21)
weighing 54 to 64 kg were prescribed 444ml/d, those weighing
between 65 and 76 kg consumed 532 ml/d, and those weighing
between 77 and 91 kg consumed 621 ml/d. Participants were
instructed to take daily quantities in equal, divided dosages
with the morning, midday and evening meals.
The primary outcomes were neurocognitive measures of
memory function administered before and after the interven-
tion. The California Verbal Learning Test
to assess verbal learning and retention, and the Spatial Paired
Associate Learning Test
was used to evaluate non-verbal
memory. The California Verbal Learning Test is a list-
learning and recall task, and the Spatial Paired Associate
Learning Test assesses memory for visual-spatial information
that is not amenable to verbal encoding. Both list-learning and
paired associate tasks have been used in the context of cogni-
tive ageing and dementia and are among the more sensitive
measures of memory decline associated with neurodegene-
(42 – 44)
. We also assessed mood as a potential covariate
of the cognitive measures with the Geriatric Depression
. We performed weight and waist circumference
measures and obtained fasting blood samples for deter-
mination of serum glucose and insulin values.
Analyses of covariance were performed for each outcome
factor to isolate effects of the intervention while controlling
for individual differences
. The outcome score from the
ﬁnal visit was the dependent measure and the corresponding
score from the baseline visit and the depressive symptom
score were covariate measures. We used eta squared values
to derive Cohen’s feffect size estimates, which are character-
ised as small (0·10), medium (0·25) and large (0·40)
Fig. 1. List acquisition performance assessing verbal learning on the
California Verbal Learning Test. Values are adjusted means, with standard
errors represented by vertical bars. Subjects consuming Concord grape juice
demonstrated signiﬁcant improvement (F(1, 8) ¼5·55; P¼0·04; Cohen’s
Grape juice supplementation improves memory 731
British Journal of Nutrition
The present study was conducted according to the guide-
lines laid down in the Declaration of Helsinki and all
procedures involving human subjects were approved by the
University of Cincinnati Medical Institutional Review Board.
Written informed consent was obtained from all subjects.
At pre-intervention baseline there was a modest, non-
signiﬁcant difference for age between the groups (80 v. 75
years; t(10) ¼1·8; P¼0·10). There was no group difference
for educational level (13·4 v. 15·2 years; t(10) ¼1·02;
P¼0·32), index of functional impairment (Clinical Dementia
Rating sum of boxes score 1·0 v. 1·0; t(10) ¼0·0; P¼1·0),
weight (74·3 v. 79·4 kg; t(10) ¼1·04; P¼0·32) and waist
circumference (92·7 v. 96·7 cm; t(10) ¼0·81; P¼0·43).
There was a group difference for level of depressive
symptoms (Geriatric Depression Scale score 7·8 v. 3·0;
t(10) ¼2·19; P¼0·05), with greater depressive symptomology
among the placebo subjects. However, the symptom level
was not clinically elevated for either group
Both the juice and placebo beverage were generally well
tolerated, and there was no consistently reported adverse
effect. Discrete concerns included, for example, increased
frequency of urination associated with greater ﬂuid
consumption and aversion to the taste of the juice or placebo
that developed over time.
As shown in Fig. 1, analysis of covariance demonstrated a
signiﬁcant effect (P¼0·04) for item acquisition across learning
trials on the California Verbal Learning Test, indicating
improvement for subjects in the Concord grape juice group
relative to those receiving placebo. The effect size was mod-
erate (Cohen’s f¼0·28). Also, there were trends toward
improved performances for the grape juice subjects with
respect to delayed verbal recall (P¼0·10; Cohen’s f¼0·33)
and spatial memory (P¼0·12; Cohen’s f¼0·67), although
these were not statistically signiﬁcant (Fig. 2).
There was no appreciable effect of the intervention on
depressive symptoms (adjusted Geriatric Depression Scale
scores 5·0 v. 7·2; F(1,8) ¼2·56; P¼0·14) and no effect on
weight (77·5 v. 77·8 kg, adjusted values; F(1, 8) ¼0·31;
P¼0·58) or waist circumference (94·9 v. 95·5 cm, adjusted
values; F(1, 8) ¼0·24; P¼063). Fasting glucose values were
not affected by the intervention (1011 v. 975 mg/l, adjusted
values; F(1, 8) ¼0·42; P¼0·53), but fasting insulin at
12 weeks was signiﬁcantly elevated for the subjects consum-
ing grape juice (10·0 v. 13·7 mU/ml, adjusted values;
F(1, 8) ¼6·07; P¼0·03). Table 1 contains the unadjusted
mean scores for the outcome measures and shows the changes
in absolute values from the baseline to ﬁnal assessment.
In this preliminary study we sought to assess the effect of
moderate-term supplementation with 100 % Concord grape
juice on cognition in older adults with early memory decline
and found that memory function was improved with regular
grape juice consumption. To our knowledge, this is the ﬁrst
controlled human trial examining neurocognitive response to
this dietary intervention, and our ﬁndings are consistent with
those of a recent animal study showing improvement in
cognitive performance with grape juice supplementation in
. Our data do not provide information as
to possible mechanisms leading to the beneﬁcial effects.
