Mediterranean diet and Alzheimer disease mortality -- Full Paper

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Background: We previously reported that the Mediterranean diet (MeDi) is related to lower risk for Alzheimer disease (AD). Whether MeDi is associated with subsequent AD course and outcomes has not been investigated.

Objectives: To examine the association between MeDi and mortality in patients with AD.

Methods: A total of 192 community-based individuals in New York who were diagnosed with AD were prospectively followed every 1.5 years. Adherence to the MeDi (0- to 9-point scale with higher scores indicating higher adherence) was the main predictor of mortality in Cox models that were adjusted for period of recruitment, age, gender, ethnicity, education, APOE genotype, caloric intake, smoking, and body mass index.

Results: Eighty-five patients with AD (44%) died during the course of 4.4 ( 3.6, 0.2 to 13.6) years of follow-up. In unadjusted models, higher adherence to MeDi was associated with lower mortality risk (for each additional MeDi point hazard ratio 0.79; 95% CI 0.69 to 0.91; p 0.001). This result remained significant after controlling for all covariates (0.76; 0.65 to 0.89; p 0.001). In adjusted models, as compared with AD patients at the lowest MeDi adherence tertile, those at the middle tertile had lower mortality risk (0.65; 0.38 to 1.09; 1.33 years' longer survival), whereas subjects at the highest tertile had an even lower risk (0.27; 0.10 to 0.69; 3.91 years' longer survival; p for trend 0.003).

Conclusion: Adherence to the Mediterranean diet (MeDi) may affect not only risk for Alzheimer disease (AD) but also subsequent disease course: Higher adherence to the MeDi is associated with lower mortality in AD. The gradual reduction in mortality risk for higher MeDi adherence tertiles suggests a possible dose-response effect.


GLOSSARY
AD Alzheimer disease; BMI body mass index; CDR Clinical Dementia Rating; HCFA Health Care Finance Administration; MeDi Mediterranean diet; WHICAP Washington Heights and Inwood Columbia Aging Project.


Nikolaos Scarmeas, Jose A. Luchsinger, Richard Mayeux and Yaakov Stern. Mediterranean diet and Alzheimer disease mortality. Neurology 2007;69;1084-1093


Because dietary patterns analysis has the ability to integrate complex or subtle interactive effects of many dietary constituents and to capture the diet’s multidimensionality,1 it has recently received growing attention in relation to many diseases (i.e., cirrhosis or various cancers). However, there is paucity of data regarding the effect of composite dietary patterns in the neurologic literature. One such dietary pattern is the Mediterranean diet (MeDi). The MeDi is characterized by high intake of vegetables, legumes, fruits, and cereals; high intake of unsaturated fatty acids (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, primarily in the form of wine and generally during meals.2 Hence, it seems to include many of the components reported as potentially beneficial for Alzheimer disease (AD) and cognitive performance.

We recently demonstrated that higher
MeDi adherence is associated with lower
AD risk.3,4 Whether MeDi adherence is as-
sociated with further AD course and prog-
nosis has not been investigated. Because
higher adherence to the MeDi has been as-
sociated with lower risk for a series of
medical conditions and diseases including
overall mortality in the general popula-
tion,2,5,6 we hypothesized that it may be
also associated with reduced mortality in
AD populations too.


METHODS

Sample and procedures.

Data were in-
cluded from individuals participating in a prospective study
of aging and dementia in 4,307 Medicare recipients, age 65
and older, residing in northern Manhattan (Washington
Heights, Hamilton Heights, Inwood; Washington Heights
and Inwood Columbia Aging Project [WHICAP]). A strati-
fied random sample of 50% of all persons older than 65 years
was obtained from the Health Care Finance Administration
(HCFA).3,4,7-10 All persons were sent a letter from HCFA ex-
plaining that they had been selected to participate in a
study of aging by investigators at Columbia University.
The sampling procedures have been described in detail
elsewhere.3,4,7-10 Each participant underwent an in-person in-
terview of general health and functional ability at the time of
entry into the study followed by a standardized assessment,
including medical history, physical and neurologic examina-
tion, and a neuropsychological battery.11 The neuropsycho-
logical battery contained tests of memory (short- and long-
term verbal and nonverbal); orientation; abstract reasoning
(verbal and nonverbal); language (naming, verbal fluency,
comprehension, and repetition); and construction (copying
and matching). Ethnic group was classified by participant’s
self-report using the format of the 1990 US Census.12 Partici-
pants were asked if they considered themselves white, black,
or other and then asked if they were Hispanic. According to
their responses they were assigned to one of four groups:
black (non-Hispanic), Hispanic, white (non-Hispanic), or
other. Participants were recruited at two time points (1992
through 1994 and 1999 through 2002). They have been fol-
lowed at approximately 18-month intervals with similar as-
sessments at each interval. Recruitment, informed consent,
and study procedures were approved by the Institutional Re-
view Boards of Columbia Presbyterian Medical Center and
Columbia University Health Sciences and the New York
State Psychiatric Institute.

