Mediterranean diet and risk for Alzheimer's disease -- Full paper

/Home/Alzheimer's Treatments/Diets and Supplements for Treating Alzheimer's/Alzheimer's and the Mediterranean Diet

OBJECTIVE: Previous research in Alzheimer's disease (AD) has focused on individual dietary components. There is converging evidence that composite dietary patterns such as the Mediterranean diet (MeDi) is related to lower risk for cardiovascular disease, several forms of cancer, and overall mortality. We sought to investigate the association between MeDi and risk for AD.

METHODS: A total of 2,258 community-based nondemented individuals in New York were prospectively evaluated every 1.5 years. Adherence to the MeDi (zero- to nine-point scale with higher scores indicating higher adherence) was the main predictor in models that were adjusted for cohort, age, sex, ethnicity, education, apolipoprotein E genotype, caloric intake, smoking, medical comorbidity index, and body mass index.

RESULTS: There were 262 incident AD cases during the course of 4 (+/-3.0; range, 0.2-13.9) years of follow-up. Higher adherence to the MeDi was associated with lower risk for AD (hazard ratio, 0.91; 95% confidence interval, 0.83-0.98; p=0.015). Compared with subjects in the lowest MeDi tertile, subjects in the middle MeDi tertile had a hazard ratio of 0.85 (95% confidence interval, 0.63-1.16) and those at the highest tertile had a hazard ratio of 0.60 (95% confidence interval, 0.42-0.87) for AD (p for trend=0.007).

INTERPRETATION: We conclude that higher adherence to the MeDi is associated with a reduction in risk for AD.


Scarmeas N, Stern Y, Tang MX, Mayeux R, Luchsinger JA. Mediterranean diet and risk for Alzheimer's disease. Ann Neurol. 2006 Apr 18;59(6):912 -- 921.


Diet may play an important role in the causation and
prevention of AD.1,2 Dietary restriction in animals ex-
tends their life span3 and increases the resistance of
neurons to degeneration.3 However, epidemiological
data on diet and AD have been conflicting. Higher in-
take of vitamin C,4 - 6 vitamin E,4 - 8 flavonoids,9 un-
saturated fatty acids,10 -12 fish12,13; higher levels of vi-
tamin B12 14 -16 and folate15,16; modest to moderate
ethanol17-21; and lower total fats22,23 have been related
to a lower risk for AD or slower cognitive decline. At
the same time, other studies have found that the risk
for AD or cognitive decline is not associated to intake
of antioxidants, such as vitamin C,24 vitamin E,24 and
carotenes,24 fats,25 or levels of vitamin B12.26

There is paucity of data regarding the effect of com-
posite dietary patterns (rather than individual foods or
nutrients) on the risk for AD. Dietary pattern analysis
in relation to many other diseases (ie, cirrhosis or var-
ious cancers) has recently received growing attention
because individuals do not consume foods or nutrients
in isolation, but rather as components of their daily
diet. Defining diet by dietary patterns has the ability to
capture its multidimensionality whereas reducing its
apparent complexity because patterns can integrate
complex or subtle interactive effects of many dietary
constituents and bypass problems generated by multi-
ple testing and the high correlations that may exist
among these constituents.27 Dietary patterns can be
developed a priori from previous knowledge concern-
ing a favorable or adverse health effect of various di-
etary constituents.

One such dietary pattern is the Mediterranean diet
(MeDi), which has received increased attention in re-
cent years because of converging ecological,28 analyti-
cal-observational,29 -33 and interventional34,35 evidence
relating it to lower risk for cardiovascular disease, sev-
eral forms of cancer, and overall mortality. The MeDi
is characterized by high intake of vegetables, legumes,
fruits, and cereals; high intake of unsaturated fatty ac-
ids (mostly in the form of olive oil), but low intake of
saturated fatty acids; a moderately high intake of fish; a
low-to-moderate intake of dairy products (mostly
cheese or yogurt); a low intake of meat and poultry;
and a regular but moderate amount of ethanol, primar-
ily in the form of wine and generally during meals.31
Therefore, the MeDi appears to include many of the
components reported as potentially beneficial for AD
and cognitive performance.

We examined the association between MeDi and
AD using data from the Washington Heights-Inwood
Columbia Aging Project (WHICAP). We hypothesized
that higher adherence to the MeDi would be associated
with lower risk for AD.


Subjects and Methods


Sample and Procedures

This study included participants of two related cohorts re-
cruited in 1992 (WHICAP 1992) and 1999 (WHICAP
1999), which were identified (via ethnicity and age stratifi-
cation processes) from a probability sample of Medicare ben-
eficiaries residing in an area of three contiguous census tracts
within a geographically defined area of northern Manhat-
tan.23,24,36,37 The same assessments and study procedures
were used in both cohorts. At entry, a physician elicited each
subject’s medical and neurological history and conducted a
standardized physical and neurological examination. All
available ancillary information (medical charts, computed to-
mography scans, or magnetic resonance images) was consid-
ered in the evaluation. A global summary score on the Clin-
ical Dementia Rating (CDR)38 scale also was assigned. Each
subject also underwent a structured in-person interview in-
cluding an assessment of health and function and a neuro-
psychological battery.39 The neuropsychological battery con-
tained tests of memory (short- and long-term verbal and
nonverbal), orientation, abstract reasoning (verbal and non-
verbal); language (naming, verbal fluency, comprehension,
and repetition), and construction (copying and matching).