However, given the existing body of research concerning
reductions of inﬂammatory and oxidative stress markers in
human subjects with CVD and lower risk of age-related
neurodegeneration with ﬂavonoid consumption, these putative
mechanisms would be primary considerations.
Fig. 2. Delayed recall performance for verbal material on the California
Verbal Learning Test (F(1, 8) ¼3·37; P¼0·10; Cohen’s f¼0·35) and for
visual-spatial material on the Spatial Paired Associate task (F(1, 8) ¼3·23;
P¼0·12; Cohen’s f¼0·67). Subjects consumed either Concord grape juice
() or a placebo drink ( ). Values are adjusted means, with standard errors
represented by vertical bars.
Table 1. Unadjusted mean values for memory, mood, anthropometric and metabolic measures by group*
Placebo (n7) Concord grape juice (n5)
Baseline Final Difference Baseline Final Difference
CVLT learning 33·2 33·2 0·0 35·2 38·6 3·4
CVLT recall 5·4 5·0 20·4 6·0 7·2 1·2
S-PAL 2·4 2·0 20·4 2·8 4·5 1·7
GDS 7·8 7·2 20·6 3·0 5·0 2·0
Weight (kg) 74·3 74·9 0·6 79·4 80·4 1·0
Waist (cm) 92·7 93·0 0·3 96·7 97·5 0·8
Glucose (mg/l) 1002 999 23 915 987 72
Insulin (mU/ml) 11·9 11·1 20·8 9·6 12·6 3·0
CVLT, California Verbal Learning Test; S-PAL, Spatial Paired Associate Learning Test; GDS, Geriatric Depression Scale.
* Baseline refers to measures obtained at the pre-intervention assessment. Final refers to measures obtained during the
ﬁnal week of the intervention. Difference ¼ﬁnal score less baseline score.
R. Krikorian et al.732
British Journal of Nutrition
Recent preliminary data involving pharmaceutical TNF-a
inhibition have suggested that acute functional improvement
can be observed in patients with Alzheimer’s disease
indicating that suppression of a pro-inﬂammatory cytokine
can ameliorate mental decline even in patients with substan-
tially more advanced neurodegeneration than in our sample
of mild cognitive impairment subjects. Accordingly, consist-
ent application of a food product with anti-inﬂammatory
effects over a brief to moderate timeframe also might
be expected to induce cognitive– cerebral enhancement,
especially in individuals with very early neurodegeneration.
Pre-clinical data indicating absorption of anthocyanins in
brain regions mediating cognition and associations with beha-
vioural indices of cognitive function
also would support
the notion that the demonstrated improvement in memory abil-
ity may reﬂect reduced inﬂammation and/or enhanced neural
function in response to the intervention. While it is not yet
clear to what extent and by what mechanism berry fruit con-
stituents cross the blood– brain barrier, anthocyanins have
been identiﬁed in speciﬁc brain tissues even when not detected
. And, it may be that consistent, moderate-term
consumption is necessary to achieve sufﬁcient concentrations
in brain sites
. Further study of Concord grape juice
supplementation for greater duration with memory and inﬂam-
matory marker outcomes will be important. Other putative
mechanisms including reduction of oxidative stress and
enhanced neuronal signalling also merit investigation, as
these factors have been demonstrated to be important in
animal studies with blueberry supplementation
Our preliminary data indicated increased fasting insulin for
those who received grape juice in the absence of changes in
weight and waist circumference. This ﬁnding was unantici-
pated and is provocative given the matched carbohydrate
load in the placebo beverage and the fact that group
differences in metabolic parameters were not observed before
the intervention. It is possible that increased insulin secretion
was induced by constituents of the grape juice other than
sugars. There are data indicating that anthocyanins derived
from blueberries inﬂuence metabolic function, in particular
enhancing the actions of insulin
. It may be that similar
or related actions were induced in the present study, with con-
sistent grape juice consumption resulting in increased insulin
secretion. However, such notions are speculative, particularly
given the small scale of this preliminary trial. Certainly, this
issue warrants further investigation with respect to its reprodu-
cibility and the speciﬁc nature and basis for the effect.
The major limitation of the present study was the small
sample size, which limited power to detect differences.
However, the moderate to large effect sizes indicate that it
would be worthwhile to conduct larger trials to evaluate the
neurocognitive beneﬁts and putative mechanisms of Concord
grape juice supplementation in pre-dementia conditions.
In view of the public health burden associated with neuro-
degeneration and Alzheimer’s disease, in particular, safe,
low-cost dietary interventions offer the possibility of inducing
Funding and material support was provided by Welch Foods,
Inc. (Concord, MA, USA).
R. K. conceived of the study and supervised the data
collection, analyses, interpretation and manuscript preparation.
T. A. N. and M. D. S. participated in data collection,
interpretation and manuscript preparation. B. S.-H. and
J. A. J. participated in manuscript preparation.
None of the authors has a ﬁnancial interest in the supporting
company or the outcome of the research activity.
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