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
physician’s assessment), and evidence of cognitive and social-
occupational function decline as compared with the past
were the criteria used for the diagnosis of dementia as re-
quired by the Diagnostic and Statistical Manual of Mental
Disorders (rev. 3rd ed.). The type of dementia was subse-
quently determined. For the diagnosis of probable or possi-
ble AD, the criteria of the National Institute of Neurological
and Communicative Disorders and Stroke/Alzheimer’s Dis-
ease and Related Disorders Association13 were used. Since in
these criteria, stroke does not preclude the diagnosis of AD
(unless cerebrovascular disease was considered the primary
cause of the dementia), the diagnosis of AD with concomi-
tant stroke was also assigned. A global summary score on
the Clinical Dementia Rating (CDR)14 was also assigned. Di-
etary data were not available to the consensus panel and
were not considered in the diagnostic process.

These analyses are restricted to subjects diagnosed with
AD at the baseline WHICAP evaluation (prevalent AD pa-
tients) (figure 1). Among 471 subjects with prevalent AD, 256
were missing dietary assessments, leaving 215 with available
dietary data. MeDi score could not be calculated for 3 and
follow-up was not available for 20, leaving 192 subjects
available for the final analyses.

Evaluation.

Predictors. Diet.
Dietary data regarding aver-
age food consumption over the last year were obtained using
a 61-item Semiquantitative Food Frequency Questionnaire
(SFFQ) (Channing Laboratory, Cambridge, MA).15 Trained
interviewers administered the SFFQ in English (46%) or
Spanish (53%). We have previously reported validity (using
two 7-day food records) and reliability (using two 3-month
frequency assessments) of various components of the SSFQ
in WHICAP.7-9

Similarly to our previous work,3,4 we followed a method
previously described2 for the construction of the MeDi score.
More specifically, we first regressed caloric intake (kcal) and
calculated the derived residuals of daily gram intake16 for
each of the following seven categories2: dairy, meat, fruits,
vegetables, legumes, cereals, and fish. A value of 0 or 1 was
assigned to each of the seven above groups, using sex-
specific medians as cut-offs. For beneficial components
(fruits, vegetables, legumes, cereals, and fish), persons whose
consumption was below the median were assigned a value of
0, and persons 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), persons whose
consumption was below the median were assigned a value of
1, and persons whose consumption was at or above the me-
dian were assigned a value of 0. For fat intake (eighth food
category), we used the ratio of daily consumption (in grams)
of monounsaturated lipids to saturated lipids2 (again using
sex-specific median cutoffs for assignment values of 0 for
low and 1 for high). For alcohol intake (ninth food category),
subjects were assigned a score of 0 for either no (0 g/day) or
more than moderate (30 g/day) consumption and a value
of 1 for mild to moderate alcohol consumption (0 to 30
g/day). This is in agreement with previous reports2 that con-
sider moderate amount of alcohol consumption as another
characteristic component of the MeDi. We classified alcohol
consumption dichotomously, also because of the skewed dis-
tribution of alcohol in our population (68% reporting no
alcohol intake, 31% reporting less than 30 g/day [mild to
moderate intake], and 1% reporting 30 g/day [heavy in-
take]). The MeDi score was generated for each participant
by adding the scores in the food categories (theoretically
ranging from 0 to 9) with higher score indicating higher ad-
herence to the MeDi.

In two previous publications, using a subset of subjects
with repeated 2-4 dietary assessments over a course of about 8
(and up to 13) years, we demonstrated that adherence to the
MeDi is remarkably stable over time.3,4 Therefore, we con-
sidered that the MeDi adherence reported at baseline evalua-
tion for our prevalent AD population reflects their dietary
habits since clinical disease onset.

Covariates.
Age (years), education (years), caloric intake
(kcal), and body mass index (BMI; weight divided by height
[kg/m2])17 were used as continuous variables. We also con-
sidered period of recruitment (1992 cohort as reference), gen-
der (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.12
Ethnicity was used as a dummy variable with white (non-
Hispanic) as the reference. APOE genotype was used dichot-
omously: absence of 4 allele vs presence of either one or two
4 alleles.

