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Abstract

Although both human epidemiologic and animal model studies have suggested that caffeine/coffee protects against Alzheimer's disease, direct human evidence for this premise has been lacking. In the present case-control study, two separate cohorts consisting of 124 total individuals (65-88 years old) were cognitively assessed and a blood sample taken for caffeine/biomarker analysis. Subjects were then monitored for cognitive status over the ensuing 2-4 year period to determine the extent to which initial plasma caffeine/biomarkers levels would be predictive of changes in cognitive status. Plasma caffeine levels at study onset were substantially lower (-51%) in mild cognitive impairment (MCI) subjects who later progressed to dementia (MCI→DEM) compared to levels in stable MCI subjects (MCI→MCI). Moreover, none of the MCI→DEM subjects had initial blood caffeine levels that were above a critical level of 1200 ng/ml, while half of stable MCI→MCI subjects had blood caffeine levels higher than that critical level. Thus, plasma caffeine levels greater than 1200 ng/ml (≈6 μM) in MCI subjects were associated with no conversion to dementia during the ensuing 2-4 year follow-up period. Among the 11 cytokines measured in plasma, three of them (GCSF, IL-10, and IL-6) were decreased in MCI→DEM subjects, but not in stable MCI→MCI subjects with high plasma caffeine levels. Coffee would appear to be the major or perhaps only source of caffeine for such stable MCI patients. This case-control study provides the first direct evidence that caffeine/coffee intake is associated with a reduced risk of dementia or delayed onset, particularly for those who already have MCI.
Journal of Alzheimer’s Disease 30 (2012) 559–572
DOI 10.3233/JAD-2012-111781
IOS Press
559
High Blood Caffeine Levels in MCI Linked
to Lack of Progression to Dementia
Chuanhai Caoa,b,c,d,, David A. Loewensteine,f, Xiaoyang Linc, Chi Zhangc,LiWang
c,
Ranjan Duarae,f,g, Yougui Wuh, Alessandra Gianninid,GeBai
i, Jianfeng Caii, Maria Greige,
Elizabeth Schofielde, Raj Ashokc, Brent Smallj, Huntington Potterc,kand Gary W. Arendashd,
aDepartment of Pharmaceutical Science, University of South Florida College of Pharmacy, Tampa, FL, USA
bDepartment of Molecular Pharmacology and Physiology, University of South Florida College of Medicine, Tampa,
FL, USA
cUSF Health Byrd Alzheimer’s Institute, Tampa, FL, USA
dDepartment of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, FL, USA
eWien Center for Alzheimer’s Disease and Memory Disorders, Mount Sinai Medical Center, Miami Beach, FL, USA
fDepartment of Psychiatry and Behavioral Sciences, Miller School of Medicine, University of Miami, Miami,
FL, USA
gDepartment of Medicine and Neurology, Miller School of Medicine, University of Miami, Miami, FL, USA
hDepartment of Epidemiology and Biostatistics, College of Public Health, University of South Florida, Tampa,
FL, USA
iDepartment of Chemistry, College of Arts and Science, University of South Florida, Tampa, FL, USA
jSchool of Aging Studies, College of Behavioral and Community Sciences, University of South Florida, Tampa,
FL, USA
kDepartment of Molecular Medicine, University of South Florida College of Medicine, Tampa, FL, USA
Accepted 21 February 2012
Abstract. Although both human epidemiologic and animal model studies have suggested that caffeine/coffee protects against
Alzheimer’s disease, direct human evidence for this premise has been lacking. In the present case-control study, two separate
cohorts consisting of 124 total individuals (65–88 years old) were cognitively assessed and a blood sample taken for caf-
feine/biomarker analysis. Subjects were then monitored for cognitive status over the ensuing 2–4 year period to determine the
extent to which initial plasma caffeine/biomarkers levels would be predictive of changes in cognitive status. Plasma caffeine
levels at study onset were substantially lower (51%) in mild cognitive impairment (MCI) subjects who later progressed to
dementia (MCIDEM) compared to levels in stable MCI subjects (MCIMCI). Moreover, none of the MCIDEM subjects
had initial blood caffeine levels that were above a critical level of 1200 ng/ml, while half of stable MCIMCI subjects had blood
caffeine levels higher than that critical level. Thus, plasma caffeine levels greater than 1200 ng/ml (6M) in MCI subjects were
associated with no conversion to dementia during the ensuing 2–4 year follow-up period. Among the 11 cytokines measured in
plasma, three of them (GCSF, IL-10, and IL-6) were decreased in MCIDEM subjects, but not in stable MCIMCI subjects
Correspondence to: Chuanhai Cao, Ph.D., USF/Byrd
Alzheimer’s Institute, 4001 E. Fletcher Avenue, Tampa,
FL 33613, USA. Tel.: +1 813 396 0711; Fax: +1 813 971
6478; E-mail: ccao@health.usf.edu. Gary W. Arendash, Ph.D.,
Department of Cell Biology, Microbiology and Molecular Biol-
ogy, University of South Florida, Tampa, FL 33620, USA.
Tel.: +1 813 732 9040; Fax: +1 813 974 1614; Email:
arendash@cas.usf.edu.
ISSN 1387-2877/12/$27.50 © 2012 – IOS Press and the authors. All rights reserved
560 C. Cao et al. / Caffeine and Lack of AD Progression
with high plasma caffeine levels. Coffee would appear to be the major or perhaps only source of caffeine for such stable MCI
patients. This case-control study provides the first direct evidence that caffeine/coffee intake is associated with a reduced risk
of dementia or delayed onset, particularly for those who already have MCI.
Keywords: Alzheimer’s disease, caffeine, coffee, dementia, immune response, mild cognitive impairment, plasma cytokines
Supplementary data available online: http://www.j-alz.com/issues/30/vol30-3.html#supplementarydata02
INTRODUCTION
There is a critical need to identify prophylac-
tics that reduce risk, or delay onset, of Alzheimer’s
disease (AD), particularly from the standpoint of
lifestyle choices. In this context, an increasing body
of scientific evidence supports the premise that caf-
feine/coffee intake can reduce the risk of AD and/or
delay the disease’s onset [see Journal of Alzheimers
Disease, Special Issue, Volume 20, Supplement 1,
2010]. That evidence began with epidemiologic human
studies and has been further supported by highly
controlled studies in AD transgenic mice. As well,
these later mouse studies have provided clear insight
into the disease-modifying mechanisms whereby caf-
feine/coffee appear to provide protection against AD.
What has been lacking to solidify caffeine/coffee as
perhaps the first dietary component to be prophylactic
against AD are controlled clinical studies. In that con-
text, the present case-control study provides the first
direct evidence that caffeine/coffee may indeed reduce
risk and/or delay onset of dementia, notably in those
that already have the prelude to AD, mild cognitive
impairment (MCI).
Epidemiologic studies have largely supported caf-
feine/coffee as protective against cognitive impairment
and AD. Early prospective studies reported signifi-
cantly less cognitive decline over a 4–10 year period
in aged men drinking 3 cups of coffee per day [1]
and in aged women whose daily caffeine intake was
equivalent to 3+ cups of coffee [2]. Two recent epi-
demiologic studies evaluated mid-life coffee intake
and risk of later AD, with one study reporting a
robust 65% decreased risk of AD in individuals who
drank 3–5 cups of coffee daily during their 40 s–50s
[3], while the other study found no association [4].
Parenthetically, the former study involved a typical
in-clinic assessment of AD, whereas the later study
utilized a telephone interview questionnaire. Perhaps
most compelling among the epidemiologic studies is
Maia and de Mendonca [5], wherein AD subjects were
found to have consumed much less caffeine (calculated
from questionnaires) during the 20 years preceding
diagnosis of AD compared with age-matched subjects
without AD. Though insightful, these epidemiologic
studies cannot provide direct evidence for a prophylac-
tic effect of caffeine/coffee against AD because they
are largely based on recall and cannot unequivocally
isolate caffeine/coffee intake from other factors that
affect cognition over a lifetime (e.g., they are not con-
trolled).
Fortunately, the creation of AD transgenic mice
has allowed highly controlled studies to be performed
that can delve into AD pathogenesis and therapeutic
development. These AD mouse models produce the
same abnormal human protein (amyloid-;A) that
is produced and aggregates in the brains of humans
destined for AD [6, 7]. During this brain Apatho-
genesis, which many researchers believe to be critical
in precipitating AD [8], AD transgenic mice become
memory-impaired and are, thus, considered appropri-
ate (though incomplete) models for the disease. We
have utilized “young adult” AD mice in demonstrat-
ing that long-term administration of a physiologic level
of caffeine in drinking water protects them from other-
wise inevitable memory impairment in older age [9], as
well as reverses already-present memory impairment
in “aged” AD mice [10]. Caffeine likely induced these
protective and treatment effects through its unique
ability to suppress both enzymes required for Apro-
duction (- and -secretase), resulting in much lower
brain Aaggregation/deposition [9, 10]. Moreover,
there are other complementary mechanisms of caffeine
action that we have identified that could contribute to
the cognitive benefits of caffeine against AD. Specif-
ically, long-term caffeine treatment in AD transgenic
mice: 1) decreases brain levels of pro-inflammatory
cytokines such as TNF-and IFN-[11], and 2)
induces beneficial effects on signal transduction fac-
tors important for neuronal plasticity and survival [12].
