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Caloric Intake and the Risk of Alzheimer Disease
Jose A. Luchsinger, MD;
Ming-Xing Tang, PhD;
Steven Shea, MD;
Richard Mayeux, MD
Arch Neurol. 2002;59:1258-1263.
ABSTRACT
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Background Diet may play a role in Alzheimer disease (AD).
Objective To examine the association between caloric intake and AD.
Methods Elderly individuals free of dementia at baseline (N = 980) were followed
for a mean of 4 years. Daily intake of calories, carbohydrates, fats, and
protein were recalled using a semiquantitative food frequency questionnaire
administered between the baseline and first follow-up visits. Proportional
hazards models were used to examine the associations of quartiles of intake
and incident AD, adjusting for confounders.
Results There were 242 incident cases of AD during 4023 years of follow-up (6
cases per 100 person-years). Compared with individuals in the lowest quartile
of caloric intake, those in the highest quartile had an increased risk of
AD (hazard ratio, 1.5; 95% confidence interval [CI], 1.0-2.2). Among individuals
with the apolipoprotein E  4 allele, the hazard ratios of AD for the
highest quartiles of calorie and fat intake were 2.3 (95% CI, 1.1-4.7) and
2.3 (95% CI, 1.1-4.9), respectively, compared with the lowest quartiles. The
hazard ratios of AD for the highest quartiles of calorie and fat intake compared
with the lowest quartiles in individuals without the apolipoprotein E 4
allele were close to 1 and were not statistically significant (P = .83 and P = .61, respectively).
Conclusion Higher intake of calories and fats may be associated with higher risk
of AD in individuals carrying the apolipoprotein E 4 allele.
INTRODUCTION
CALORIC INTAKE has been shown to affect aging in animals and possibly
in humans.1 Caloric restriction in mice and
rats increases average and maximum life span,2
presumably through decreased oxidative damage.3
The balance of macronutrients in the diet may also affect oxidative stress
unrelated to total caloric intake,4 which in
turn may be involved in the pathogenesis of Alzheimer disease (AD).5 The generation of reactive oxygen species increases
the damage related to deposition of amyloid ß in the brain through at
least 3 potential mechanisms: protein oxidation, DNA oxidation, and lipid
peroxidation.5 It is, therefore, possible that
dietary factors that decrease oxidative stress would lower AD risk.
Studies6-7 examining the
association between caloric intake and cognition in animals have conflicting
findings. Patients with dementia increase their caloric intake and change
their food choice,8-9 eating less
protein and more sweets than individuals without dementia.8, 10
The relation between caloric intake and AD could have important public health
implications. Our objective was to examine the association between total calorie
and macronutrient intake in relation to the risk of AD.
PARTICIPANTS AND METHODS
STUDY PARTICIPANTS
Participants were enrolled in the Washington Heights–Inwood Columbia
Aging Project cohort by random sampling of healthy Medicare beneficiaries
65 years or older residing in a geographically defined area of northern Manhattan,
NY.11 At entry, each individual underwent a
structured in-person interview, including an assessment of health and function,
a standard medical history, physical and neurological examinations, and a
neuropsychological battery.12 Participants
were recruited between 1991 and 1996 and were followed annually, with the
baseline examination repeated at each follow-up. Individuals who completed
at least 1 year of follow-up were included in the analysis. A food frequency
questionnaire was completed by 1422 individuals between the baseline and first
follow-up examinations. Of these 1422 individuals, 230 were excluded owing
to prevalent dementia, 210 owing to loss to follow-up, and 2 because of missing
data for macronutrient intake. Thus, the analytic sample comprised 980 individuals.
This study was approved by the institutional review board of Columbia-Presbyterian
Medical Center, New York.