Outcomes.
Mortality was tracked through follow-up in-
terviews every 18 months and through submission of identi-
fying information for subjects reported to be dead or lost to
follow-up to the National Death Index.

Statistical analyses.

Characteristics of patients by mortal-
ity and by MeDi tertiles were compared using t test or analy-
sis of variance for continuous variables and 2 test for
categorical variables.

We calculated a basic Cox proportional hazards models
with mortality as the dichotomous outcome. The time-to-
event variable was time from baseline evaluation to death;
persons who did not die were censored at the time of their
last follow-up. MeDi score (from the baseline visit) was the
main predictor (in a continuous form initially and in tertile
form for trend test calculation subsequently). In subsequent
Cox models we simultaneously adjusted for the following
variables: period of recruitment, age at recruitment in the
study, gender, ethnicity, education, APOE, smoking, caloric
intake, and BMI.

We then constructed a series of supplementary models.
Despite having demonstrated stability of adherence to the
MeDi, it is always possible that subjects’ dietary habits are
affected by progressing disease. It is also possible that dietary
information collected from AD patients may be subject to
decreased accuracy because of poor recall. To further ex-
plore the contribution of these factors to our results, we con-
structed four additional exploratory models. First, we
repeated the above analyses excluding AD patients with
CDR > 1 (n = 18). Second, we included baseline cognitive
performance (in the form of a composite standard z score
calculated using 12 neuropsychological tests from the admin-
istered battery11 [details previously published]4,18]) as a co-
variate. Third, we excluded a subset of subjects whose
dietary assessment was more than 1 year after baseline cog-
nitive assessment (n = 34). Fourth, we recalculated the
modes in a subset of incident AD patients (i.e., subjects who
were nondemented when they were first included in the
study and had their dietary evaluation and who developed
AD during follow-up). In other supplementary analyses, we
included only subjects who were diagnosed as having AD
with stroke (n = 61) using only AD without stroke as our
population. In additional models we included as covariates
baseline cardiovascular risk factors including diabetes, hy-
pertension, and heart disease, as defined in our previous
work.3 In brief, these covariates were defined by self-report
or by the use of disease-specific medications and they have
been shown to be reliable, sensitive, and specific in our study
using medical records as the gold standard.3,19


RESULTS

Missing data analyses.

The main reason
why patients with prevalent AD were missing di-
etary information was the fact that dietary assess-
ment was not fully implemented since the
beginning of the WHICAP but was added as a
standard part of the evaluation after initiation of
the study: 189 of 256 (74%) subjects with missing
dietary information were recruited in the 1992 co-
hort, but only 67 of 256 (26%) in the 1999 cohort
(p = 0.001). Mostly due to their earlier recruit-
ment in the study, subjects with missing dietary
information (n = 256) compared with subjects
with available dietary information (n = 215) had
also higher mortality (70 vs 33%; p = 0.001). Ad-
ditionally, they had lower baseline cognitive per-
formance (composite z score 1.33 vs -1.16; p =
0.004), and they were less likely to be smokers (3
vs 8%; p = 0.01) and hypertensive (55 vs 65%;
p = 0.05). There were no significant differences
between subjects with missing and those with
available dietary information in gender, age,
ethnicity, education, APOE genotype, BMI,
history of diabetes, or heart disease.

Given that the study is still ongoing, subjects
with missing follow-up (n = 20) as compared
with subjects with available follow-up (n = 192)
were more likely to belong to the 1999 cohort (80
vs 56%; p = 0.04). They were less likely to be
whites and more likely to belong to other ethnici-
ties (white 5%, black 35%, Hispanic 55%, other
5% vs white 9%, black 33%, Hispanic 58%,
other 0%; p = 0.02) and experienced less heart
disease (5 vs 24%; p = 0.05). There were no sig-
nificant differences between subjects with missing
and those with available follow-up in gender, age,
education, BMI, caloric intake, APOE genotype,
baseline cognitive function, smoking status, his-
tory of diabetes, and hypertension. Most impor-
tant, there was no difference in MeDi score (4.1 vs
3.8; p = 0.37).

Clinical -- demographic -- dietary characteristics.

Compared with AD patients who remained alive,
AD patients who died did not differ in any clini-
cal- demographic characteristic, with the excep-
tion of being older and having lower MeDi scores
(table 1). There was no association between
MeDi score and any clinical- demographic char-
acteristic (table 2).

MeDi and mortality.