Thus, our studies in AD mice indicate that caffeine
is likely to be a multi-mechanistic, disease-modifying
therapeutic against development of AD. The extent to
which adenosine receptor antagonism by caffeine is
involved in the aforementioned mechanisms has yet to
be determined.
C. Cao et al. / Caffeine and Lack of AD Progression 561
Aside from caffeine, coffee is rich in many other
components (e.g., antioxidants, anti-inflammatory
compounds) that may also complement caffeine’s
actions to reduce risk of AD [13–17]. In this regard,
we most recently reported that AD mice treated twice-
weekly with caffeinated coffee (but not those treated
with decaffeinated coffee) showed enhanced mem-
ory [18]. Since treatment was given every 72 hours,
the cognitive-enhancing ability of caffeinated coffee
involved a mechanism that out-lives the presence of
coffee’s components (including caffeine) in plasma.
In that same study, we showed that a single oral
administration of caffeinated coffee induced dramatic
elevations in three plasma cytokines (granulocyte-
colony stimulating factor (GCSF), IL-10, and IL-6)
several hours thereafter, with all remaining cytokines
unaffected. This plasma cytokine profile was not seen
following administration of either decaffeinated cof-
fee or caffeine, indicating that some as-yet unidentified
component of coffee synergizes with caffeineto greatly
enhance plasma levels of three beneficial cytokines
[18]. This cytokine response, particularly for GCSF,
appears to trigger long-term beneficial mechanisms
against AD (e.g., recruitment of bone marrow cells to
remove brain A, enhanced synaptogenesis, increased
neurogenesis) that out-live coffee’s various plasma
components. Thus, coffee would seem to provide pro-
tective effects against AD that are not possible with
caffeine or decaffeinated coffee alone. Consistent with
this premise are epidemiologic studies showing that
caffeinated coffee intake (but not caffeinated tea or
overall caffeine intake) was associated with better cog-
nitive function in aged humans [19], while mid-life
caffeinated coffee (but not caffeinated tea intake) was
associated with later reduced risk of AD [3].
Although AD starts in the brain several decades
prior to AD diagnosis, performing prospective
(longitudinal) human studies over decades to test
therapeutics for their “protective” potential against AD
would be most challenging. Patients with mild cog-
nitive impairment (MCI) already have considerable
AD neuropathology accompanied by a mild loss of
short-term memory [20]. Inasmuch as 12–15% of MCI
patients will go on to develop dementia per year in
populations seeking evaluation for memory disorders
[21, 22], they are a good population to test the ability
of candidate prophylactics to protect against AD or
conversion to AD over a relatively short study period.
The present case-control study links epidemiologic
evidence suggesting caffeine/coffee as prophylactic
against AD to our recent findings from AD mice
in reporting that: 1) MCI patients with high blood
caffeine levels at the beginning of a 2–4 year assess-
ment period had a 100% chance of avoiding conversion
to dementia over that period, and 2) caffeine/coffee
may have provided this protection, in part, by pre-
venting a selective immune decline that we found to
occur in MCI patients several years prior to dementia
conversion. Although our findings are associative and
require verification via controlled clinical trials with
caffeine/coffee administrated over several years to
MCI patients, the present study establishes a linkage
between higher caffeine/coffee intake in MCI patients
and prevention or delaying of progression to dementia.
MATERIALS AND METHODS
Study population
Subjects were previously recruited through the
Florida Alzheimer’s Disease Research Center
(FADRC) as part of a multisite study of persons aged
65 years and over from the Miami and Tampa areas.
The present case-control study involved a total of 124
randomly-selected subjects between 65 and 88 years
of age at study onset, with the Miami cohort comprised
of 81 subjects and the Tampa cohort comprised of
43 subjects. The original FADRC study protocol, to
longitudinally monitor cognitive status and blood
biomarkers, was approved by both the University of
Miami and University of South Florida Institutional
Review Boards. Prior to the start of the study, all
participants gave their written informed consent.
General protocol
At the initial visit (between February 2006–July
2007), all subjects were neurologically assessed
through the following evaluations: 1) full clinical his-
tory, obtained from the participant and corroborated
by a reliable informant; 2) neurological evaluation; 3)
psychiatric evaluation, including administration of the
Geriatric Depression Scale [23] and the Neuropsychi-
atric Inventory [24]; 4) Clinical Dementia Rating scale
(CDR) [25]; 5) Mini-Mental State Evaluation (MMSE)
[26]; and 6) a neuropsychological test battery, as out-
lined by the National Alzheimer’s Coordinating Center
for National Alzheimer’s Disease Research and Clin-
ical Centers (NACC) protocol [27], which includes
standard measures of memory, language, visuospatial
and executive function. Also included were additional
tests, including the Three-Trial Fuld Object Memory
Evaluation [28] and Hopkins Verbal Learning Test-
Revised [29]. In addition, MRI scans were acquired
562 C. Cao et al. / Caffeine and Lack of AD Progression
using a proprietary 3-D (volumetric) protocol on a
Siemens Symphony, 1.5 Tesla machine (Iselin, NJ).
Based on the above neurologic evaluation at the
initial visit, subjects were diagnosed as either aged
normal, MCI (both amnestic and non-amnestic), or
dementia (DEM). At that same visit, a fasting blood
sample was taken via venous puncture during the
morning hours. Plasma was immediately separated by
centrifugation, frozen, and stored at 80C until assay.
Over the ensuing 2–4 year period, subjects came in on a
yearly basis for re-assessment of cognitive status. Five
groups resulted from the follow-up analysis:
NN Initially normal and remained so dur-
ing 2–4 year follow-up
NMCI Initially normal, but converted to MCI
during 2–4 year follow-up
MCIMCI Initially MCI and remained so during
2–4 year follow-up
MCIDEM Initially MCI, but converted to
dementia during 2–4 year follow-up
DEM Initially dementia and remained
dementia during follow-up
Diagnostic procedures
The physician initially assigned a cognitive diagno-
sis of N, MCI, or dementia, based on the subject’s entire
clinical history using a reliable informant, including
his/her functional status (which was derived from the
history itself and from the CDR rating and a func-
tional activity questionnaire), as well as the MMSE
score and sub-scores. All neuropsychological tests
were administered in the subjects’ native language
(English or Spanish), and age and education adjusted
normative data applicable to both language groups
were used to assess the cut points for impairment
in each test, based on a large co-normed normative
database used in previous studies [30]. Memory was
assessed, with the 3-trial Fuld Object Memory Eval-
uation [28] and Delayed Visual Reproduction of the
Wechsler Memory Scale-R [31]. Tests of non-memory
function included category fluency (language) [32],
letter fluency (language) [33], Block Design-WAIS-
III (visuospatial) [31], Trails B (Executive) [34], and
Similarities-WAIS-R (Executive) [31]. Neuropsycho-
logical classification was achieved employing methods
developed by Loewenstein et al. [30]. The thresholds
used were: (a) a test score of 1.5 SD or greater below
expected normative values on any single test for MCI
syndromes and (b) 2.0 SD or greater below expected
normative values in one memory and one non-memory
test for dementia (corresponding to NINCDS-ADRDA
criteria).
Consensus diagnoses
The final consensus cognitive diagnosis was made
using a computational algorithm developed and vali-
dated in the Florida ADRC which combined the AlgDx
assigned each NACC diagnosis by combining the
physician diagnoses with the neuropsychological eval-
uation. Subjects diagnosed with aMCI or non-amnestic
MCI (naMCI) in the FADRC-CC were judged to have
met Petersen’s criteria for MCI [21], as well as crite-
ria for a diagnosis of Cognitive Impairment without
Dementia [35]. Subjects judged to meet criteria for
dementia were impaired on neuropsychological testing
and judged by the clinician to have sufficient memory,
or other cognitive and functional impairment, to meet
criteria for dementia by DSM-IV criteria [36].
Progression over time
Progression from a normal diagnosis to aMCI or
naMCI required a diagnosis of MCI by clinical evalua-
tion made by the patient’s physician, with confirmation
of cognitive deficits by the neuropsychologist who
used a threshold of 1.5 SD or below expected levels
of performance on one or more memory measures,
with or without non-memory impairment (aMCI) or
one or more non-memory measures (naMCI). While
the follow-up diagnosis by the physician and the neu-
ropsychologist were made independently, they were
not blind to the previous or baseline diagnoses, as is
the case with most longitudinal studies. These clini-
cians were directed to adhere to as strictly as possible to
guidelines or rules in making the consensus diagnosis
at baseline and all of their yearly follow-up evalua-
tions. Subjects were considered to have progressed to
dementia if in their physician’s judgment, social and
occupational function was sufficiently impaired to ful-
fill DSM-IV criteria for a dementia syndrome [3] and
the patient had deficits on memory testing equal to or
greater than 1.5 SD below expected levels. For several
patients diagnosed with dementia upon initial year 01
follow-up, later clinical follow-up was not performed.