A consensus diagnosis for the presence or absence of de-
mentia was made at a diagnostic conference of neurologists
and neuropsychologists where information of all the above
evaluations was presented. Evidence of cognitive deficit
(based on the neuropsychological scores as described above),
evidence of impairment in social or occupational function (as
assessed by the Blessed Dementia Rating Scale, the Schwab
and England Activities of Daily Living Scale, and the physi-
cian’s assessment), and evidence of cognitive and social-
occupational function decline compared with the past were
the criteria used for the diagnosis of dementia as required by
the Diagnostic and Statistical Manual of Mental Disorders, Re-
vised Third Edition (DSM-III-R). The type of dementia was
subsequently determined. For the diagnosis of probable or
possible AD, the criteria of the National Institute of Neuro-
logical and Communicative Disorders and Stroke-
Alzheimer’s Disease and Related Disorders Association40
were used. Because in these criteria stroke does not preclude
the diagnosis of AD (unless cerebrovascular disease was con-
sidered the primary cause of the dementia), the diagnosis of
AD with concomitant stroke also was assigned. Dietary data
were not available to the consensus panel and were not con-
sidered in the diagnostic process.

Subjects were followed up at intervals of approximately
1.5 years, repeating the baseline examination and consensus
diagnosis at each follow-up. The initial sample for this study
was 4,166 individuals, of whom 3,436 were without demen-
tia at initial evaluation (Fig 1). Because the dietary assess-
ment component was added after initiation of the study, di-
etary information was missing for some subjects (n = 527).
An additional 24 subjects were excluded due to incomplete
dietary information. From the remaining 2,885 subjects,
follow-up was not available for 627 (including 101 because
they died relatively soon after the baseline assessment). Thus,
the initial analytic sample for the survival analyses comprised
2,258 subjects (1,037 [46%] from the WHICAP 1992 and
1,221 [54%] from the WHICAP 1999 cohort).

Evaluation

PREDICTORS
Diet. Dietary data regarding average food consumption
over the past year were obtained using a 61-item version of
Willett’s semiquantitative food frequency questionnaire
(SFFQ; Channing Laboratory, Cambridge, MA).41 Trained
interviewers administered the SFFQ in English or Spanish.
We have previously reported validity (using two 7-day food
records) and reliability (using two 3-month frequency assess-
ments) of various components of the SFFQ in WHI-
CAP.23,24,36

We followed the method that Trichopoulou and col-
leagues31 described previously for the construction of the
MeDi score. More specifically, we first regressed caloric in-
take (measured in kilocalories) and calculated the derived re-
siduals of daily gram intake (as Willet and Stampfer42 rec-
ommended) for each of the following seven categories (which
define the components of the MeDi that Trichopoulou and
colleagues31 defined previously): dairy, meat, fruits, vegeta-
bles, legumes, cereals, and fish. A value of 0 or 1 was as-
signed to each of these seven groups, using sex-specific me-
dians as cutoffs. For beneficial components (fruits,
vegetables, legumes, cereals, and fish), individuals whose con-
sumption was below the median were assigned a value of 0,
and individuals whose consumption was at or above the me-
dian were assigned a value of 1. For components presumed
to be detrimental (meat and dairy products), individuals
whose consumption was below the median were assigned a
value of 1, and individuals whose consumption was at or
above the median were assigned a value of 0. For fat intake
(the eighth food category), we used the ratio of daily con-
sumption (in grams) of monounsaturated lipids to saturated
lipids31 (again using sex-specific median cutoffs for assign-
ment values of 0 for low and 1 for high). For alcohol intake
(the ninth food category), subjects were assigned a score of 0
for either no (0gm/day) or more than moderate (30gm/
day) consumption, and a value of 1 for mild-moderate alco-
hol consumption (0 to 30gm/day). This agrees with
Trichopoulou’s31 previous reports that consider moderate
amount of alcohol consumption as another characteristic
component of the MeDi. We classified alcohol consumption
dichotomously, because of the skewed distribution of alcohol
in our population (68% reporting no alcohol intake, 31%
reporting less than 30gm/day [mild-to-moderate intake], and
1% reporting 30gm/day [heavy intake]). The MeDi score
was generated for each participant by adding the scores in
the food categories (theoretically ranging from 0 -9) with the
higher score indicating stricter adherence to the MeDi. Me-
dian intake of consumption for MeDi food categories is pre-
sented in Table 1. We used MeDi score from the baseline
visit as the main predictor in the survival analyses.

Covariates. Age (years), education (years), caloric intake
(kcal), and body mass index (weight in kilograms divided by
height in square meters [kg/m2])43 were used as continuous
variables. We also considered cohort (1992 cohort as refer-
ence), sex (men as reference), and smoking status at baseline
evaluation (no smoking as reference). Ethnic group was
based on self-report using the format of the 1990 census.44
Participants then were assigned to one of four groups: Black
(non-Hispanic), Hispanic, White (non-Hispanic), or Other.
Ethnicity was used as a dummy variable with White (non-
Hispanic) as the reference. Apolipoprotein E (APOE) geno-
type was used dichotomously: absence of ε4 allele versus
presence of either 1 or 2 ε4 alleles.

A modified version45,46 of the Charlson Index of Comor-
bidity47 (referred to as “comorbidity index”) was included as
a continuous variable. It included items for myocardial in-
farct, congestive heart failure, peripheral vascular disease, hy-
pertension, chronic obstructive pulmonary disease, arthritis,
gastrointestinal disease, mild liver disease, diabetes, chronic
renal disease, and systemic malignancy from the baseline
visit. All items received weights of one, with the exception of
chronic renal disease and systemic malignancy, which were
weighted two.