DIAGNOSIS OF DEMENTIA AND COGNITIVE IMPAIRMENT
A group of neurologists, psychiatrists, and neuropsychologists reviewed
data gathered at the initial and follow-up visits. By consensus, diagnosis
of dementia was made based on Diagnostic and Statistical
Manual of Mental Disorders, Fourth Edition, criteria13
and required evidence of cognitive decline on the neuropsychological test
battery and evidence of impairment in social or occupational function (Clinical
Dementia Rating  0.5).14 This excluded individuals
who might have had prevalent dementia at baseline that was mild enough not
to be detected, possibly biasing the results of the study. Diagnosis of AD
was based on the National Institute of Neurological and Cognitive Disorders
and Stroke–Alzheimer's Disease and Related Disorders Association criteria.15 These criteria and diagnostic methods have been used
extensively in the analysis of data in this cohort.16-17
DIETARY DATA
Dietary data were obtained using a 61-item version of the semiquantitative
food frequency questionnaire (Channing Laboratory, Cambridge, Mass) of Willett
et al.18 The semiquantitative food frequency
questionnaire was administered by telephone between the baseline and first
follow-up examinations by trained interviewers in English or Spanish. Total
caloric intake was measured in kilocalories per day. Intakes of macronutrients—carbohydrates,
fats, and protein—were measured in grams per day and were adjusted for
total caloric intake as recommended by Willett19
by calculating the residuals from linear regression models (nutrient intake
regressed on total caloric intake using transformed values for nutrients and
calories) and adding a constant (mean nutrient intake). Square root transformation
was used for total calories, carbohydrates, fats, and protein. Semiquantitative
food frequency questionnaires have been used and validated for the determination
of nutrient intake in the elderly.20-28
The validity of the questionnaire used in this study was assessed in a subsample
of 78 individuals using two 7-day food records as the criterion. The intraclass
correlations for energy-adjusted nutrients were 0.30 for total calories, 0.28
for carbohydrates, 0.41 for fats, and 0.33 for protein, based on energy-adjusted
nutrient intakes (Maliha Siddiqui, MS, MPH, written communication, December
7, 2000).
DEFINITIONS OF COVARIATES
Ethnic group was based on self-report using the format of the 1990 census.29 Individuals were also asked whether they were of
Hispanic origin. Participants were then assigned to 1 of 3 groups: black (non-Hispanic),
Hispanic, or white (non-Hispanic). Data on years of education were obtained
by self-report. Apolipoprotein E (APOE) genotyping was obtained by amplification
of genomic DNA with polymerase chain reaction subjected to CfoI restriction analysis using APOE primers and conditions similar
to those described by Hixson and Vernier.30
Participants were classified as positive for the APOE 4 allele genotype
if they had 1 or 2 4 alleles.
DATA ANALYSIS
Participants were grouped by the 2 highest vs 2 lowest quartiles of
caloric and macronutrient intake and were compared with respect to sex and
APOE 4 status using  2 tests. T
tests (2 sample) were used to compare mean age and number of years of education.
Proportional hazards regression was used for multivariate analyses, with the
time-to-event variable in the models specified as the time from baseline examination
to onset of AD. In light of the association reported between education and
macronutrient intake,31 the final model was
stratified by number of years of education. Calorie and macronutrient intakes
were categorized as quartiles and were included in the multivariate models
as dummy variables, using the lowest quartile of intake as the reference.
Dietary intakes and other covariates were treated as baseline time constant
covariates. Trend tests were conducted using Cox proportional hazards regression,
with each dietary intake variable categorized into quartiles of intake; the P value for the coefficient of the dietary intake variable
was used as the P value for the trend test.32 We also conducted additional analyses stratifying
by the presence of the APOE 4 allele. Statistical software (SAS Version
7 for Windows; SAS Institute Inc, Cary, NC) was used for all analyses. Data
are given as mean ± SD.
RESULTS
The mean age of the sample was 75.3 ± 5.8 years, and 67% were
women, 25% were white, 43% were Hispanic, and 32% were black. The median number
of years of education was 9. Twenty-eight percent of the cohort were homozygous
or heterozygous for the APOE 4 allele, 16% were current smokers, and
33% were former smokers. There were 242 cases of incident AD during 4023 person-years
of observation (6 cases per 100 person-years). The mean duration of observation
was 4.0 ± 1.5 years.