Plasma analysis
Caffeine
Plasma caffeine concentrations were measured via
compete ELISA Kits from Neogen (WI, USA), fol-
lowing manufacturer’s protocol. In brief, the enzyme
conjugate solution was prepared by diluting the 180×
enzyme conjugate stock 1 to 180 in the EIA buffer
C. Cao et al. / Caffeine and Lack of AD Progression 563
provided. Caffeine was then diluted with EIA buffer at
two-fold dilutions from 200 ng/ml to 0.39ng/ml. Then
20 l standard of each dilution was added into the
coated plate. Plasma samples were then diluted with
EIA buffer, with 20 l of this dilution added into the
coated plate. Both standard and samples were run in
duplicate in the plate. Positive and negative controls
of 20 l were loaded to each plate. Then 180 lof
diluted drug-enzyme conjugate was added into each
well and mixed by gently shaking the plate. Plates
were covered with plastic film and incubated at room
temperature for 45 min. During the incubation, a 10×
wash buffer was diluted to 1×with DI water and mixed
thoroughly. Once incubation was completed, the liquid
was dumped from the wells. Plates were then taped
on a clean lint-free towel to remove any remaining
liquid in the wells. Then each well was washed with
300 l of diluted wash buffer 3 times. After complet-
ing the last wash step, the bottom of the wells was
wiped with a lint-free towel to remove any liquid on
the outside of the wells. Then 150 l of the K-Blue
Substrate was added to each well with a multi-channel
pipette. The plate was then mixed by gently shak-
ing, followed by incubation at room temperature for
5 to 20 min. To stop the enzyme reaction, 50 lof
red stop solution was added to each well and gen-
tly mixed. The absorbance was then measured with
a plate reader (Synergy HT, Biotek, VT) at a wave-
length of 650 nm. The absorbance was converted into
concentration using Gen5 software.
Aβ1-40 and Aβ1-42
Plasma A1-40 and A1-42 levels were detected
by using ELISA kits (Invotrogen, Camarilla, CA).
Standard and samples were mixed with detection anti-
body and loaded on the antibody pre-coated plate as
the designated wells after three hours of incubation
at room temperature. HRP-conjugated antibody was
added after wash, and substrates were added for colori-
metric reaction, which was then stopped with sulfuric
acid. Optical density was obtained and concentrations
were calculated according a standard curve.
Cytokines/chemokines/growth factors
For both human plasma samples, as well as plasma
samples from a prior mouse study [18] presented in the
Discussion, a total of eight cytokines and chemokines
were measured with Lumenix multiplex assay (GCSF,
IL-10, IL-6, TNF-, IL-1, IL-17, IFN-, and IP-10).
An addition four cytokines/growth factors (ENA-
78, PDGF BB, NGF, and MCP-1) were analyzed
from human plasma samples. Expression profiles and
levels were detected using the Bio-Rad Bio-Plex, with
reagents being ordered from Millipore as customer
kits (Millipore, CA). All samples and standards were
prepared using company protocols. Plasma samples
were prepared for analysis by diluting 1 volume of the
serum sample with 3 volumes of the Bio-Plex mouse or
human sample diluent. Detailed procedures were per-
formed by following the protocol provided by the man-
ufacture. Finally, the plates were read. Each cytokine
level was calculated based on its own standard curve.
Immunoglobulin isotyping assay
Plasma levels of IgG1, IgG2, IgG3, and IgG4 were
determined with Beadlyte Human IgG subclass isotyp-
ing kits (Millipore, CA) by using Luminex detection
assay and following the protocol provided by manu-
facturer. Briefly, each plasma sample was diluted with
dilution buffer in a 96 well sample-preparing plate. Iso-
typing beads were then added into each well, mixed
and incubated for 1 hour at room temperature on a
plate shaker. Then samples were transferred into a pre-
wet membrane plate and washed under a controlled
vacuum system. Detection antibody was then added
into each well, followed by incubation at room tem-
perature for 30 minutes. Plates were then washed with
controlled vacuum and submitted to Luminex-100 after
suspension in wash buffer. The concentration of each
IgG subtype was calculated according to the standard
curve.
Statistical analysis
Statistical analysis of subject profiles and plasma
biomarkers between clinical groups were initially per-
formed using ANOVA, which was then followed by
Tukey HSD tests or additional ANOVAs for planned
pair-by-pair comparisons. Very infrequently, outlier
analysis (Grubb’s test) of a group’s data for a given
biomarker indicated removal of a single subject’s
data from statistical analysis involving that particu-
lar marker, which was then done. All clinical data
are presented as mean ±SEM, with significance group
differences designated at the p< 0.05 or higher level.
RESULTS
Table 1 shows the subject profiles for both Miami
and Tampa cohorts combined (n= 125), as well as for
each cohort separately. For age at study onset, a three-
group comparison (N, MCI, and DEM) for the Miami
and Tampa cohorts separately revealed no overall
differences via ANOVA for either cohort
564 C. Cao et al. / Caffeine and Lack of AD Progression
Table 1
Subject profiles for Miami +Tampa cohorts combined, as well as for each cohort separately
Miami +Tampa Cohorts combined Miami cohort Tampa cohort
Subjects and gender (M/F) Age Follow-up (yrs) Subjects Age Subjects Age
N 69 20/49 73.4 ±0.7 2.75 ±0.08 45 73.3 ±0.8 24 73.5 ±1.2
MCI 32 17/15 76.5 ±1.1 2.51 ±0.11 24 76.7 ±1.4 8 75.9 ±2.0
DEM 23 12/11 77.1 ±1.32.35 ±0.14 12 77.5 ±2.1 11 76.7 ±1.4
NN 60 18/42 72.9 ±0.7 2.73 ±0.09 38 72.7 ±0.9 22 73.1 ±1.2
NMCI 9 2/7 76.6 ±1.3 2.88 ±0.20 7 76.3 ±1.4 2 78.0 ±4.0
MCIMCI 21 15/6 75.0 ±1.5 2.62 ±0.15 15 74.7 ±1.9 6 75.7 ±2.7
MCIDEM 11 2/9 79.4 ±1.42.33 ±0.14 9 80.0 ±1.6 2 76.5 ±2.5
DEM 23 12/11 77.1 ±1.3 2.35 ±0.14 12 77.5 ±2.1 11 76.7 ±1.4
p< 0.05 versus N or [NN].
[F(2,78) = 2.40; p= 0.10 and F(2,40) = 1.72; p= 0.19,
respectively]. For both cohorts combined, there
was a significant overall difference in age for the
three-group comparison [F(2,121) = 3.83; p< 0.03)],
with DEM subjects being significantly older than
normals at study initiation (p< 0.05). If age at
study onset is compared in terms of the five-groups
resulting from the 2–4 year follow-up (e.g., NN,
NMCI, MCIMCI, MCIDEM, DEM), an
overall group difference in age was present for
both cohorts combined [F(4,119) = 3.56; p< 0.004],
with post hoc analysis showing that only the NN
versus MCIDEM groups differed significantly in
age (p< 0.05). For each cohort separately, no age
differences were present among the five groups. It
is important to underscore that, for the important
pair-by-pair comparisons of [NN versus NMCI]
and [MCIMCI versus MCIDEM], there were
no differences in age irrespective of combined or
separate cohort analysis. For all subjects in this study,
the average follow-up period after initial cognitive
assessment was around 2½–3 years (Table 1).
Plasma caffeine levels were analyzed simultane-
ously by utilizing the same kits for both Miami and
Tampa cohorts, thus allowing combination of data
from the two cohorts. Plasma caffeine levels did not
co-vary with age since the correlation between age
and caffeine levels was not significant (r=0.09;
p> 0.34) for the combined cohorts. Moreover, there
were no statistically significant caffeine versus age
correlations among normal, MCI, or DEM sub-groups.
Analysis of plasma caffeine levels from the initial
visit in relation to initial diagnosis (Fig. 1a) revealed
significantly lower caffeine levels in MCI subjects
relative to normals [F(1,99) = 5.52; p< 0.03]. Lower
caffeine levels were also present in DEM subjects
compared to normals, but not to statistical significance
[F(1,90) = 3.42; p< 0.07)] (Fig. 1a). There were no
statistically significant differences between MCI and
DEM subjects with regards to plasma caffeine levels.
