Tessier 2024 Oi 240363 1714140452.68651

Original Investigation | Nutrition, Obesity, and Exercise
Consumption of Olive Oil and Diet Quality and Risk of Dementia-Related Death
Anne-Julie Tessier, PhD; Marianna Cortese, PhD; Changzheng Yuan, ScD; Kjetil Bjornevik, PhD; Alberto Ascherio, DrPH; Daniel D. Wang, MD, ScD; Jorge E. Chavarro, ScD;
Meir J. Stampfer, DrPH; Frank B. Hu, PhD; Walter C. Willett, DrPH; Marta Guasch-Ferré, PhD
Abstract Key Points

Question Is the long-term consumption
IMPORTANCE Age-standardized dementia mortality rates are on the rise. Whether long-term
of olive oil associated with dementia-
consumption of olive oil and diet quality are associated with dementia-related death is unknown.
related death risk?
OBJECTIVE To examine the association of olive oil intake with the subsequent risk of dementia- Findings In a prospective cohort study
related death and assess the joint association with diet quality and substitution for other fats. of 92 383 adults observed over 28 years,
the consumption of more than 7 g/d of
DESIGN, SETTING, AND PARTICIPANTS This prospective cohort study examined data from the olive oil was associated with a 28%
Nurses’ Health Study (NHS; 1990-2018) and Health Professionals Follow-Up Study (HPFS; lower risk of dementia-related death
1990-2018). The population included women from the NHS and men from the HPFS who were free compared with never or rarely
of cardiovascular disease and cancer at baseline. Data were analyzed from May 2022 to July 2023. consuming olive oil, irrespective of
diet quality.
EXPOSURES Olive oil intake was assessed every 4 years using a food frequency questionnaire and
Meaning These results suggest that
categorized as (1) never or less than once per month, (2) greater than 0 to less than or equal to 4.5
olive oil intake represents a potential
g/d, (3) greater than 4.5 g/d to less than or equal to 7 g/d, and (4) greater than 7 g/d. Diet quality was
strategy to reduce dementia
based on the Alternative Healthy Eating Index and Mediterranean Diet score.
mortality risk.
MAIN OUTCOME AND MEASURE Dementia death was ascertained from death records.
Multivariable Cox proportional hazards regressions were used to estimate hazard ratios (HRs) and + Supplemental content
95% CIs adjusted for confounders including genetic, sociodemographic, and lifestyle factors. Author affiliations and article information are
listed at the end of this article.
RESULTS Of 92 383 participants, 60 582 (65.6%) were women and the mean (SD) age was 56.4
(8.0) years. During 28 years of follow-up (2 183 095 person-years), 4751 dementia-related deaths
occurred. Individuals who were homozygous for the apolipoprotein ε4 (APOE ε4) allele were 5 to 9
times more likely to die with dementia. Consuming at least 7 g/d of olive oil was associated with a
28% lower risk of dementia-related death (adjusted pooled HR, 0.72 [95% CI, 0.64-0.81]) compared
with never or rarely consuming olive oil (P for trend < .001); results were consistent after further
adjustment for APOE ε4. No interaction by diet quality scores was found. In modeled substitution
analyses, replacing 5 g/d of margarine and mayonnaise with the equivalent amount of olive oil was
associated with an 8% (95% CI, 4%-12%) to 14% (95% CI, 7%-20%) lower risk of dementia mortality.
Substitutions for other vegetable oils or butter were not significant.
CONCLUSIONS AND RELEVANCE In US adults, higher olive oil intake was associated with a lower
risk of dementia-related mortality, irrespective of diet quality. Beyond heart health, the findings
extend the current dietary recommendations of choosing olive oil and other vegetable oils for
cognitive-related health.
JAMA Network Open. 2024;7(5):e2410021. doi:10.1001/jamanetworkopen.2024.10021
Open Access. This is an open access article distributed under the terms of the CC-BY License.
JAMA Network Open. 2024;7(5):e2410021. doi:10.1001/jamanetworkopen.2024.10021 (Reprinted) May 6, 2024 1/13
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JAMA Network Open | Nutrition, Obesity, and Exercise Consumption of Olive Oil and Diet Quality and Risk of Dementia-Related Death