The mean reported intake of total calories was 1267 ± 453 kcal/d
(1186 ± 437 kcal/d in women and 1316 ± 469 kcal/d in men; P<.001). The mean daily intake of fats was 38 ±
19 g; protein, 60 ± 22 g; and carbohydrates, 176 ± 67 g. There
were more women in the 2 lowest quartiles of caloric intake. Individuals in
the 2 highest quartiles of caloric intake were older and had more years of
education than those in the 2 lowest quartiles (Table 1).
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Table 1. Comparison of Characteristics Between Individuals in the 2
Lowest and 2 Highest Quartiles of Daily Total Calorie and Macronutrient Intake,
Washington Heights–Inwood Columbia Aging Project, New York, NY, 1991-1996
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Compared with the lowest quartile, the hazard ratio (HR) of AD for the
highest quartile of caloric intake was 1.5 (95% confidence interval [CI],
1.0-2.2; P = .06 for trend) (Table 2). Compared with the lowest quartile, the HR of AD was 1.4
(95% CI, 0.9-2.1) for the highest quartile of calorie-adjusted fat intake,
and the trend was not significant (Table
3). The HR of AD for the highest quartile of intake of carbohydrates
was 0.8 (95% CI, 0.5-1.1; P = .08 for trend), and
the HR of protein intake was 1.1 (95% CI, 0.7-1.5; P
= .88 for trend) compared with the lowest quartile (Table 3).
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Table 2. Hazards Ratios of Alzheimer Disease for Individuals in Each
Quartile of Total Daily Calorie Intake Using the Lowest Quartile as a Reference*
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Table 3. Hazard Ratios of Alzheimer Disease for Individuals in Each
Quartile of Daily Macronutrient Intake Using the Lowest Quartile as a Reference*
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We also examined the association between the type of fat and AD. Compared
with the lowest quartiles, the HR of AD for the fourth quartile of saturated
fat intake was 1.3 (95% CI, 0.9-1.9; P = .08 for
trend); monounsaturated fat intake, 1.6 (95% CI, 1.0-2.4; P = .17 for trend); and polyunsaturated fats, 0.9 (95% CI, 0.6-1.4; P = .87 for trend).
We examined whether the association between total calories and AD risk
was modified by the presence of APOE 4. The increased risk of AD in
the highest quartile of calorie intake and the highest quartile of calorie-adjusted
fat intake compared with that of individuals in the lowest quartile was limited
to the 263 individuals who were homozygous or heterozygous for the APOE 4
allele (Table 4). The HRs of AD
for the highest quartiles of calorie and fat intake were 2.3 (95% CI, 1.1-4.7; P = .07 for trend) and 2.3 (95% CI, 1.1-4.9; P = .02 for trend), respectively. Stratified analyses by APOE 4
allele status of the relation between fat types and AD, carbohydrates and
AD, and protein and AD did not show appreciable differences in HRs and were
not statistically significant. The association between calories and fats and
AD did not change by including stroke in the models. In models adjusting for
stroke, the HRs of AD in individuals in the highest quartile were 2.30 (95%
CI, 1.12-4.75; P = .05 for trend) for calorie intake
and 2.24 (95% CI, 1.05-4.81; P = .02 for trend) for
fat intake compared with individuals in the lowest quartiles.
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Table 4. Adjusted Hazard Ratios of Alzheimer Disease per Quartile of
Daily Calorie Intake and per Quartile of Fat Intake by Apolipoprotein E (APOE) 4
Status*
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COMMENT
Our analyses of 242 cases of incident AD in 4023 person-years of observation
with 4 years of follow-up (6 cases per 100 person-years) revealed that the
risk of AD is associated with higher total calorie intake and fat intake in
individuals homozygous or heterozygous for the APOE 4 allele. In individuals
without the APOE 4 allele, calorie and fat intake were not associated
with risk of AD.
Rodents under caloric restriction perform better in tests of cognitive
performance compared with rats fed ad libitum.33-35
Moreover, caloric restriction is related to neuronal protection in rat models
of AD.36-37 Rats with increased
saturated fatty acid intake have impairment on tests of cognitive performance
compared with rats with low intakes,7 presumably
because of a deleterious effect of saturated fatty acids on the metabolism
of amyloid ß. The main effect of caloric restriction on aging may be
a decrease in oxidative damage.3 Experimental
evidence5, 38-39 suggests
that accumulation of amyloid ß protein generates reactive oxygen species
that are toxic to neurons. Oxidative stress has also been shown to promote
the intracellular accumulation of amyloid ß protein by enhancement of
the amyloidogenic pathway.40 The relation between
total caloric intake and intake of specific macronutrients and AD could be
mediated through oxidative stress and its effect on amyloid ß deposition.