Normal and MCI groups were then further sub-
divided according to whether subjects remained stable
or declined in cognitive status over the 2–4 year follow-
up (Fig. 1b). For initially-diagnosed normal subjects,
a 26% lower plasma level of caffeine in normals
that converted to MCI (NMCI) compared to sta-
ble normals (NN) was not significance because of
considerable variability in caffeine levels among indi-
viduals in both of these sub-groups. In contrast, 11
MCI subjects that progressed to DEM (MCIDEM)
had much lower plasma caffeine levels [F(1,30) = 6.77;
p< 0.02)] that were 51% below levels at study initiation
when compared to MCI subjects that remained MCI
(MCIMCI; Fig. 1b). Plotting of blood caffeine levels
for all individuals in the MCIMCI and MCIDEM
groups revealed that none of the MCIDEM subjects
had initial blood caffeine levels that were above an
apparent critical value of 1200 ng/ml (Fig. 1c). By con-
trast, approximately half of MCIMCI subjects had
blood caffeine levels at least that high. The data from
this combined 2-cohort study indicates that blood caf-
feine levels greater than 1200 ng/ml (t6M plasma
caffeine) in MCI patients at the start of the study were
associated with a 100% chance of avoiding progression
to dementia during the 2–4 year follow-up.
We then focused on the Miami cohort for additional
analysis because the Tampa cohort had several sub-
groups with very few subjects (Table 1). Moreover,
with the exception of caffeine levels, plasma levels of
all other biomarkers were analyzed separately for the
Miami and Tampa cohorts; ensuing statistical analy-
ses indicated the data from both cohorts could not
be combined due to the two independent biomarker
analyses.
As was the case for both Miami and Tampa cohorts
combined (Fig. 1b), MCI subjects in the Miami
C. Cao et al. / Caffeine and Lack of AD Progression 565
Fig. 1. Plasma caffeine levels at the beginning of a 2–4 year cognitive assessment period in subjects from two combined cohorts (Miami and
Tampa). a) Caffeine levels in subjects grouped by their initial cognitive status as Normal (N), mild cognitive impairment (MCI), or dementia
(DEM). Lower caffeine levels were present in MCI and DEM subjects at study initiation. ∗∗p< 0.02 versus N; p= 0.07 versus N. b) Caffeine
levels in subjects grouped by their eventual cognitive status during follow-up as stable Normal (NN), Normal converting to MCI (NMCI),
stable MCI (MCIMCI), or MCI converting to DEM (MCIDEM). Blood plasma caffeine levels at study initiation were substantially lower
in MCI patients who eventually progressed to DEM compared to those that remained stable MCI. ∗∗p< 0.02. c) Plotting of caffeine levels in
individual MCI subjects who progressed to DEM and those that remained stable MCI (group means indicated by horizontal lines). None of the
MCIDEM subjects had initial caffeine levels above a critical level of 1200 ng/ml, while half of stable MCI subjects had levels higher than
that level. Thus, subjects with the initial diagnosis of MCI and who possessed plasma caffeine levels above 1200 ng/ml at that time had a 100%
chance of avoiding DEM during the ensuing 2–4 years.
cohort that progressed to DEM had much lower initial
caffeine levels (56%) compared to MCI subjects that
remained stable [F(1,22) = 7.63; p< 0.02] (Fig. 2a).
Interestingly, DEM subjects in the Miami cohort had
caffeine levels significantly higher than those of MCI
subjects that progressed to DEM [F(1,19) = 7.69;
p< 0.02] (Fig. 2a). Analysis of all 11 cytokines
analyzed from the initial blood sample revealed 3
cytokines that were particularly affected—GCSF, IL-
10, and IL-6 (Fig. 2b–d). All three of these cytokines
were lower in plasma of MCI patients that were des-
tined for AD conversion (MCIDEM) in comparison
to both non-converting MCI subjects (MCIMCI)
and DEM subjects. For GCSF, IL-10, and IL-6 com-
parisons involving MCIDEM versus MCIMCI,
[F(1,22) = 2.38; p= 0.13], [F(1,21) = 2.33; p= 0.14],
and [F(1,21) = 4.1; p< 0.05], respectively. For cytokine
comparisons involving MCIDEM versus DEM,
[F(1,19) = 5.6; p< 0.05], [F(1,18) = 7.9; p< 0.02], and
[F(1,18) = 8.52; p< 0.02], respectively. The 39–55%
lower levels of these three cytokines in MCIDEM
subjects compared to MCIMCI subjects were simi-
lar to the 56% lower plasma caffeine levels in the same
MCIDEM subjects. No such differences in plasma
caffeine or the same three cytokines were evident for
NN versus NMCI subjects (Fig. 2). Indeed, there
were no differences between these two sub-groups
of normal subjects for any of the 11 cytokines, 4
IgGs, and 2 Aisoforms analyzed in plasma (data not
shown). Moreover, there were no group differences
between normal subjects and stable MCI subjects for
any biomarker analyzed (Fig. 2). Group differences
(suppressions) in plasma caffeine and cytokine levels
were largely restricted to the MCIDEM group.
In contrast to the three cytokines shown to be lower
in MCI subjects destined for DEM conversion com-
pared to MCI stable subjects (Fig. 2b–d), none of the
other 8 plasma cytokines or plasma NGF showed any
such profile when the same two MCI sub-groups were
compared (Table 2). In MCIDEM subjects, these
9 cytokines/growth factors varied between reductions
to overt elevations compared to MCIMCI subjects.
566 C. Cao et al. / Caffeine and Lack of AD Progression
Fig. 2. a–d) Plasma caffeine, GCSF, IL-10, and IL-6 levels at the
beginning of a 2–4 year cognitive assessment period in subjects from
the Miami cohort. All four biomarkers were significantly or near-
significantly lower in MCI subjects who later progressed to DEM
(MCIDEM) compared to MCI subjects that remained stable, or
compared to subjects initially classified as AD. p< 0.05; ∗∗p< 0.02.
For all four IgGs and both Aisoforms measured in
plasma, no differences were observed between the two
MCI sub-groups.
Figure 2 indicates a relationship between blood lev-
els of caffeine and the three cytokines GCSF, IL-10,
and IL-6, with low levels of all four being found in MCI
patients destined to progress to DEM during the ensu-
ing 2–4 years. To further elucidate the linkage between
blood caffeine levels, these three cytokines, and cog-
nitive status, we re-examined caffeine levels for the
two MCI subgroups in Fig. 2a. For the MCIMCI
group, we took the three subjects having the highest
plasma caffeine levels (caf. group) and the three
subjects with the lowest caffeine levels (caf. group).
Plasma markers from these two groups of subjects were
compared with three subjects from the MCIDEM
group that had plasma caffeine levels very compara-
ble to the (caf.) MCIMCI group (Fig. 3). When
caffeine, GCSF, IL-10, and IL-6 levels were compared
between these subjects, it became clear that high blood
caffeine levels in MCIMCI subjects are linked to
high blood levels of GCSF, IL-10, and IL-6 in those
same subjects. By contrast, low blood caffeine levels in
either MCIMCI or MCIDEM subjects are linked
to lower levels of all three cytokines (Fig. 3).
Although the dietary source of caffeine for sub-
jects in this study was not determined or available, the
fact that high plasma caffeine levels were selectively
associated with high plasma levels of three cytokines
(GCSF, IL-10, and IL-6) suggests that coffee was the
major or perhaps only source of caffeine for MCI
patients that did not convert to DEM (MCIMCI).
Figure 4, which depicts transformed data from our
earlier study [18], underscores the reasoning for that
premise and is addressed in the Discussion’s Interpre-
tations and Implications sub-section.
DISCUSSION
This study provides an intriguing association
between plasma caffeine levels in MCI patients and
their ensuing progression (or not) to dementia. High
plasma caffeine levels in MCI patients at the begin-
ning of a 2–4 year cognitive assessment period were
associated with complete avoidance of progression to
dementia over that period. Although several studies
have previously associated caffeine/coffee intake with
reduced risk of AD [1–3, 5], in the present study we
provide more direct evidence of this association by
measuring plasma caffeine levels. If caffeine/coffee
intake was indeed critical to protection against demen-
tia progression, it likely provides this protection in
part by preventing a selective immune decline in
MCI patients—an immune decline characterized by
C. Cao et al. / Caffeine and Lack of AD Progression 567
Table 2
A comparison of initial plasma biomarkers in MCIMCI and MCIDEM subjects from the Miami cohort
MCIMCI MCIDEM Percent change
(n= 15) (n=9) (%)
Cytokines (pg/ml)
TNF-0.65 ±0.07 0.73 ±0.11 +12
IFN-5.95 ±1.28 4.62 ±1.6 22
IL-11.09 ±0.15 0.91 ±0.14 16
IL-17 13.1 ±5.1 17.8 ±15.4 +35
ENA-78 72.1±10.3 74.4 ±11.3 +3
IP-10 71.1 ±8.3 90.8 ±12.2 +28
PDGF BB 5.53 ±1.42 7.21 ±2.2 +30
MCP-1 2.11 ±0.34 2.42 ±0.33 +15
Growth factors
NGF (pg/ml) 8.8 ±2.1 2.95 ±0.5 66
IgGs (pg/ml)
IgG1 7147 ±800 6512 ±519 9
IgG2 85 ±20 58 ±17 31
IgG3 1288 ±139 1700 ±334 +32
IgG4 718 ±174 592 ±278 17
Amyloid-(pg/ml)
A1-40 213 ±18 235 ±20 +10
A1-42 28 ±225±411
Fig. 3. a–d) Plasma caffeine, GCSF, IL-10, and IL-6 levels in the three stable MCI subjects who initially had the highest and lowest plasma
caffeine levels. Also plotted are these same four biomarkers in three MCI subjects who eventually progressed to DEM and whose plasma
caffeine levels were comparable to stable MCI patients with the lowest caffeine levels. MCI subjects that remained stable and who had the
highest caffeine levels at study onset had plasma levels of GCSF, IL-10, and IL-6 that were higher than the other two groups. Horizontal lines
are the average for that given triple sampling.
decreases in plasma GCSF, IL-10, and IL-6 levels
several years prior to dementia conversion. The higher
caffeine levels (most likely associated with coffee
intake) in many stable MCI subjects were probably
important for maintaining plasma levels of these three
critical cytokines and preventing dementia conversion.