STATISTICAL ANALYSES. Baseline characteristics of patients
by availability of follow-up, outcome of interest, and MeDi
tertiles were compared using t test or analysis of variance for
continuous variables and 2 test for categorical variables.

Mediterranean Diet Score Stability. We used generalized es-
timating equations (GEEs) to test whether there were signif-
icant changes of MeDi score over time for a subset of sub-
jects with more than one dietary assessment. These repeated
dietary assessments were performed to obtain information on
the temporal stability of dietary reporting. GEE takes into
account the multiple visits per subject and that the charac-
teristics of the same individual over time are likely to be cor-
related. The repeated measures for each subject are treated as
a cluster. The GEE model included the MeDi score as the
dependent variable and time (years) as predictor. A signifi-
cant time effect would indicate a significant change of MeDi
score over time. We performed separate exploratory analyses
for subjects who experienced development of AD and for
ones who remained nondemented.


Survival Analyses. We calculated Cox proportional hazards
models with AD as the dichotomous outcome. Subjects who
experienced development of other dementias (n = 32) were
excluded from these analyses. In exploratory analyses that
censored (rather than excluded) these subjects, the results
were unchanged (these analyses are not presented). The time-
to-event variable was time from recording of baseline diet to
first visit of dementia diagnosis; subjects who did not expe-
rience development of dementia were censored at the time of
their last follow-up. The main predictor was MeDi score
(from the baseline visit) as a continuous variable initially and
in tertiles form subsequently (used for trend test calculation).
We simultaneously adjusted for the following variables: co-
hort, age at intake in the study, sex, ethnicity, education,
APOE, smoking, comorbidity index, and body mass index.
Although caloric intake adjusted residuals were used in the
MeDi score calculation, we also included caloric intake as a
covariate in the models (as Willet and colleagues42 recom-
mended). All predictors were used as time-constant covari-
ates. We performed two additional sets of sensitivity analyses.
First, we recalculated the models using as dementia diagnosis
date the last date when subjects were considered to be cog-
nitively nondemented. Second, we recalculated the models
using as dementia date the midpoint between last nonde-
mentia diagnosis and first dementia diagnosis.

In other exploratory models, we repeated the analyses ex-
cluding subjects who were diagnosed as AD with stroke (ie,
using only AD without stroke as the outcome). To increase
our confidence that the degree of adherence to MeDi was
not affected by early, subclinical dementia process, we per-
formed additional analyses. First, we recomputed the Cox
models excluding subjects with mild cognitive deficits at
baseline (ie, CDR = 0.5). Second, we excluded both subjects
with mild cognitive deficits at baseline (ie, CDR = 0.5) and
subjects who were followed for less than 2 years.

To examine whether possible associations between MeDi
and risk for AD were driven by associations of particular
food categories, in further supplementary analyses, we in-
cluded all nine individual components used to calculate the
MeDi score in stepwise forward selection Cox models (entry
criterion: p < 0.05; removal criterion: p > 0.05). The Cox
models fulfilled the proportionality assumption (martingale
residuals method).


RATES OF COGNITIVE DECLINE IN RELATION TO THE
MEDITERRANEAN DIET. The primary outcome in these
analyses was rate of decline in cognition as assessed at each
study visit. Using 12 neuropsychological tests from the ad-
ministered battery,48 -54 we calculated a composite cognitive
measure. Details about this procedure have been published
previously.55 In brief, to derive the composite measure, we
first transformed each of the 12 individual cognitive tests
into Z-scores. Means and standard deviations for each test
were calculated from baseline scores of nondemented sub-
jects, and Z-scores were averaged initially in cognitive do-
mains, which were subsequently averaged again to produce
the composite cognitive score. The Z-score of the composite
cognitive measure at each evaluation was the primary out-
come.

We used GEEs to test whether MeDi adherence was as-
sociated with differential rates of cognitive change. The re-
peated cognitive performance scores for each subject were
treated as a cluster. The GEE models included the composite
cognitive measure as the dependent variable and, as predic-
tors, cohort, age, sex, education, ethnicity, baseline cognitive
performance, MeDi at baseline, time (in years from baseline
assessment), and a MeDi time interaction. A significant
interaction term would indicate differential rates of change in
cognitive function as a function of MeDi adherence.



Results


Missing Data Analyses

Compared with subjects with available dietary informa-
tion, subjects with missing dietary information (n =
527) (see Fig 1) had slightly lower education (9.1 vs
9.9 years; p = 0.001). Subjects with missing dietary
information also had higher proportions of dementia
(17.5 vs 11%; p < 0.001) and higher mortality (32 vs
18%; p < 0.001), which may be related to that the
dietary assessment was added after initiation of the
study and was not available for subjects recruited ear-
lier on. There were no significant differences between
subjects with missing and those with available dietary
information in age (76.7 vs 77; p = 0.30), sex (33%
male vs 33% male; p = 0.68), ethnicity (White 25%,
Black 31%, Hispanic 43%, Other 1% vs White 27%,
Black 33%, Hispanic 39%, Other 1%; p = 0.24),
medical comorbidity index (2.1 vs 2.0; p = 0.27), or
APOE genotype (ε4 carriers 27 vs 28%; p = 0.79).