Introduction
One-third of older adults die with Alzheimer disease or another dementia.1 While deaths from
diseases such as stroke and heart disease have been decreasing over the past 20 years,
age-standardized dementia mortality rates have been on the rise.2 The Mediterranean diet has
gained in popularity owing to its recognized, multifaceted health benefits, particularly on
cardiovascular outcomes.3 Accruing evidence suggests this dietary pattern also has a beneficial
effect on cognitive health.4 As part of the Mediterranean diet, olive oil may exert anti-inflammatory
and neuroprotective effects due to its high content of monounsaturated fatty acids and other
compounds with antioxidant properties such as vitamin E and polyphenols.5 A substudy conducted
as part of the Prevencion con Dieta Mediterranea (PREDIMED) randomized trial provided evidence
that higher intake of olive oil for 6.5 years combined with adherence to a Mediterranean diet was
protective of cognitive decline when compared with a low-fat control diet.6-8
Given that most previous studies on olive oil consumption and cognition were conducted in
Mediterranean countries,7-10 studying the US population, where olive oil consumption is generally
lower, could offer unique insights. Recently, we showed that olive oil consumption was associated
with a lower risk of total and cause-specific mortality in large US prospective cohort studies, including
a 29% (95% CI, 22%-36%) lower risk for neurodegenerative disease mortality in participants who
consumed more than 7 g/d of olive oil compared with little or none.11 However, this previous analysis
was not designed to examine the association of olive oil and diet quality with dementia-related
mortality, and therefore the latter remains unclear.
In this study, we examined the association between total olive oil consumption and the
subsequent risk of dementia-related mortality in 2 large prospective studies of US women and men.
Additionally, we evaluated the joint associations of diet quality (adherence to the Mediterranean diet
and Alternative Healthy Eating Index [AHEI] score) and olive oil consumption with the risk of
dementia-related mortality. We also estimated the difference in the risk of dementia-related
mortality when other dietary fats were substituted with an equivalent amount of olive oil.
Methods
Study Population
Analyses were performed in 2 large US prospective cohorts: the Nurses’ Health Study I (NHS) and the
Health Professionals Follow-Up Study (HPFS). The NHS was initiated in 1976 and recruited 121 700
US female registered nurses aged 30 to 55 years.12 The HPFS was established in 1986 and included
51 525 male health professionals aged 40 to 75 years.13 The cohorts have been described
elsewhere.12,13 Lifestyle factors and medical history were assessed biennially through mailed
questionnaires, with a follow-up rate greater than 90%. Baseline for this analysis was 1990, which is
when the food frequency questionnaires (FFQs) first included information on olive oil consumption.
Participants with a history of cardiovascular disease (CVD) or cancer at baseline, with missing
data on olive oil consumption, or who reported implausible total energy intakes (<500 or >3500
kcal/d for women and <800 or >4200 kcal/d for men) were excluded. The completion of the
questionnaire self-selected cognitively highly functioning women and men. In total, 60 582 women
and 31 801 men were included. The study protocol was approved by the institutional review boards
of the Brigham and Women’s Hospital and Harvard T.H. Chan School of Public Health, which deemed
the participants’ completion of the questionnaire to be considered as implied consent. This report
followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE)
reporting guideline.
Dietary Assessment
Dietary intake was measured using a validated greater than 130-item FFQ administered in 1990 and
every 4 years thereafter. The validity and reliability of the FFQ have been described previously.14