As detailed below under “Interpretations and Implica-
tions”, these stable MCI subjects exhibited the exact
568 C. Cao et al. / Caffeine and Lack of AD Progression
Fig. 4. a) Levels of eight plasma cytokines in MCI subjects that
remained stable (MCIMCI) over the subsequent 2–4 year period,
with each cytokine graphed as a percent difference in reference to
values from MCI subjects who progressed to DEM (MCIDEM)
during the same time period. Note that three cytokines (GCSF, IL-10,
and IL-6) are selectively elevatedin stable MCI subjects. b–d) Levels
of the same eight plasma cytokines, but in AD transgenic mice that
had been given acute treatment three hours earlier with caffeinated
coffee (b), caffeine (c), or decaffeinated coffee (d). Cytokine levels
for all three treatments are graphed as a percent difference in refer-
ence to values from AD mice treated with saline control. The original
data (i.e., actual plasma cytokine levels) are presented in Cao et al.
[18]. Note that only caffeinated coffee treatment (b) resulted in a
plasma cytokine profile in AD mice that was similar to that of sta-
ble MCI subjects (a), both having elevated GCSF, IL-10, and IL-6
levels.
same plasma cytokine profile (e.g., elevated GCSF,
IL-10, and IL-6 levels) as AD transgenic mice given
caffeinated coffee, a cytokine profile not provided by
decaffeinated coffee or caffeine alone in such mice
[18]. Thus, it is likely that stable MCI subjects were
getting most or all of their caffeine from caffeinated
coffee. Our results clearly warrant controlled clinical
trials with caffeine/coffee administration to MCI
subjects over a 2–4 year period to definitively eluci-
date the ability of caffeine/coffee to protect against
dementia/AD, as well as the mechanisms involved.
It should be noted that the dementia subjects in this
study were diagnosed through “cognitive” assessment.
As such, the vast majority of these dementia subjects
were undoubtedly AD patients (although not all),
necessitating use of the term “dementia” rather than
AD” for the results of this study.
Comparison to other studies
Prior epidemiologic-based studies have reported an
association between moderate caffeine/coffee intake in
mid-life [3] or in older age [1, 2, 5, 19] and reduced risk
of cognitive impairment/AD. Highly controlled AD
mouse studies have further strengthened the linkage
between caffeine/coffee and protection against AD.
These studies have demonstrated that long-term oral
treatment of AD mice with caffeine [9] or caffeinated
coffee [18] prevents cognitive impairment. Utilizing
these same AD mouse, we have identified specific
“disease-modifying” mechanisms for caffeine alone,
and in combination with other components of coffee.
Caffeine alone suppresses brain levels of both enzymes
(- and -secretase) required for Aproduction [9]
via targeting of specific signal transduction mecha-
nisms [10, 12]. As well, caffeine has anti-inflammatory
actions in AD mouse brains [11]. Most recently, we
have uncovered a surprising synergy between caffeine
and some as-yet unidentified component of coffee to
provide a highly beneficial increase in three key plasma
cytokines [18]. GCSF is the most notable of these three
because of its beneficial cognitive actions in AD mice
that involve synaptogenesis, neurogenesis, and recruit-
ment of bone marrow stems cells to phagocytize brain
A[6]. Thus, coffee’s caffeine and non-caffeinergic
components would appear to exert multiple anti-AD
actions.
The aforementioned studies underscore a substantial
body of both human epidemiologic and mouse model
work that had already linked caffeine/coffee to pro-
tection against AD prior to the present study—what
has been lacking is direct human evidence for that
C. Cao et al. / Caffeine and Lack of AD Progression 569
linkage. The present case-control study addressed this
need by directly measuring caffeine levels in blood of
aged individuals (65–88) to determine if those levels
were predictive of future cognitive status. Thus, certain
limitations inherent to standard epidemiologic studies
(e.g., recall bias, variable control) were avoided.
Interpretation and implications
When subjects were groups according to their “ini-
tial” cognitive status (Normal, MCI, or DEM), there
were group differences in plasma caffeine, with MCI
subjects having significantly lower levels compared
to Normals. When Normal and MCI subjects were
further sub-divided into groups that either remained
stable or that converted to MCI or DEM, respec-
tively, Normals that converted to MCI had generally
lower initial caffeine levels compared to Normals that
remained stable. However, this 26% lower caffeine
level was not significant due to the large variation
in caffeine levels among subjects in both of the ini-
tially Normal sub-groups. Factors that could account
for this variability in plasma caffeine levels are: marked
individual differences in caffeine intake, individual dif-
ferences in caffeine metabolism, and extent of smoking
(which affects caffeine metabolism). Moreover, multi-
ple non-caffeinergic factors could be important in aged
Normals for determining whether or not they converted
to MCI.
No other plasma biomarkers were initially different
for Normals that converted to MCI versus Normals that
did not, including the 3 cytokines (GCSF, IL-10, and
IL-6) that collectively were different between convert-
ing and non-converting MCI subjects. These results
suggest that the mild short-term memory impairment
of MCI does not involve any advance changes in
plasma cytokines, A, or immunoglobulins several
years before MCI diagnosis. Moreover, there were
no differences between normal subjects and stable
MCI subjects for any biomarker analyzed, indicat-
ing an inability of “individual” plasma biomarkers
to distinguish between Normal and MCI subjects at
study initiation. These results are consistent with prior
studies, which have largely reported no consistent dif-
ferences in individual plasma cytokines between aged
normal and MCI subjects [37, 38]. Other than the
present study, we are aware of no earlier study that
investigated whether plasma cytokine levels of nor-
mal subjects were predictive of later MCI diagnosis.
Although any single cytokine may not have this pre-
dictive potential, a combination of plasma cytokines in
normal aged individuals may be predictive [38].
In subjects that were initially MCI, however, plasma
caffeine levels were predictive for MCI subjects that
would remain stable (e.g., not progress to DEM) over
the ensuing 2–4 year cognitive assessment period. In
MCI subjects, plasma caffeine levels above a criti-
cal value of 1200 ng/ml were associated with a 100%
chance of avoiding AD conversion over that period.
The resultant t6M plasma caffeine concentration
is typically present several hours after intake of 1-
2 cups of coffee [39], given that the half-life of
plasma caffeine is 3-4 hours and peak plasma caffeine
levels of 10–20 M occur around 1 hour following
such oral caffeine ingestion [40]. By contrast, MCI
subjects that did progress to DEM had initial caffeine
levels that were substantially (56%) lower compared
to stable MCI subjects. Interestingly, both sub-groups
of MCI subjects exhibited less variability in plasma
caffeine concentration compared to the sub-groups of
Normals.
For subjects that were already diagnosed with DEM
at the beginning of the study, plasma caffeine levels
were comparable to stable MCI subjects and signif-
icantly higher than MCIDEM subjects. Moreover,
accompanying levels of GCSF, IL-10, and IL-6 in
DEM subjects were also significantly higher than those
in MCIDEM subjects. Although increased plasma
cytokine levels in AD were anticipated as part of a
heightened inflammatory response following diagnosis
of DEM (see next section), the elevated caffeine levels
in DEM subjects compared to MCIDEM subjects
were not anticipated. It is important to keep in mind,
however, that caffeine levels in DEM subjects were
only higher in comparison to the very low levels of
MCIDEM subjects; plasma caffeine levels in DEM
subjects were still 40% lower than those of all Normals
and near-identical to the low levels present in all MCI
subjects.
A number of prior studies have investigated the pos-
sibility that plasma cytokine levels could be viable
biomarkers for progression from Normal or MCI to AD
[37, 41, 42]. Although no single cytokine/growth factor
has been identified thus far as predictive of impending
MCI or AD, Laske and colleagues have determined
that blood levels of several neurotrophic/hematopoietic
factors (e.g., GCSF, BDNF, and SCF) are decrease
in “early AD” [43–45], resulting in deficient neu-
rotrophic/hematopoietic brain support. We believe this
deficient brain support actually begins to occur in
late MCI, several years prior to AD conversion, and
is important for AD conversion. In this context, the
present study provides initial evidence that three key
cytokines (GCSF, IL-10, and IL-6) become collectively
570 C. Cao et al. / Caffeine and Lack of AD Progression
decreased in MCI patients several years prior to their
conversion to DEM. Thus, a selective immune decline
would seem to occur during those years. If this immune
decline can be verified in larger cohorts of MCI
subjects, regular monitoring of these three plasma
cytokines beginning at onset of MCI may provide sev-
eral years warning of impending conversion to DEM.