Compared with subjects with available cognitive
follow-up (n = 2,258), subjects with missing follow-up
(n = 627) (see Fig 1) were slightly younger (76.4 vs
77.2 years; p = 0.01), had lower education (9.4 vs
10.0 years; p = 0.005), more medical comorbidities
(2.2 vs 1.9; p = 0.002), and higher mortality (30 vs
15%; p = 0.001). There were no significant differences
between subjects with missing and those with available
follow-up in caloric intake (1,466 vs 1,428; p = 0.12),
sex (35% male vs 33% male; p = 0.42), ethnicity
(White 26%, Black 36%, Hispanic 38%, Other 1% vs
White 28%, Black 33%, Hispanic 38%, Other 2%;
p = 0.39), or APOE genotype (ε4 carriers 29 vs 28%;
p = 0.67). Most important, there was no difference in
MeDi score (4.3 vs 4.4; p = 0.21).

Examining evaluations for subjects who had available
follow-up, 76 subjects were missing 1 evaluation, 11
were missing 1 evaluation, and 2 were missing 3 eval-
uations. Examining, in particular, the time period ei-
ther between the dementia incidence evaluation and
the evaluation preceding that (for AD subjects) or be-
tween the last evaluation and the evaluation preceding
that (for nondemented subjects), only 23 subjects (7
AD and 16 nondemented) had 1 missing evaluation
and only 2 subjects (1 AD and 1 nondemented) had 2
missing evaluations. Therefore, missing evaluations for
subjects with available follow-up was a rare phenome-
non in our study.


Stability of Mediterranean Diet Score

There were 390 subjects with multiple dietary assess-
ments who did not experience development of AD or
other dementia during follow-up. There were 2 dietary
assessments available for 308 subjects, 3 for 71 sub-
jects, and 4 for 11 subjects. The mean time interval
between dietary assessments was 7.1 years (standard de-
viation, 2.36; range, 1-12.8). The reported MeDi
score was stable (0.01; p = 0.41).

There were 89 subjects with multiple dietary assess-
ments who developed AD during follow-up; there were
2 assessments available for 78 participants, 3 for 8 par-
ticipants, and 4 for 3 participants. The mean time in-
terval between dietary assessments was 8.1 years (stan-
dard deviation, 1.9; range, 1.8 -11.9). Again, the
reported MeDi score did not change over time (
0.05; p = 0.09).


Clinical-Demographic-Dietary Characteristics

Subjects were followed (until AD incidence or last
follow-up for subjects who remained without de-
mented) for an average of 4.0 (3.0; range, 0.2-13.9)
years. Overall, 294 subjects experienced development
of incident dementia; AD developed in 262 of these
subjects (184/262 had AD without stroke).

Compared with subjects who remained without de-
mentia, subjects in whom AD had developed at
follow-up were older, less educated, and had a lower
body mass index (Table 2). There was a higher pro-
portion of Hispanics and a lower proportion of Whites
(non-Hispanic) among subjects who experienced devel-
opment of AD. Presence of ε4 allele was more frequent
and caloric intake was higher for subjects in whom AD
developed compared with subjects who remained with-
out dementia, but the associations were not significant.
Subjects who did and did not acquire AD did not dif-
fer in sex, medical comorbidity index, or smoking sta-
tus. Compared with subjects who remained nonde-
mented, subjects who experienced development of AD
had lower MeDi scores.

There was no association between MeDi score and
age, sex, education, APOE genotype, medical comor-
bidity index, or body mass index (Table 3). Hispanics
adhered more and Blacks less to the MeDi pattern.
Subjects adhering more to the MeDi tended to smoke
less and had lower caloric intake.


Mediterranean Diet and Risk for Alzheimer’s Disease
and Cognitive Decline

Higher adherence to the MeDi was associated with
significantly lower risk for development of AD (Table
4 and Fig 2). The results were similar in adjusted and
unadjusted models. Each additional unit of the MeDi
score was associated with 9 to 10% less risk for de-
velopment of AD. Compared with subjects in the
lowest MeDi tertile (low adherence to the MeDi),
subjects in the middle MeDi score tertile had 15 to
21% less risk for development of AD, whereas those
at the highest tertile (high adherence to the MeDi)
had 39 to 40% less risk for development of AD, with
a significant trend for a dose-response effect. In sen-
sitivity analyses using alternative dementia diagnosis
dates (either last date when subjects were deemed
nondemented or the midpoint between last nonde-
mentia and first dementia diagnosis) the associations
were unchanged.

The coefficients remained virtually unchanged and
the associations significant in models excluding subjects
with baseline evidence of mild cognitive impairment
(CDR p = 0.5): 1,898 subjects at risk with 156 inci-
dent AD cases; hazard ratio, 0.88 (95% confidence in-
terval, 0.80 - 0.97); p = 0.007, tertile analyses; p for
trend 0.018. When both persons with CDR = 0.5
and those followed for less than 2 years were excluded,
the coefficients remained essentially unchanged: 1,575
subjects at risk with 134 incident AD cases; hazard ra-
tio: 0.89 (95% confidence interval, 0.80 - 0.98); p =
0.020, tertile analyses; p for trend 0.027. Results
were similar in adjusted models.

When the same models were run with probable AD
without stroke as the outcome (excluding AD with co-
existing stroke, n = 78), the associations were un-
changed: 2,144 subjects at risk with 184 incident prob-
able AD without stroke; hazard ratio, 0.90 (95%
confidence interval, 0.83- 0.98); p = 0.015, tertile
analyses; p for trend 0.018. Adjusted models pro-
duced similar results.

Regarding associations of other nutrition-related ele-
ments with risk for AD, and in agreement with previ-
ous publications,23,56 lower caloric intake (0.9997 for
each additional kilocalorie; range, 0.9994 - 0.9999; p =
0.007) and higher body mass index (0.96; range, 0.93-
0.98; p = 0.002) were related to lower risk for AD in
the adjusted models.