AD patients were followed
for 4.4 years (SD 3.6; range 0.2 to 13.6). Mean
survival was 7.55 years (95% CI 6.73 to 8.37).
Higher adherence to the MeDi was associated
with significantly lower mortality risk (table 3
and figure 2). The results were similar in adjusted
and unadjusted models (table 3, models 1 and 2).
Each additional unit of the MeDi score was asso-
ciated with 21 to 24% lower risk of death. In un-
adjusted models, compared with AD patients in
the lowest MeDi tertile (low adherence to the
MeDi; mean survival 6.59 [5.53 to 7.66] years),
AD patients in the middle MeDi score tertile had
29% lower risk of death (mean survival 7.92 [6.60
to 9.24] years), whereas those at the highest tertile
(high adherence to the MeDi) had 67% lower
mortality risk (mean survival 10.50 [8.08 to 12.92]
years), with a significant a trend for a dose-
response effect. Adjustment for all potential co-
variates made the associations even stronger:
35% less risk for the middle and 73% less mortal-
ity risk for the highest MeDi tertile.

Supplementary analyses.

The majority of our sub-
jects were of nonwhite ethnicity. Excluding the
white subjects and repeating the analyses in black
and Hispanic AD patients only did not change the
associations (unadjusted models, HR 0.79; 0.67 to
0.92; p = 0.002; tertile analyses p for trend =
0.01; adjusted models, HR 0.78; 0.66 to 0.91; p =
0.002; tertile analyses p for trend 0.004).

In models excluding AD patients with baseline
CDR > 1 (remaining in the analyses n = 174, 73
death events), higher adherence to the MeDi was
associated with lower mortality risk in both un-
adjusted (HR 0.78; 0.67 to 0.91; p = 0.001; tertile
analyses p for trend 0.02) and adjusted models
(HR 0.78; 0.66 to 0.92; p = 0.003; tertile analyses
p for trend = 0.013).

Adding baseline cognitive performance as a
covariate in the adjusted models did not change
the associations (HR 0.78; 0.67 to 0.92; p = 0.003;
tertile analyses p for trend = 0.005).

When including only AD patients whose di-
etary assessment was performed not later than 1
year after the baseline cognitive assessment (n =
158, 74 death events), the associations between
MeDi and mortality remained strong in both un-
adjusted (HR, 0.77; 0.66 to 0.90; p = 0.001; tertile
analyses p for trend = 0.01) and adjusted analyses
(HR, 0.73; 0.61 to 0.88; p = 0.001; tertile analyses
p for trend = 0.006).

When the analyses were performed in a sepa-
rate sample of incident AD patients (n = 288, 106
death events), the associations between MeDi and
mortality were again significant: adjusted analy-
ses (HR, 0.83; 0.72 to 0.96; p = 0.014; tertile anal-
yses p for trend = 0.022).

When the models were run including only
probable prevalent AD without stroke patients
(n = 131; 61 death events), the associations were
unchanged (HR, 0.72; 0.60 to 0.86; p = 0.001;
tertile analyses p for trend = 0.005). Adjusted
models produced even stronger associations (OR,
0.62; 0.50 to 0.76; p = 0.001; tertile analyses p for
trend = 0.001).

Finally, in adjusted models additionally in-
cluding terms for cardiovascular risk factors (dia-
betes, hypertension, heart disease), the
associations between MeDi adherence and mor-
tality were again unchanged (HR, 0.77; 0.65 to
0.91; p = 0.002; tertile analyses p for trend =
0.005).


DISCUSSION

In our previous work we reported
that higher adherence to the MeDi seems to re-
duce risk for getting AD.3,4 According to the cur-
rent analyses, MeDi seems to affect subsequent
AD course too. We found that higher adherence
to the MeDi was associated with lower mortality
in AD. We noted a gradual reduction in mortality
risk for higher MeDi adherence tertiles, which
suggests a possible dose-response effect. The
magnitude of the effect was considerable: As
compared with subjects in the lowest MeDi ad-
herence tertile, those in the medium MeDi adher-
ence were 29 to 35% less likely to die, whereas
those at the highest MeDi adherence tertile had a
67 to 73% reduction in mortality. Translating it
into mean survival times, as compared with sub-
jects in the lowest MeDi adherence tertile, those
in the medium MeDi adherence lived 1.33 years
longer, whereas those at the highest MeDi adher-
ence tertile had a longer survival of 3.91 years.