Diets higher in carbohydrates, particularly complex carbohydrates, fruits,
and vegetables and lower in saturated fats exert a lower oxidative burden
on the organism than high-calorie, high-fat diets.4
Calorie restriction may also decrease neuronal death and increase expression
of neurotrophic factors in the brain.41 Reduced
caloric intake can increase the brain's capacity for plasticity and repair
in neurodegenerative disorders, including AD.42
Individuals with dementia increase their caloric intake and change their
food choices,8 eating less protein and more
sweets than controls without dementia.10 A
1-year follow-up study9 found a significantly
higher energy intake in patients with AD compared with controls. Higher intake
of complex carbohydrates, fruits, and vegetables and lower intake of saturated
fat were associated with better cognition, as measured by the Mini-Mental
State Examination.43 However, another study44 reported that macronutrient intake is of little importance
in the worsening cognition related to aging. Kalmijn et al45
reported a higher risk of incident AD with higher intake of total fat in more
than 5000 individuals 55 years and older without dementia at baseline followed
for 2 years. We report similar results in 980 individuals 65 years and older
without dementia at baseline followed for 4 years.
Apolipoprotein E 4 is a predictor of the development of AD.46 The mechanism for the effect of APOE 4 on the
risk of AD is not clear, but it probably involves an increase in the deposition
of amyloid ß in the brain.46 The interaction
between APOE 4 and other potential risk factors for AD is not well understood.
The study of the interaction between diet and genes is a relatively new area
of research, and several studies have shown that lipid profiles respond differently
to dietary interventions when individuals with and without the APOE 4
allele are compared.47 Serum low-density lipoprotein
levels are higher in alcohol drinkers with the APOE 4 allele compared
with carriers of the APOE 2 allele,48
and the correlation between intake of saturated fats and low-density lipoprotein
level is higher in carriers of APOE 449
compared with individuals without the allele. One50
study reported that middle-aged carriers of APOE 4 who consumed a high-fat
diet had a greater risk of developing AD compared with individuals without
the allele. These findings suggest that the impact of nutrient intake, particularly
fats, is modified by the presence of the APOE 4 allele, and it is possible
that the presence of the APOE 4 allele modifies the effect of high calorie
and fat intake on amyloid ß metabolism, consistent with our observation
of an increased risk of AD with higher intake of fats and calories confined
to APOE 4 carriers. It seems reasonable to assume that the deleterious
effects of high calorie and fat intake (or the protective effects of low calorie
and fat intake) would be more prominent in individuals most susceptible to
developing AD. The mechanisms underlying this interaction need further investigation.
Individuals with the highest intake of calories and fats may have been
in the preclinical stage of dementia at baseline. Increased energy intake
has been reported in individuals with AD, making this explanation possible.8-9 However, all individuals with cognitive
impairments and even mild impairment of function were excluded, making it
unlikely. The mean time from beginning of observation to diagnosis of dementia
was 3.4 ± 1.4 years (interquartile range, 2.1-4.9 years). In our cohort,
a prodromal change in dietary habits would have had to precede the diagnosis
of AD by 2 years in most cases to bias our findings.
It is also possible that known risk factors for dementia were associated
with caloric and macronutrient intake in such a way that our results were
explained by confounding. Lower education has been reported to be associated
with higher caloric intake and a higher intake of saturated fats.31 However, we adjusted all our models by years of education
and other known risk factors for dementia, and in most cases there was no
appreciable change between HRs. The relationship between macronutrients and
AD may not be specific and may reflect the association between caloric intake
and AD. Intake of carbohydrates was inversely related to fat intake. Because
increased fat intake would be expected to be associated with higher caloric
intake, the association between fat intake and AD would parallel the association
between calorie intake and AD. All measures of macronutrient intake were adjusted
for calories and were uncorrelated with total calorie intake. Thus, our findings
of relations between macronutrients and AD are intended to be independent
of caloric intake, and, if causal, they would reflect the specific effects
of each macronutrient. The relationship between macronutrient intake and disease
is not well understood, and we must also consider the possibility of unmeasured
confounders.