By the time cognitive impairment becomes severe
enough to warrant clinical diagnosis of DEM, plasma
levels of the 3-cytokines appear to have re-established
their higher levels, but this elevated immune response
would seem to come too late for cognitive protection.
We propose that higher caffeine intake (very likely
in association with coffee) maintains the levels of
these three critical cytokines in MCI subjects, such
that progression to DEM occurs later or perhaps not
at all.
Caffeinated coffee was very likely the primary
dietary source of caffeine for stable MCI subjects
because their blood cytokine profile was very similar
to that of AD (APPsw+PS1) transgenic mice acutely
given caffeinated coffee (see Cao et al. [18]). In that
recent study, AD transgenic mice were given a sin-
gle treatment with caffeinated coffee, decaffeinated
coffee, caffeine, or saline. Of all four acute treat-
ments, AD mice only responded to caffeinated coffee
with greatly and selectively increased plasma levels of
GCSF, IL-10, and IL-6. The methodology of this AD
mouse study relevant to the present study is briefly
indicated in the Supplementary Data section (avail-
able online: http://www.j-alz.com/issues/30/vol30-
3.html#supplementarydata02). Figure 4 compares
plasma cytokine data from MCI patients of the present
study with the same cytokines from the AD mouse
study. Only administration of caffeinated coffee pro-
vided the same profile of substantially elevated GCSF,
IL-10, and IL-6 levels in transgenic mice that is seen
in stable MCIMCI patients. Thus, it is likely that
“caffeinated coffee” was the source of caffeine associ-
ated with cognitive stability in the present study’s MCI
patients.
Although stable MCIMCI subjects as a group
had substantially higher plasma caffeine levels com-
pared to those MCI subjects that progressed to DEM
(MCIDEM), it is important to recognize that half of
these stable MCI subjects had caffeine levels below the
critical level for protection (e.g., 1200 ng/ml), yet they
did not progress to DEM during the 2–4 year follow-
up period. Clearly, other dietary/life-style choices, risk
factors, and extent of disease progression entered into
determining which MCI patients progressed to DEM
and which ones did not. Nonetheless, we predict that
those stable MCI patients with low caffeine levels (e.g.,
below 1200 ng/ml) and concomitantly low levels of
GCSF, IL-10, and IL-6, will progress to DEM sooner
than MCI patients with high caffeine/GCSF/IL-10/IL-
6 levels.
Finally, it should be underscored that the lack of
differences between the two MCI sub-groups in mul-
tiple plasma IgGs, Aisoforms, and the 8 unaffected
plasma cytokines, indicates that these biomarkers were
not independently predictive of impending MCI pro-
gression to DEM.
Strengths and limitations
A key strength of our study was the direct measure-
ment of blood caffeine levels, rather than reliance on
recall or dietary surveys of caffeine intake, as has been
typical of prior retrospective/longitudinal epidemio-
logic studies. However, our measurement of blood
caffeine levels was also the largest study limitation
because of a lack of ancillary data collection that would
have provided greater insight. First, we did not take
multiple blood samples for caffeine analysis during the
2–4 year study period, only at the study’s inception.
This is because the study was created retrospectively
from available blood (taken at initial clinical exam) and
follow-up clinical evaluations available over 2–4 years
as part of the FADRC’s ongoing longitudinal assess-
ment of aged individuals for biomarkers and cognitive
status. Second, the extent to which caffeine levels at
study onset were indicative of daily caffeine intake
was not determined. For example, we did not monitor
the primary source(s) of caffeine in study partici-
pants (although we presented evidence that the primary
source was caffeinated coffee for stable MCI subjects).
We also did not ask participants when their last caffeine
intake was prior to coming in for the initial visit/blood
sample. As well, we did not ask subjects about their
long-term caffeine/coffee intake habits, although it is
likely that subjects with high plasma caffeine levels are
habitual/moderate coffee drinkers. Additionally, com-
plete data on ApoE status, education level, ethnicity,
dietary habits, and lifestyle choices were not avail-
able for all study participants, so none of these can
presently be eliminated as contributory to the results
observed. Finally, the follow-up time of 2–4 years was
relatively short for establishing causality and reverse
causation (i.e., subjects with poorer cognitive perfor-
mance may have reduced caffeine/coffee intake) is
possible. Nonetheless, the fact that MCI subjects in
Miami and Tampa cohorts independently showed the
same relationship between blood caffeine levels and
C. Cao et al. / Caffeine and Lack of AD Progression 571
later risk of DEM progression provides a degree of
confidence regarding this association.
CONCLUSION
In providing initial direct evidence for caf-
feine/coffee being protective against dementia/AD,
the present case-control study is nonetheless based
on association, wherein caffeine/coffee could simply
be associated with stable cognitive status in MCI
and not contribute to that cognitive stability. It is
also important to recognize that the AD pathogenic
process begins in the brain 1-2 decades before any
evident cognitive impairment; prophylactic interven-
tion should ideally begin that far in advance of AD
symptoms. In that context, moderate caffeine/coffee
intake is safe for most humans, appears to attack mul-
tiple aspects of the disease process, and is convenient
for long-term/widespread dietary intake. If controlled
clinical trials further support caffeine/coffee as protec-
tive against AD diagnosis, compelling evidence will
be given for the general public to adopt this strategy to
reduce risk of AD.
ACKNOWLEDGMENTS
This research was supported by the National Insti-
tute of Aging, NIH 5R01AG020094-03 and NIH
1P50AG025711-03, & USF/Byrd Alzheimer Center
and Research Institute funds.
Authors’ disclosures available online (http://www.j-
alz.com/disclosures/view.php?id=1187).
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... The experimental studies have shown that caffeine has effects on the rise in alertness and it also reduces extreme tiredness or fatigue (Cropley et al., 2012). One of the studies suggested that the individuals who consumed 1 to 2 cups of coffee in a day have mild cognitive impairment with increased levels of caffeine and had lesser progress to dementia when compared with the individuals who had decreased levels of caffeine in the blood (Cao et al., 2012). When experiments were conducted on animal models, there was proof that caffeine has neu-IJFS October 2022 Volume 11 pages 386-401 roprotective properties and regulates the Aβ-P metabolism (Carman et al., 2014). ...
... Around 537,039 autosomal single nucleotide polymorphisms were genotyped on 2032 individuals who were diagnosed with Alzheimer's disease (Barberger-Gateau et al., 2012). A case-control study involved 124 participants, and in the initial visit, the participants were neurologically assessed and blood samples were collected from them (Cao et al., 2012). After centrifugation of the blood, the blood plasma was measured for caffeine concentration using Enzyme-linked immunosorbent assay laboratory technique and the participants were monitored during the 2-4-year duration of follow-up. ...
... After centrifugation of the blood, the blood plasma was measured for caffeine concentration using Enzyme-linked immunosorbent assay laboratory technique and the participants were monitored during the 2-4-year duration of follow-up. The caffeine level in the blood plasma was 51% lower in the participants who progressed from mild cognitive impairment to dementia than the participants who did not progress to dementia from mild cognitive impairment (Barberger-Gateau et al., 2012;Cao et al., 2012). The participants diagnosed with AD in these studies could have inherited the APOE gene which is a genetic risk factor to progression to AD (Lindsay et al., 2002). ...
Article
Coffee is a popular beverage, and it contains caffeine, a psychoactive substance. Consuming coffee may reduce the risk of developing Alzheimer’s disease (AD). However, the association between the reduced risk of developing AD and the consumption of coffee is controversial. Therefore, we conducted a systematic literature review and quantitative synthesis meta-analysis that included dose-response analysis on the relationship between the consumption of coffee and the risk of developing AD. Based on PRISMA guidelines, we analysed standard databases of journals published between January 1999 and May 2020. We included the two population-based cohort studies and one case-control study. All studies included looked at the association between consuming many cups of coffee, the amount of coffee consumed in milligrams per day and the risk of developing AD. The systematic literature review and meta-analysis had 1670 participants with follow-up years that ranged from 5 to 21. The consumption of moderate or 3-5 cups per day reduces the risk of developing AD. The pooled relative risk and 95% confidence interval of the 3 included studies were 0.63 (0.3, 1.54). Dose-response curve analysis appears to be U-shaped. The results of the forest plot showed that there is low heterogeneity between the studies. Plotting the funnel plot and the Galbraith plot demonstrated publication bias of the three included studies. More prospective and long-term studies have to be conducted in other countries to determine the exact risk of developing AD.