In unadjusted Cox models that included the nine
individual dietary components of the MeDi as predic-
tors, mild-to-moderate alcohol consumption (0.61
[0.45- 0.82]; p = 0.001) and higher vegetable con-
sumption (0.76 [0.60 - 0.97]; p = 0.030) were associ-
ated with decreased risk for AD. In adjusted models,
none of the individual components was a significant
AD predictor.

In GEE analyses, there was a significant MeDi
time interaction beta = 0.003; p = 0.047) indicating an
association between higher adherence to MeDi and
slower cognitive decline: each additional unit of adher-
ence to the MeDi was associated with 0.3% of a stan-
dard deviation less decline per year.



Discussion



This study suggests that higher adherence to the MeDi
is associated with a reduction in risk for AD and slower
cognitive decline. The gradual reduction in AD risk for
higher tertiles of MeDi adherence also suggests a pos-
sible dose-response effect. The associations between
MeDi and incident AD remained unchanged and sig-
nificant even when simultaneously adjusting for the
most commonly considered potential confounders for
AD, such as age, sex, ethnicity, education, APOE ge-
notype, caloric intake, and body mass index. Higher
adherence to MeDi reduced risk for probable AD ei-
ther with or without coexisting stroke.

The association between high adherence to the
MeDi and lower risk for AD may be mediated by the
composite effect of some of its beneficial components,
such as higher intake of fish,12,13 fruits, and vegetables
rich in antioxidants such as vitamin C,4 - 6 vitamin
E,4 - 8 and flavonoids9 and higher intake of unsaturated
fatty acids.10 -12 Some of the inconsistencies regarding
some of the above dietary elements and risk for AD in
the existing literature may be a result of failure to con-
sider possible additive and interactive (antagonistic or
synergistic) effects among nutritional components,
which may be captured in a composite dietary pattern
such as the MeDi. For example, the effect of fish con-
sumption in reducing blood pressure57 and blood lip-
ids58 appears to be much more pronounced in subjects
following a low-fat diet. When individual components
used to derive the MeDi pattern were examined in our
study, mild-to-moderate alcohol consumption and
higher vegetable intake were associated with decreased
risk for AD in unadjusted models. Nevertheless, none
of the individual components was a significant AD pre-
dictor when other confounders were considered. These
results strengthen even further our initial hypothesis
that composite dietary patterns can capture dimensions
of nutrition that may be missed by individual compo-
nents, and that an overall dietary pattern is likely to
have a greater effect on health than a single nutrient.

The MeDi may play a role in multiple potential
mechanisms including oxidative stress and inflamma-
tion, which are both important in the pathogenesis of
AD.59 Complex phenols and many other substances
with important antioxidant properties such as vitamin
C, vitamin E, and carotenoid60 - 62 are found in high
concentrations in the typical components of the MeDi.
In the Attica epidemiological study, participants on the
highest tertile of the MeDi score had 20% lower CRP
levels and 17% lower interleukin-6 serum levels.63
Higher adherence to the MeDi also has been associated
with significant reduction in various other inflamma-
tory and coagulation markers including white blood
cell counts and fibrinogen levels.63

Given the growing evidence for contribution of vas-
cular risk factors in AD risk,64,65 vascular mechanisms
are important to consider.59 There is strong evidence
relating the MeDi to lower risk for vascular risk factors
such as hypertension, dyslipidemia, and diabe-
tes.29,34,35,66 Subjects in the highest tertile of MeDi
adherence have also been reported to have 15% lower
homocysteine levels.63 Thus, vascular variables are
likely to be in the causal pathway between MeDi and
AD and should be considered as possible mediators.
Because mediators, as contrasted with confounders,
should not be controlled for in the statistical analysis,67
and in accordance with previous MeDi-related analyt-
ical approaches,68 we did not include specific vascular
variables in our models.

Although most studies of the MeDi have been con-
ducted in Mediterranean populations, recent studies
have indicated MeDi-related health benefits in other
populations such as northern European,68,69 Indian,35
and Australian populations,70 suggesting that the ad-
vantages of the MeDi are transferable to other popula-
tions. Our study provided the opportunity to examine
the effect of MeDi in a multiethnic community in the
United States, and our results support the notion that
the beneficial effects of the MeDi are generalizable to
different populations.

This study has limitations. The use of an a priori
distribution-derived MeDi score assumes underlying
monotonic effects, does not address possible thresholds
or the shape of the underlying curve, and weighs
equally the underlying individual food categories,
which, in turn, are composed of different numbers of
food constituents. Frequencies of food intake are based
on relatively few diet constituents, which may under-
estimate the overall quantity of food in each food cat-
egory, and a common limitation of studies of diet and
disease is misclassification of exposure due to limited
accuracy. However, assuming that the measurement er-
ror was random, our results may actually underestimate
the association between high MeDi adherence and
lower AD risk.

Despite the use of standard criteria, the diagnostic
expertise of our center, and the thorough workup,
there is always the possibility of disease misclassifica-
tion bias.71 We partially addressed this issue by con-
ducting secondary analyses considering only probable
AD without stroke as the outcome, and our results
were virtually unchanged. Subjects who were lost to
follow-up were younger, less educated, and had more
medical comorbidities, but MeDi was not related to
age, education, or medical comorbidity burden. Also,
the MeDi scores did not differ between subjects who
remained in the study and those lost to follow-up.
Therefore, it does not appear likely that our results
could be explained by biases related to loss to follow-
up.