Previous large general population studies indi-
cated that the MeDi seems to protect from death
from any cause.2,5,6 To our knowledge, no previ-
ous studies have investigated the effect of either
dietary habits in general or of MeDi in particular
regarding mortality risk in AD patients. In previ-
ous studies (either observational epidemiologic or
interventional- clinical trials), higher adherence
to the MeDi has been associated with reduced
cardiac mortality2, 6, 20, 21 and reduced mortality
from cancer.2 At the same time, medical comor-
bidities and in particular cardiovascular disease
have been reported as predictors of mortality in
dementia.22-26 We have not been able to investi-
gate disease-specific mortality in this study. How-
ever, we attempted to partially address this issue
by considering only subjects with probable AD
(i.e., excluding AD patients with coexisting
stroke) in the analyses and by adjusting for pres-
ence of baseline cardiovascular risk factors. The
associations between MeDi and mortality re-
mained unchanged.

The protection from mortality was present de-
spite controlling for multiple other potential con-
founders. Weight loss in dementia and AD has
been well documented.27-33 BMI 23 has been re-
lated to reduced 7-year survival of demented pa-
tients in one study.34 In another one, weight loss
5% per year was a predictor of mortality
among subjects with AD, whereas weight gain ap-
peared to have a protective effect.27 In a prospec-
tive community study of patients with AD,
presence of cachexia was associated with in-
creased mortality,35 and in another study malnu-
trition has been related to worse survival.26 In our
study, there were no BMI differences for different
MeDi adherence degrees. Additionally, the asso-
ciation between MeDi and AD mortality persisted
despite controlling for BMI.

Older age has been associated with worse sur-
vival in multiple studies.25,26,36-44 Many studies
have reported shorter survival for men with de-
mentia as compared with women.42,45-48 Regard-
ing ethnic differences, the literature is mixed, with
some studies finding higher mortality for Cauca-
sians with AD26,49 and some others reporting no
race differences.36,39,50 Higher education has been
associated with faster rates of cognitive decline18
and increased mortality38 in patients with AD. In
our data we detected no association between
MeDi adherence and either gender or ethnicity or
education, while the associations with age were
borderline nonsignificant. Most important, the
association between MeDi and AD mortality per-
sisted despite controlling for all the above
characteristics.

The APOE genotype has been related to mor-
tality in the general population,51-53 although this
effect may vary for different ethnicities.51 In AD,
the APOE genotype has been shown to relate to
clinical54-56 and physiologic57-59 heterogeneity, but
its relation to mortality has been debat-
able.52,56,60,61 Because of the above, we considered
the APOE genotype in our analyses, but we de-
tected no differences in MeDi adherence between
4 carriers and noncarriers and no modification
of the MeDi-mortality association when adjust-
ing for APOE genotype.

Our study was conducted in a multiethnic ur-
ban cohort of New York City, which is unlikely
to strictly consume foods typical of Mediterra-
nean countries. Therefore, “true MeDi” adher-
ence in our population may be significantly lower
as compared with Mediterranean populations,
and subjects with high MeDi adherence in New
York may be potentially categorized as low MeDi
adherence subjects if viewed in comparison with
Mediterranean populations. This neither invali-
dates nor minimizes the significance of our find-
ing because 1) transferability of the MeDi
mortality advantages to other populations has
been clearly demonstrated in multiple previous
studies,6,62,63 and 2) there exists variability in
MeDi adherence not only within our population
but also within Mediterranean populations too.2
Therefore, the mortality risk for AD patients in
New York with somehow higher MeDi adherence
in comparison with AD patients in New York
who are even further away from MeDi principles
could be still lower. Given the known heterogene-
ity in diets across the globe, we fully realize that
not all diets will fit the “true MeDi,” but if we can
identify those dietary habits that protect against
AD mortality, we have made an important step in
public health.

This study has limitations. The use of an a pri-
ori distribution-derived MeDi score assumes un-
derlying monotonic effects, does not address
possible thresholds or the shape of the underlying
curve, and weighs equally the underlying indi-
vidual food categories, which in turn are com-
posed of different number of food constituents.
Frequencies of food intake are based on rela-
tively few diet constituents, which may under-
estimate the overall quantity of food in each
f ood category, and a common limitation of
studies of diet and disease is misclassification
of exposure due to limited accuracy. However,
assuming that the measurement error was ran-
dom, our results may actually underestimate
the association between high MeDi adherence
and lower AD mortality.