Participants were asked how frequently they consumed specific foods, including types of fats and oils
used for cooking or added to meals in the past 12 months. Total olive oil intake was determined by
summing up answers to 3 questions related to olive oil consumption (ie, olive oil used for salad
dressings, olive oil added to food or bread, and olive oil used for baking and frying at home). The
equivalent of 1 tablespoon of olive oil was considered to be 13.5 g. Intakes of other fats and nutrients
were calculated using the United States Department of Agriculture and Harvard University Food
Composition Database,15 and biochemical analyses. The nutritional composition of olive oil and other
types of fat, as well as trends of types of fat intake in the NHS and HPFS, have been reported
previously.11
Adherence to the Mediterranean diet was assessed using a modified version of the 9-point
Alternative Mediterranean index (AMED) score.16 Adherence to the AHEI (0-110), previously
associated with lower risk of chronic disease, was also computed.17 Higher scores indicated better
overall diet quality.
APOE Genotyping
The apolipoprotein E ε4 (APOE ε4) allele is known to interfere with lipid and glucose metabolism
such that it increases the risk of dementia.18 APOE genotyping was conducted in a subset of 27 296
participants. Blood samples were collected between 1989 and 1990 in the NHS and between 1993
and 1995 in the HPFS. NHS participants who had not provided blood samples were invited to
contribute buccal samples from 2002 to 2004. DNA was extracted with the ReturPureGene DNA
Isolation Kit (Gentra Systems). The APOE genotype was determined using a Taqman Assay (Applied
Biosystems)19 in 5069 participants, and through imputation from multiple genome-wide association
studies,20 which has shown high accuracy,20 in the remaining subset.
Ascertainment of Dementia-Related Death

Deaths were ascertained from state vital statistics records and the National Death Index or by reports
from next of kin or the postal authorities. The follow-up for mortality exceeded 98% in these cohorts.
Dementia deaths were determined by physician review of medical records, autopsy reports, or death
certificates. Dementia deaths were those in which dementia was listed as the underlying cause of
death, or as a contributing cause of death, or as reported by the family, in the absence of a more likely
cause. The International Classification of Diseases, Eighth Revision (ICD-8) was used in the NHS and
ICD-9 in the HPFS, which were the revisions used at the inception of those cohorts. Dementia deaths
included codes 290.0 (senile dementia, simple type), 290.1 (presenile dementia), and 331.0
(Alzheimer disease). To test the validity of the dementia mortality outcome, we examined the
likelihood of dementia mortality by APOE ε4 allelic dosage (eTable 1 in Supplement 1).18 A composite
outcome was also created including both participants who reported having dementia during
follow-up and later died, with those who had dementia reported on their death certificate.
Assessment of Covariates
Participants completed biennial questionnaires reporting updates on body weight, smoking, physical
activity, multivitamin use, menopausal status, and postmenopausal hormone use in women, family
history of dementia, self-report of chronic diseases, and ancestry. History of depression was
identified based on antidepressive medication use and self-report of depression. Socioeconomic
status (SES) was established through a composite score derived from home address details and
various factors such as income, education, and housing; the composite score methods are described
in a previous report.21 Body mass index (BMI) was obtained by dividing the weight in kilograms by
the height in meters squared.
Statistical Analysis
In each cohort, age-stratified Cox proportional hazard models were used to evaluate the association
of olive oil intake with dementia-related mortality. Participant person-time was calculated from