Our study has several strengths. The main purpose of the Washington
Heights–Inwood Columbia Aging Project was the longitudinal study of
dementia and determination of its risk factors, and all measurements were
made prospectively with that intention. The determination of dementia was
made in a standardized fashion according to widely accepted criteria. In addition,
measures were available for other established risk factors for AD, including
education and APOE 4 status.
The main limitation of our study pertains to the measure of nutrient
intake. The food frequency questionnaire is a measure of habitual intake during
1 year and does not account for day-to-day variation or for longer-term periods
of intake. The measures obtained from the semiquantitative food frequency
questionnaire may not have enough precision to make inferences about absolute
levels of nutrient intake as related to the occurrence of disease. The results
of this study should be interpreted in terms of the relation between ranks
of intake of nutrients (higher or lower) and incident AD rather than in terms
of the absolute values in the quartiles of intake we defined. Elderly men
and women have been shown to consistently underreport caloric intake,51 and this may account for the apparently low caloric
intakes that we report. However, to the extent that this measurement error
is random (ie, not related to AD incidence or to covariates used to adjust
the multivariate risk for AD), this would reduce statistical power and bias
the magnitude of the observed effects toward the null.32
However, there may be other reasons for the reported low caloric intakes.
Food intake decreases with age for reasons that are unclear.52-53
The responsiveness of energy expenditure to negative energy balance is attenuated
in old age,54 suggesting that energy regulation
is disregulated in old age, making such low intakes possible. Dietary intake
has been reported to decrease 1000 to 1200 kcal in men and 600 to 800 kcal
in women,55 which would make the reported intakes
plausible.
Higher intake of total calories and fats in elderly individuals without
dementia is associated with higher risk of AD in carriers of the APOE 4
allele. There is no association between calorie and fat intake and AD in noncarriers
of APOE 4. Our findings indirectly support the theory that caloric restriction
modifies aging-related conditions in humans and also suggest the possibility
of modifying the risk of AD with caloric restriction and low-fat diets in
susceptible individuals.
AUTHOR INFORMATION
Accepted for publication March 19, 2002.
Author contributions: Study concept and design (Drs Luchsinger, Shea, and Mayeux); acquisition of data (Drs Tang and Mayeux); analysis and interpretation of data (Drs Luchsinger, Tang, and Mayeux); drafting of the manuscript (Drs Luchsinger and Mayeux); critical revision of the manuscript
for important intellectual content (Drs Luchsinger, Tang,
Shea, and Mayeux); statistical expertise (Dr Tang); obtained funding (Drs Luchsinger and Mayeux);
administrative, technical, and material support (Dr Mayeux); study supervision (Drs Shea and Mayeux).
This study was supported by grants AG07232 and AG07702 from the National
Institute of Aging, Bethesda, Md; and the Charles S. Robertson Memorial Gift
for research on AD, the Blanchette Hooker Rockefeller Foundation, and the
New York City Council Speaker's Fund for Public Health Research, New York,
NY.
Corresponding author and reprints: Richard Mayeux, MD, Gertrude H.
Sergievsky Center, Columbia University, PH-19, 630 W 168th St, New York, NY
10032 (e-mail: rpm2{at}columbia.edu).
From the Taub Institute for Research of Alzheimer's Disease and the
Aging Brain (Drs Luchsinger, Tang, and Mayeux), the Divisions of Biostatistics
(Dr Tang) and Epidemiology (Drs Shea and Mayeux), Joseph P. Mailman School
of Public Health, and the Gertrude H. Sergievsky Center (Dr Mayeux), Columbia
University, the Division of General Medicine, Department of Medicine (Drs
Luchsinger and Shea), and the Departments of Neurology (Dr Mayeux) and Psychiatry
(Dr Mayeux), Columbia University College of Physicians and Surgeons, New York,
NY.
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