Despite the use of standard criteria, the diag-
nostic expertise of our center, and the thorough
workup, there is always the possibility of disease
misclassification bias.64 As compared with sub-
jects included in the current analyses, subjects
with missing dietary information had higher mor-
tality and lower baseline cognitive performance
and were more likely nonsmokers and normoten-
sive. Higher mortality for subjects without di-
etary assessments reflects to a certain degree
earlier recruitment in the study as dietary pro-
cedures were not implemented from the begin-
ning of the 1992 cohort. However, we cannot
completely exclude the possibility of bias due to
attrition. Lower baseline cognitive perfor -
mance may predispose to shorter survival, but
nonsmoking status and normotension may pre-
dispose to longer one. Additionally, neither
baseline cognition nor smoking status nor hy-
pertensi on was associ ated wi th MeDi adher-
ence in these patients with prevalent AD with
available dietary assessments. We also included
all these covariates in the adjusted models. Pa-
tients with AD with missing follow-up were
few. They were mostly nonwhites with lower
prevalence of heart disease. We detected no as-
sociation between any of the above factors and
MeDi adherence, and we considered all of them
i n the adj usted anal yses. Overal l , we cannot
completely exclude (although it does not seem
very likely) that our results could be explained
by biases related to either missing dietary infor-
mation or to loss from follow-up.

It is possible that diet is related to socioeco-
nomic status or to other habits or characteristics
related to better health and a lower risk for AD
mortality. For the AD patients included in our
study, MeDi was not related to vascular comor-
bidities, education, smoking, or ethnicity. We ad-
dressed this potential bias by also adjusting for all
the above variables, but we cannot completely
rule out residual confounding as an explanation
for our findings.

It has been noted that dietary habits may
change in AD.65-67 At the same time, better cogni-
tive performance at baseline has been associated
with longer AD survival.22-25,68-73 Therefore, an-
other explanation for our findings is that differen-
tial adherence to the MeDi could be an indirect
index of AD severity. A closely related issue is the
potential inaccuracies in dietary reports by sub-
jects with cognitive problems such as the patients
with AD in this study. This may increase the over-
all dietary measurement error (which may actu-
ally bias the results toward the null), but there is
no obvious reason to suggest that it may lead to
misclassification bias (i.e., AD patients with
longer future survival reporting “healthier” di-
etary habits). However, because we cannot com-
pletely exclude the above possibilities, we
addressed them in several ways. First, we have
previously reported stability in MeDi scores over
intervals greater than 7 years for subjects with
multiple dietary assessments who were not de-
mented at baseline but developed AD during
follow-up.3,4 Additionally, we have reported simi-
lar stability for MeDi adherence even for subjects
without dementia.4 Second, when excluding sub-
jects whose dietary assessments took place long
after baseline cognitive assessment- diagnosis, the
associations between MeDi and mortality were
unchanged. Third, MeDi adherence was not re-
lated to baseline cognitive performance in this
population. Fourth, when we adjusted for base-
line cognitive performance, the associations were
unchanged. Fifth, when we included in our analy-
ses only patients at the early stages of AD (CDR
not greater than 1), the associations were again
unchanged. Si xt h, t he as s oci at i ons bet ween
MeDi and mortality were present in a separate
sample of AD patients, for whom the dietary
quest i onnai re was admi ni st ered years bef ore
clinical AD incidence, when they were cogni-
tively nondemented.

The noted associations between MeDi and
mortality are based on relatively small sample
sizes, including small number of death events and
relatively short follow-up. Although we repli-
cated the associations in a separate sample of inci-
dent AD patients, independent confirmation of
our findings in other studies is necessary. It
should be also noted that the vast majority of our
population is Hispanics and blacks and inferences
regarding similar effects in whites may be limited.
Last, we could not account for possible differ-
ences in end-of-life care, such as the use of artifi-
cial feeding or antibiotic therapy. However,
despite some reports suggesting possible protec-
tive effect for such interventions,74 their effective-
ness has been questioned by multiple studies.74-76
Additionally there is no obvious reason to suggest
that differential MeDi adherence would be re-
lated to differential utilization of such end-of-life
measures.

Confidence in our findings is strengthened by
the following factors. Dietary data were collected
with a previously validated and used widely in ep-
idemiologic studies instrument.15 We used an a
priori developed dietary pattern.1,2 Measures for
multiple potential mortality risk factors have
been carefully recorded and adjusted for in the
analyses. The diagnosis of AD took place in a uni-
versity hospital with expertise in dementia and
was based on comprehensive assessment and
standard research criteria. The study is commu-
nity based, and the population is multiethnic.


Received November 21, 2006. Accepted in final form April 9,
2007.


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