It is possible that diet is related to socioeconomic
status or to other habits or characteristics related to
better health and a lower risk for AD. In our data,
MeDi was not related to education or the overall bur-
den of medical comorbidities, but was related to eth-
nicity and smoking. We addressed this by adjusting for
years of education, ethnic group, medical comorbidity
index, and smoking, but we cannot completely rule out
residual confounding as an explanation for our find-
ings. Another confounder usually considered in nutri-
tional epidemiology is caloric intake,42,72 and higher
MeDi adherence was related to lower caloric intake in
our data. We used caloric intake adjusted residuals for
MeDi calculation and also included caloric intake as a
covariate (as Willet and Stampfer42 recommended).
We found that higher MeDi adherence was related to a
lower risk for AD over and above caloric intake.

Despite an average follow-up of 4 years, several stud-
ies have shown that subtle cognitive changes antedate
the clinical diagnosis of AD by many years.55,73 There-
fore, it is still possible that lower adherence to the
MeDi could represent a consequence and not a cause
of AD. We addressed this possibility in several ways.
We found remarkable stability in MeDi scores over in-
tervals greater than 7 years for subjects with multiple
dietary assessments regardless of dementia status. In ad-
dition, the associations between MeDi score and inci-
dent AD did not change when subjects with mild cog-
nitive deficits at baseline and subjects with less than 2
years of follow-up were excluded. Thus, bias due to
preclinical disease does not appear to be a likely expla-
nation for our findings.

Confidence in our findings is also strengthened by
the following factors. Dietary data were collected with
a previously validated instrument that was used widely
in epidemiological studies.41 We used an a priori de-
veloped dietary pattern.27,31,74 Measures for multiple
potential AD risk factors have been recorded carefully
and adjusted for in the analyses. The diagnosis of AD
took place in a university hospital with expertise in de-
mentia and was based on comprehensive assessment
and standard research criteria. The patients were fol-
lowed prospectively at relatively short intervals. The
study is community-based and the population is mul-
tiethnic, increasing the external validity of the findings.

___

This study was supported by the NIH (National Institute on Aging,
AG07232, M-X.T., R.M., J.A.L., AG07702, M-X.T., R.M.,
AG15294-06, J.A.L., 1K08AG20856-01, J.A.L.; RR00645, Colum-
bia University General Clinical Research Center), the Charles S.
Robertson Memorial Gift for Research in Alzheimer’s disease (R.M),
the Blanchette Hooker Rockefeller Foundation (R.M), the New
York City Council Speaker’s Fund for Public Health Research
(J.A.L.), and the Taub Institute for Research on Alzheimer’s Disease
and the Aging Brain. N.S., R.M., J.A.L.).



References


1. Solfrizzi V, Panza F, Capurso A. The role of diet in cognitive
decline. J Neural Transm 2003;110:95-110.
2. Luchsinger JA, Mayeux R. Dietary factors and Alzheimer’s dis-
ease. Lancet Neurol 2004;3:579 -587.
3. Mattson MP. Emerging neuroprotective strategies for Alzhei-
mer’s disease: dietary restriction, telomerase activation, and
stem cell therapy. Exp Gerontol 2000;35:489 -502.
4. Zandi PP, Anthony JC, Khachaturian AS, et al. Reduced risk of
alzheimer disease in users of antioxidant vitamin supplements:
the Cache County Study. Arch Neurol 2004;61:82- 88.
5. Engelhart MJ, Geerlings MI, Ruitenberg A, et al. Dietary in-
take of antioxidants and risk of Alzheimer disease. JAMA 2002;
287:3223-3229.
6. Masaki KH, Losonczy KG, Izmirlian G, et al. Association of
vitamin E and C supplement use with cognitive function and
dementia in elderly men. Neurology 2000;54:1265-1272.
7. Morris MC, Evans DA, Bienias JL, et al. Vitamin E and cog-
nitive decline in older persons. Arch Neurol 2002;59:
1125-1132.
8. Morris MC, Evans DA, Bienias JL, et al. Dietary intake of an-
tioxidant nutrients and the risk of incident Alzheimer disease in
a biracial community study. JAMA 2002;287:3230 -3237.
9. Commenges D, Scotet V, Renaud S, et al. Intake of flavonoids
and risk of dementia. Eur J Epidemiol 2000;16:357-363.
10. Kalmijn S, Feskens EJ, Launer LJ, Kromhout D. Polyunsatu-
rated fatty acids, antioxidants, and cognitive function in very
old men. Am J Epidemiol 1997;145:33- 41.
11. Morris MC, Evans DA, Bienias JL, et al. Dietary fats and the
risk of incident Alzheimer disease. Arch Neurol 2003;60:
194 -200.
12. Morris MC, Evans DA, Bienias JL, et al. Consumption of fish
and n-3 fatty acids and risk of incident Alzheimer disease. Arch
Neurol 2003;60:940 -946.