... Cao et al., gathered two cohorts of 124 participants (65-88 yrs old) and measured their plasma caffeine concentration as well as their initial neurological status (based on clinical history, clinical dementia rating (CDR), Multi-Mental State evaluation (MMSE), psychiatric evaluation, Three-trial Fluid Object Memory Evaluation (TFOME), Hopkins's verbal Learning Test Revised (HVLTR), MRI-volumetric protocol and National Alzheimer's Disease and Clinical Centre (NACC) protocol [20]. Participants were grouped into three categories of cognitive functions: Normal (M), Mild cognitive impairment (MCI), and Dementia (DEM); then, the participants were followed up for a period of 2-4 yrs, and their cognition was reassessed (same protocol) [20]. ...
... Cao et al., gathered two cohorts of 124 participants (65-88 yrs old) and measured their plasma caffeine concentration as well as their initial neurological status (based on clinical history, clinical dementia rating (CDR), Multi-Mental State evaluation (MMSE), psychiatric evaluation, Three-trial Fluid Object Memory Evaluation (TFOME), Hopkins's verbal Learning Test Revised (HVLTR), MRI-volumetric protocol and National Alzheimer's Disease and Clinical Centre (NACC) protocol [20]. Participants were grouped into three categories of cognitive functions: Normal (M), Mild cognitive impairment (MCI), and Dementia (DEM); then, the participants were followed up for a period of 2-4 yrs, and their cognition was reassessed (same protocol) [20]. This study found that participants who demonstrated a cognitive decline from initial MCI to DEM had a significantly lower plasma caffeine concentration (by 51%) than participants who maintained the level of cognitive impairment (stable MCI) [20]. ...
... Participants were grouped into three categories of cognitive functions: Normal (M), Mild cognitive impairment (MCI), and Dementia (DEM); then, the participants were followed up for a period of 2-4 yrs, and their cognition was reassessed (same protocol) [20]. This study found that participants who demonstrated a cognitive decline from initial MCI to DEM had a significantly lower plasma caffeine concentration (by 51%) than participants who maintained the level of cognitive impairment (stable MCI) [20]. Furthermore, none of the subjects with a critical plasma caffeine concentration (>1200 ng/mL) converted to DEM, and half of stable MCI had plasma concentrations greater than this critical value [20]. ...
Article
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Alzheimer's disease (AD) is the leading cause of dementia, predicted to be the most significant health burden of the 21st century, with an estimated 131.5 million dementia patients by the year 2050. This review aims to provide an overview of the effect of caffeine on AD and cognition by summarizing relevant research conducted on this topic. We searched the Web of Science core collection and PubMed for studies related to the effect of caffeine on AD and cognition using title search terms: caffeine; coffee; Alzheimer's; cognition. There is suggestive evidence from clinical studies that caffeine is neuroprotective against dementia and possibly AD (20 out of 30 studies support this), but further studies, such as the "ideal" study proposed in this review, are required to prove this link. Clinical studies also indicate that caffeine is a cognitive normalizer and not a cognitive enhancer. Furthermore, clinical studies suggest the neuroprotective effect of caffeine might be confounded by gender. There is robust evidence based on in vivo and in vitro studies that caffeine has neuroprotective properties in AD animal models (21 out of 22 studies support this), but further studies are needed to identify the mechanistic pathways mediating these effects.
... Other studies have shown that coffee stalls AD progression and reduces Aβ production with greater efficacy compared to pure caffeine or decaffeinated coffee, indicating that other compounds in coffee function synergistically with caffeine (55,66,67). Human studies have also demonstrated that habitual coffee consumption plays a significant role in stalling the progression of cognitive decline (68,69). Eskelinen et al. reported that participants who consumed 2 or less cups of coffee were reported as the group with the highest occurrence of dementia and AD later in life compared to those who consumed greater quantities (70,71). ...
... Caffeine concentrations were measured using ELISA Kits from Neogen (WI, USA), following the manufacturer's protocol. The enzyme conjugate solution was prepared by diluting the 180X enzyme conjugate stock in a 1:180 dilution in the EIA buffer provided, and the remainder of the assay was performed as documented in Cao et al. (68). ...
... Coffee has been one of the most popularly consumed beverage for centuries, yet research regarding its health benefits has only been prevalent in the past few decades (54,66,68,77). An increasing number of publications favor the medical functions of coffee, but the preparation method and correlation between dose and health benefits is still uncertain (74,76). ...
Article
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Background Alzheimer's disease (AD) is a multifactorial neurological disease with neurofibrillary tangles and neuritic plaques as histopathological markers. Due to this, although AD is the leading cause of dementia worldwide, clinical AD dementia cannot be certainly diagnosed until neuropathological post-mortem evaluation. Coffee has been reported to have neurologically protective factors, particularly against AD, but coffee brand and type have not been taken into consideration in previous studies. We examined the discrepancies among popular commercial and instant coffees in limiting the development and progression through Aβ1-40 and Aβ1-42 production, and hypothesized that coffee consumption, regardless of brand or type, is beneficial for stalling the progression and development of Aβ-related AD. Methods Coffee samples from four commercial coffee brands and four instant coffees were purchased or prepared following given instructions and filtered for the study. 5, 2.5, and 1.25% concentrations of each coffee were used to treat N2a/APPswe cell lines. MTT assay was used to assess cell viability for coffee concentrations, as well as pure caffeine concentrations. Sandwich ELISA assay was used to determine Aβ concentration for Aβ1-40 and Aβ1-42 peptides of coffee-treated cells. Results Caffeine concentrations were significantly varied among all coffees (DC vs. MDC, PC, SB, NIN, MIN p < 0.05). There was no correlation between caffeine concentration and cell toxicity among brands and types of coffee, with no toxicity at 0.5 mg/ml caffeine and lower. Most coffees were toxic to N2a/APPswe cells at 5% ( p < 0.05), but not at 2.5%. Most coffees at a 2.5% concentration reduced Aβ1-40 and Aβ1-42 production, with comparable results between commercial and instant coffees. Conclusion All coffees tested have beneficial health effects for AD through lowering Aβ1-40 and Aβ1-42 production, with Dunkin' Donuts® medium roast coffee demonstrating the most consistent and optimal cell survival rates and Aβ concentration. On the other hand, Starbucks® coffee exhibited the highest cell toxicity rates among the tested coffees.
... The initial meta-analysis of the effects of coffee and caffeine on Alzheimer's disease found four studies (44). After adjusting for smoking and hypertension, a second meta-analysis of the association between caffeine consumption and Alzheimer's disease risk found a summary RR of 0.80-0.83.According to a recent study of 124 people between the ages of 65 and 88 (45), those who progressed from "moderate cognitive decline" to Alzheimer's disease during the two to four-year follow-up period had blood circulating concentrations that were 51 percent lower than those who remained at the moderate cognitive decline level (46). ...
Article
Throughout the beyond a decade, Food Rule Experts have deduced that caffeine usage isn't risky at whatever point consumed at levels of 200 mg at a time (around 2½ cups of coffee) or 400 mg everyday (around 5 cups of coffee). Moreover, caffeine has various positive exercises on the frontal cortex. It can augment availability and success, help obsession, further foster perspective likewise, limit distress. Caffeine could disturb rest, regardless, simply in fragile individuals. It could raise anxiety in a little subset of particularly fragile people. Caffeine does not seem to provoke dependence, yet a minority of people experience withdrawal secondary effects. Caffeine can potentiate the effect of standard torment alleviating drugs in cerebral agony and migraine. Well established coffee/caffeine usage has been connected with expectation of mental disintegration, and diminished risk of making stroke, Parkinson's ailment and Alzheimer's ailment. Its usage does not seem to influence seizure occasion. Thusly, everyday coffee and caffeine confirmation can be significant for a strong changed diet; its use does not ought to be ended in elderly people.
... Epidemiological studies have reported an inverse association between caffeine intake and AD/dementia risk [213][214][215][216][217]. Significant caffeine consumption is associated with a lowered rate of Aβ positivity as measured by PET [218]. ...
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Alzheimer’s disease (AD) is the most common dementia in the elderly and its increasing prevalence presents treatment challenges. Despite a better understanding of the disease, the current mainstay of treatment cannot modify pathogenesis or effectively address the associated cognitive and memory deficits. Emerging evidence suggests adenosine G protein-coupled receptors (GPCRs) are promising therapeutic targets for Alzheimer’s disease. The adenosine A 1 and A 2A receptors are expressed in the human brain and have a proposed involvement in the pathogenesis of dementia. Targeting these receptors preclinically can mitigate pathogenic β-amyloid and tau neurotoxicity whilst improving cognition and memory. In this review, we provide an accessible summary of the literature on Alzheimer’s disease and the therapeutic potential of A 1 and A 2A receptors. Although there are no available medicines targeting these receptors approved for treating dementia, we provide insights into some novel strategies, including allosterism and the targeting of oligomers, which may increase drug discovery success and enhance the therapeutic response.
... The suggestive finding for genetically predicted higher plasma caffeine and reduced risk of Alzheimer's disease is consistent with experimental data, which indicate that caffeine may have a protective role [1]. Furthermore, a case-control study found that plasma caffeine levels were associated with reduced odds of dementia or delayed onset of dementia, particularly in individuals with mild cognitive impairment [9]. The association with consumption of coffee, which is the main source of caffeine in many populations, has not been strongly associated with risk of Alzheimer's disease or dementia in the few cohort studies assessing this association [2]. ...