13. Barberger-Gateau P, Letenneur L, Deschamps V, et al. Fish,
meat, and risk of dementia: cohort study. BMJ 2002;325:
932-933.
14. La Rue A, Koehler KM, Wayne SJ, et al. Nutritional status and
cognitive functioning in a normally aging sample: a 6-y reas-
sessment. Am J Clin Nutr 1997;65:20 -29.
15. Clarke R, Smith AD, Jobst KA, et al. Folate, vitamin B12, and
serum total homocysteine levels in confirmed Alzheimer disease.
Arch Neurol 1998;55:1449 -1455.
16. Wang HX, Wahlin A, Basun H, et al. Vitamin B(12) and folate
in relation to the development of Alzheimer’s disease. Neurol-
ogy 2001;56:1188 -1194.
17. Ruitenberg A, van Swieten JC, Witteman JC, et al. Alcohol
consumption and risk of dementia: the Rotterdam Study. Lan-
cet 2002;359:281-286.
18. Mukamal KJ, Kuller LH, Fitzpatrick AL, et al. Prospective
study of alcohol consumption and risk of dementia in older
adults. JAMA 2003;289:1405-1413.
19. Luchsinger JA, Tang MX, Siddiqui M, et al. Alcohol intake and
risk of dementia. J Am Geriatr Soc 2004;52:540 -546.
20. Truelsen T, Thudium D, Gronbaek M, Copenhagen City
Heart Study. Amount and type of alcohol and risk of dementia:
the Copenhagen City Heart Study. Neurology 2002;59:
1313-1319.
21. Orgogozo JM, Dartigues JF, Lafont S, et al. Wine consumption
and dementia in the elderly: a prospective community study in
the Bordeaux area. Rev Neurol (Paris) 1997;153:185-192.
22. Kalmijn S, Launer LJ, Ott A, et al. Dietary fat intake and the
risk of incident dementia in the Rotterdam Study. Ann Neurol
1997;42:776 -782.
23. Luchsinger JA, Tang MX, Shea S, Mayeux R. Caloric intake
and the risk of Alzheimer disease. Arch Neurol 2002;59:
1258 -1263.
24. Luchsinger JA, Tang MX, Shea S, Mayeux R. Antioxidant vi-
tamin intake and risk of Alzheimer disease. Arch Neurol 2003;
60:203-208.
25. Engelhart MJ, Geerlings MI, Ruitenberg A, et al. Diet and risk
of dementia: does fat matter?: the Rotterdam Study. Neurology
2002;59:1915-1921.
26. Crystal HA, Ortof E, Frishman WH, et al. Serum vitamin B12
levels and incidence of dementia in a healthy elderly
population: a report from the Bronx Longitudinal Aging Study.
J Am Geriatr Soc 1994;42:933-936.
27. Jacques PF, Tucker KL. Are dietary patterns useful for under-
standing the role of diet in chronic disease? Am J Clin Nutr
2001;73:1-2.
28. Lagiou P, Trichopoulou A, Henderickx HK, et al. Household
budget survey nutritional data in relation to mortality from cor-
onary heart disease, colorectal cancer and female breast cancer
in European countries. DAFNE I and II projects of the Euro-
pean Commission. Data Food Networking. Eur J Clin Nutr
1999;53:328 -332.
29. Panagiotakos DB, Pitsavos CH, Chrysohoou C, et al. Status
and management of hypertension in Greece: role of the adop-
tion of a Mediterranean diet: the Attica study. J Hypertens
2003;21:1483-1489.
30. Trichopoulou A, Kouris-Blazos A, Wahlqvist ML, et al. Diet
and overall survival in elderly people. BMJ 1995;311:
1457-1460.
31. Trichopoulou A, Costacou T, Bamia C, Trichopoulos D. Ad-
herence to a Mediterranean diet and survival in a Greek popu-
lation. N Engl J Med 2003;348:2599 -2608.
32. Lasheras C, Fernandez S, Patterson AM. Mediterranean diet
and age with respect to overall survival in institutionalized,
nonsmoking elderly people. Am J Clin Nutr 2000;71:987-992.
33. Trichopoulou A, Lagiou P, Kuper H, Trichopoulos D. Cancer
and mediterranean dietary traditions. Cancer Epidemiol Bi-
omarkers Prev 2000;9:869 - 873.
34. de Lorgeril M, Salen P, Martin JL, et al. Mediterranean diet,
traditional risk factors, and the rate of cardiovascular complica-
tions after myocardial infarction: final report of the Lyon Diet
Heart Study. Circulation 1999;99:779 -785.
35. Singh RB, Dubnov G, Niaz MA, et al. Effect of an Indo-
Mediterranean diet on progression of coronary artery disease in
high risk patients (Indo-Mediterranean Diet Heart Study): a
randomised single-blind trial. Lancet 2002;360:1455-1461.
36. Luchsinger JA, Tang MX, Siddiqui M, et al. Alcohol intake and
risk of dementia. J Am Geriatr Soc 2004;52:540 -546.
37. Scarmeas N, Levy G, Tang MX, et al. Influence of leisure ac-
tivity on the incidence of Alzheimer’s disease. Neurology 2001;
57:2236 -2242.
38. Hughes CP, Berg L, Danziger WL, et al. A new clinical scale
for the staging of dementia. Br J Psychiatry 1982;140:566 -572.
39. Stern Y, Andrews H, Pittman J, et al. Diagnosis of dementia in
a heterogeneous population. Development of a neuropsycholog-
ical paradigm-based diagnosis of dementia and quantified cor-
rection for the effects of education. Arch Neurol 1992;49:
453- 460.
40. McKhann G, Drachman D, Folstein M, et al. Clinical diagno-
sis of Alzheimer’s disease: report of the NINCDS-ADRDA
Work Group under the auspices of Department of Health and
Human Services Task Force on Alzheimer’s Disease. Neurology
1984;34:939 -944.
41. Willett WC, Sampson L, Stampfer MJ, et al. Reproducibility
and validity of a semiquantitative food frequency questionnaire.
Am J Epidemiol 1985;122:51- 65.
42. Willett W, Stampfer M. Implications of total energy intake for
epidemiological analyses. In: Willett W, ed. Nutritional epide-
miology. New York: Oxford University Press, 1998:273-301.
43. Kuczmarski R, Carroll M, Flegal K, Troiano R. Varying body
mass index cutoff points to describe overweight prevalence
among U.S. adults: NHANES III (1988 to 1994). Obes Res
1997;5:542-548.
44. Census of Population and Housing. Summary tape file 1, tech-
nical documentation. Washington, DC: Bureau of the Consen-
sus, 1991.
45. Scarmeas N, Brandt J, Albert M, et al. Delusions and halluci-
nations are associated with worse outcome in Alzheimer disease.
Arch Neurol 2005;62:1601-1608.
46. Scarmeas N, Albert M, Brandt J, et al. Motor signs predict
poor outcomes in Alzheimer disease. Neurology 2005;64:
1696 -1703.
47. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new
method of classifying prognostic comorbidity in longitudinal
studies: development and validation. J Chronic Dis 1987;40:
373-383.
48. Buschke H, Fuld PA. Evaluating storage, retention, and re-
trieval in disordered memory and learning. Neurology 1974;24:
1019 -1025.
49. Benton A. The Visual Retention Test. New York: The Psycho-
logical Corporation, 1955.
50. Wechsler D. Wechsler Adult Intelligence Scale Revised. New
York: The Psychological Corporation, 1981.
51. Mattis S. Mental status examination for organic mental syn-
drome in the elderly patient. In: Bellak L, Karasu TB, eds. Ge-
riatric psychiatry. New York: Grune & Stratton, 1976:77-121.
52. Rosen WG. The Rosen Drawing Test. Bronx, NY: Veterans
Administration Medical Center, 1981.
53. Goodglass H, Kaplan D. The assessment of aphasia and related
disorders. 2nd ed. Philadelphia: Lea & Febiger, 1983.