Article
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We leveraged genetic variants associated with caffeine metabolism in the two-sample Mendelian randomization framework to investigate the effect of plasma caffeine levels on the risk of Alzheimer's disease and Parkinson's disease. Genetic association estimates for the outcomes were obtained from the International Genomics of Alzheimer's Project, the International Parkinson's Disease Genomics consortium, the FinnGen consortium, and the UK Biobank. Genetically predicted higher plasma caffeine levels were associated with a non-significant lower risk of Alzheimer's disease (odds ratio 0.87; 95% confidence interval 0.76, 1.00; p = 0.056). A suggestive association was observed for genetically predicted higher plasma caffeine levels and lower risk of Parkinson's disease in the FinnGen consortium. but not in the International Parkinson's Disease Genomics consortium; no overall association was found (odds ratio 0.92; 95% confidence interval 0.77, 1.10; p = 0.347). This study found possible suggestive evidence of a protective role of caffeine in Alzheimer's disease. The association between caffeine and Parkinson's disease requires further study.
... A lifetime coffee intake is positively associated with long-term and short-term memory, recall, language, calculation, attention, and orientation (Johnson-Kozlow et al., 2002). Moreover, Cao et al. (2012) could show an absence of progression to dementia in people with a mild cognitive impairment when they had high levels of caffeine in the blood. However, despite these advantages, like nicotine, also caffeine increases blood pressure and thus represents a risk to cardiovascular health (Grosso et al., 2017) in older populations (Lawes et al., 2004), but also in younger people (Nwabuo et al., 2021). ...
Article
Full-text available
Smoking and caffeine improves some aspects of cognitive performance but it also brings with it some serious cardiovascular health risks. We investigated whether quiet and focused visual attention can reduce blood pressure in nicotine and coffee consumers. Participants either smoked (n=40), or drank coffee (n=40) on a daily basis. The control group neither smoked nor drank coffee (n=40), total n=120. We measured blood pressure before and after the Attentional Blink Task (ABT) which consists of a visual perception task that requires attention to very fast appearing and disappearing targets without and with delay due to distracters. Performance gains due to nicotine and caffeine were limited to immediate perception but were sensitive to delay. The nicotine group had a significantly higher systolic and the caffeine group a significantly higher diastolic blood pressure before the ABT, but both were significantly reduced afterwards showing a blood pressure regulation effect of sustained, focused visual attention.
... A lifetime coffee intake is positively associated with long-term and short-term memory, recall, language, calculation, attention, and orientation (Johnson-Kozlow et al., 2002). Moreover, Cao et al. (2012) could show an absence of progression to dementia in people with a mild cognitive impairment when they had high levels of caffeine in the blood. However, despite these advantages, like nicotine, also caffeine increases blood pressure and thus represents a risk to cardiovascular health (Grosso et al., 2017) in older populations (Lawes et al., 2004), but also in younger people (Nwabuo et al., 2021). ...
Preprint
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Smoking and caffeine improves some aspects of cognitive performance but it also brings with it some serious cardiovascular health risks. We investigated whether quiet and focused visual attention can reduce blood pressure in nicotine and coffee consumers. Participants either smoked (n=40), or drank coffee (n=40) on a daily basis. The control group neither smoked nor drank coffee (n=40), total n=120. We measured blood pressure before and after the Attentional Blink Task (ABT) which consists a visual perception task that requires attention to very fast appearing and disappearing targets without and with delay due to distracters. Performance gains due to nicotine and caffeine were limited to immediate perception but sensitive to delay. The nicotine group had a significantly higher systolic and the caffeine group a significantly higher diastolic blood pressure before the ABT, but both were significantly reduced afterwards showing a blood pressure regulation effect of sustained, focused visual attention.
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Alzheimer's Disease (AD) is a neurodegenerative disorder that can cause life-altering and debilitating cognitive decline. AD's etiology is poorly understood, and no disease-modifying therapeutics exist. Here, we describe the use of 2D and 3D tissue culture models of herpesvirus-induced AD, which recapitulate hallmark disease features of plaque formation, gliosis, neuroinflammation, and impaired neuronal signaling, to screen a panel of 21 medications, supplements, and nutraceuticals with purported neuroprotective benefits. This screen identified green tea catechins and resveratrol as having strong anti-plaque properties, functional neuroprotective benefits, and minimal neurotoxicity, providing support for their further investigation as AD preventives and therapies. Two other candidates, citicoline and metformin, reduced plaque formation and were minimally toxic, but did not protect against virus-induced impairments in neuronal signaling. This study establishes a simple platform for rapidly screening and characterizing AD compounds of interest in 2D and 3D human cortical tissue models representing physiologically relevant disease features.
Chapter
Alzheimer’s Disease (AD), a common type of dementia, characterized by the presence of aggregated extracellular amyloid-beta (Aβ), intracellular hyper phosphorylation of tau protein and neurodegenerative with cognitive decline. It is projected that 141 million people will be suffering with AD by 2050 but no effective drug treatment is discovered without side effects. There is an urgent need for the application of alternative and non-pharmacological interventions for AD. Sporadically found that exercise or diet therapy or social activity may positively influence the AD. In this review we discussed the process of how Exercise-Eating pattern and Social inclusion (EES) has been shown to have fewer side effects and better adherence with AD. In this mechanism the EES can modulate the brain metabolic factors, brain-derived neurotrophic, ketone bodies, lactate, cathepsin-B, irisin, hormonal balance in AD. This review also described the potential biological mechanisms underlying exercise (modulation of biomolecule turnover, antioxidant and anti inflammation), eating pattern (bioactive compounds) and social inclusion that is very important to ameliorate the pathophysiological hallmarks of Alzheimer’s disease. Thus, this EES can be an effective approach to manage the neurodegenerative disorder as well as Alzheimer’s disease.
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The Hopkins Verbal Learning Test (HVLT) is a brief verbal learning and memory test with six alternate forms. The HVLT is ideal in situations calling for repeated neuropsychological examinations, but it lacks a delayed recall trial which is essential for the assessment of abnormal forgetting. We present a revised version of the HVLT which includes a delayed recall trial, and therefore delays the yes/no recognition trial. The equivalence of test forms was examined in two separate studies using between-groups and within-subjects research designs. In both studies, the six forms of the revised HVLT (HVLT-R) were found to be equivalent with respect to the recall trials, but there were some modest differences in recognition. Recommendations for the use of the HVLT-R in serial neuropsychological examinations are provided, as well as normative data tables from a sample of 541 subjects, spanning ages 17 to 88 years.
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Caffeine intake has been associated with a lower incidence of Alzheimer's disease (AD) in humans. In AD mouse models, caffeine significantly decreases senile plaques and amyloid beta (Aβ) levels while also protecting against or reversing cognitive impairment. To understand the mechanism(s) underlying the protective effects of caffeine against AD pathology, we investigated the effects of a two-week treatment with caffeine (3mg/day) in transgenic (APPswe) mice and non-transgenic (NT) mice on signaling factors involved in neuronal plasticity and survival. We evaluated cAMP-dependent protein kinase A (PKA), phospho-cyclic AMP response-element binding protein (phospho-CREB), and the pro-apoptotic protein kinases extracellular signal-regulated kinase 1/2 (phospho-ERK) and phospho-c-Jun N-terminal kinase 1 (phospho-JNK) in the striatum and frontal cortex of caffeine-treated mice. In the striatum, APPswe control mice exhibited a significant decrease in phospho-CREB, as well as significant increases in phospho-JNK and phospho-ERK in comparison to NT mice. Caffeine treatment stimulated PKA activity, increased phospho-CREB levels, and decreased phospho-JNK and phospho-ERK expression in the striatum of APPswe mice, all of which are thought to be beneficial changes for brain function. Even caffeine-treated NT mice exhibited some of these changes in striatum. In the frontal cortex, caffeine did not significantly increase phospho-CREB and PKA activity, but significantly reduced phospho-JNK and phospho-ERK expression in both APPswe and NT mice. These results suggest that caffeine shifts the balance between neurodegeneration and neuronal survival toward the stimulation of pro-survival cascades and inhibition of pro-apoptotic pathways in the striatum and/or cortex, which may contribute to its beneficial effects against AD.
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Alzheimer's disease constitutes a personal and societal tragedy of immense proportions. Since 1960, research in laboratories and clinics worldwide has elucidated many features of this insidious and ultimately fatal syndrome, and this progress has led to initial human trials of potentially disease-modifying agents. However, some of these agents have already failed. Gnawing controversies and important gaps in our knowledge seem to cast additional doubt on the ability of the field to move forward effectively. Here I discuss some of these looming concerns and offer possible explanations for the major trial failures that suggest they are not predictive of the future. Rigorous preclinical validation of mechanism-based therapeutic agents followed by meticulously designed trials that focus on the cardinal cognitive symptoms and their associated biomarkers in the mild or presymptomatic phases of Alzheimer's disease are likely to lead to success, perhaps in the not-too-distant future.