54. Benton AL, Hamsher K, Sivan AB. Manual for the multilingual
aphasia examination. 3rd ed. Iowa City, IA: AJA Associates,
1994.
55. Scarmeas N, Albert SM, Manly JJ, Stern Y. Education and rates
of cognitive decline in incident Alzheimer’s disease. J Neurol
Neurosurg Psychiatry 2006;77:308 -316.
56. Stewart R, Masaki K, Xue Q-L, et al. A 32-year prospective
study of change in body weight and incident dementia: the
Honolulu-Asia Aging Study. Arch Neurol 2005;62:55- 60.
57. Vandongen R, Mori TA, Burke V, et al. Effects on blood pres-
sure of omega 3 fats in subjects at increased risk of cardiovas-
cular disease. Hypertension 1993;22:371-379.
58. Mori TA, Vandongen R, Beilin LJ, et al. Effects of varying
dietary fat, fish, and fish oils on blood lipids in a randomized
controlled trial in men at risk of heart disease. Am J Clin Nutr
1994;59:1060 -1068.
59. Cummings JL. Alzheimer’s disease. N Engl J Med 2004;351:
56 - 67.
60. Joshipura KJ, Hu FB, Manson JE, et al. The effect of fruit and
vegetable intake on risk for coronary heart disease. Ann Intern
Med 2001;134:1106 -1114.
61. Witztum JL. The oxidation hypothesis of atherosclerosis. Lan-
cet 1994;344:793-795.
62. Byers T, Perry G. Dietary carotenes, vitamin C, and vitamin E
as protective antioxidants in human cancers. Annu Rev Nutr
1992;12:139 -159.
63. Chrysohoou C, Panagiotakos DB, Pitsavos C, et al. Adherence
to the Mediterranean diet attenuates inflammation and coagu-
lation process in healthy adults: the ATTICA Study. J Am Coll
Cardiol 2004;44:152-158.
64. Breteler MM. Vascular risk factors for Alzheimer’s disease: an
epidemiologic perspective. Neurobiol Aging 2000;21:153-160.
65. Luchsinger J, Mayeux R. Cardiovascular risk factors and Alz-
heimer’s disease. Curr Atheroscler Rep 2004;6:261-266.
66. Psaltopoulou T, Naska A, Orfanos P, et al. Olive oil, the Med-
iterranean diet, and arterial blood pressure: the Greek European
Prospective Investigation into Cancer and Nutrition (EPIC)
study. Am J Clin Nutr 2004;80:1012-1018.
67. MacMahon B, Trichopoulos D. Epidemiology: principles and
methods. 2nd ed. Boston: Little Brown, 1996.
68. Trichopoulou A, Orfanos P, Norat T, et al. Modified Mediter-
ranean diet and survival: EPIC-elderly prospective cohort study.
Rapid responses. BMJ 2005;330:991.
69. Knoops KT, de Groot LC, Kromhout D, et al. Mediterranean
diet, lifestyle factors, and 10-year mortality in elderly European
men and women: the HALE project. JAMA 2004;292:
1433-1439.
70. Kouris-Blazos A, Gnardellis C, Wahlqvist ML, et al. Are the
advantages of the Mediterranean diet transferable to other pop-
ulations? A cohort study in Melbourne, Australia. Br J Nutr
1999;82:57- 61.
71. Knopman DS, DeKosky ST, Cummings JL, et al. Practice
parameter: diagnosis of dementia (an evidence-based review).
Report of the Quality Standards Subcommittee of the American
Academy of Neurology. Neurology 2001;56:1143-1153.
72. Willett W, Stampfer MJ. Total energy intake: implications for
epidemiologic analyses. Am J Epidemiol 1986;124:17-27.
73. Elias MF, Beiser A, Wolf PA, et al. The preclinical phase of
Alzheimer disease: a 22-year prospective study of the Framing-
ham cohort. Arch Neurol 2000;57:808 - 813.
74. Trichopoulos D, Lagiou P. Mediterranean diet and cardiovas-
cular epidemiology. Eur J Epidemiol 2004;19:7- 8.