baseline until end of follow-up (June 30, 2018, in NHS; January 31, 2018, in HPFS), loss to follow-up,
or death, whichever came first. The cumulative average (mean) of olive oil intake from all available
FFQs, from baseline until 2014 (or loss to follow-up or death), was used as the exposure. Because
potential diet modifications following cancer or CVD diagnosis may not represent long-term diet, we
ceased updating dietary variables upon report of these conditions. For missing covariates, we carried
forward nonmissing values from previous questionnaires and assigned median values for continuous
variables.
Participants were categorized by olive oil intake frequency: never or less than once per month
(reference group), greater than 0 to less than or equal to 4.5 g/d, greater than 4.5 g/d to less than or
equal to 7 g/d, and greater than 7 g/d. P values for linear trends were obtained using the Wald test
on a continuous variable represented by the median intake of each category. Multivariable Cox
proportional hazard models were used to estimate the hazard ratios (HRs) and 95% CIs for dementia
mortality according to categories of olive oil intake, separately in each cohort. Participants were
censored at death from causes other than dementia. Model 1 was stratified for age and calendar time.
Multivariable model 2 was adjusted for Southern European/Mediterranean ancestry, married, living
alone, smoking, alcohol intake, physical activity, multivitamin use, history of hypertension and
hypercholesterolemia, in women postmenopausal status and menopausal hormone use, total energy
intake, family history of dementia, history of depression, census SES, and BMI. Multivariable model
3 was further adjusted for intake of red meat, fruits and vegetables, nuts, soda, whole grains, and
trans-fat, all indicative of diet quality.
In a secondary analysis we used the composite outcome for dementia-related deaths. We also
repeated the main analysis in the genotyping subsample. We carried out mediation analyses to
calculate the percentage of the association between olive oil intake and dementia-related mortality
that is attributable to CVD, hypercholesterolemia, hypertension, and diabetes. We also performed
stratified analyses by prespecified subgroups (eMethods in Supplement 1).
A joint analysis was performed to test whether olive oil intake (never or <1/mo, >0 to ⱕ7g/d, and
>7g/d) and the AMED or the AHEI score (tertiles) combined as the exposure was associated with de-
mentia mortality. In substitution analyses, we assessed the risk of dementia-related mortality by replac-
ing 5 g/d of different fat sources, including margarine, mayonnaise, butter, and a combination of other
vegetable oils (corn, safflower, soybean, and canola), with olive oil. Both continuous variables as 5-g/d
increments were included in a multivariable model 3, mutually adjusted for other types of fat. The dif-
ference in the coefficients obtained for olive oil and the substituted fat provided the estimated HR and
95% CI for substituting 5 g/d of olive oil for an equivalent amount of the other fats.
Several exploratory sensitivity analyses were performed including a 4-year lagged analysis,
analyses adjusting for other covariates, a cause-specific competing risk model and analyses excluding
participants who self-reported having dementia at baseline (n = 12) (eMethods in Supplement 1).
Analyses were performed from May 2022 to July 2023 using SAS version 9.4 (SAS Institute). All
statistical tests were 2-sided with an α = .05.
Results
Over 2 183 095 person-years of follow-up, this study documented a total of 4751 dementia deaths
(3473 in NHS and 1278 in HPFS; 37 649 total deaths). Among 92 383 participants included at baseline
in 1990, 60 582 (65.6%) were women, and the mean (SD) age was 56.4 (8.0) years. Mean (SD) olive
oil intake was 1.3 (2.5) g/d in both NHS and HPFS; the mean (SD) adherence score for the
Mediterranean diet was 4.5 (1.9) points in the NHS and 4.2 (1.9) points in the HPFS; and the mean
(SD) AHEI diet quality score was 52.5 (11.1) points in the NHS and 53.4 (11.6) points in the HPFS.
Table 1 shows baseline characteristics of participants categorized by total olive oil intake.
Participants with a higher olive oil intake (>7 g/d) at baseline had an overall higher caloric intake, but
not a higher BMI, had better diet quality, had higher alcohol intake, were more physically active, and
were less likely to smoke compared with those never consuming olive oil or less than once per month

Table 1. Age-Standardized Baseline Characteristics of Participants by Cohortsa
Olive oil intake

Never or <1/mo >0-≤4.5 g/d >4.5-≤7 g/d >7 g/d
NHS
No. of participants 32 360 22 684 2393 3145
Total olive oil, g/d 0 1.5 (1.2) 5.8 (0.5) 9.0 (4.7)
Age, y 56.2 (7.2) 56.1 (7) 56.3 (7) 56.5 (7)
BMI 25.8 (5) 25.4 (4.7) 25.3 (4.5) 25.3 (4.6)
Hypertension, % 18.3 18.3 17.2 17.6
Hypercholesterolemia, % 28.3 31.2 31.3 32.6
Diabetes, % 3.1 2.4 2.3 2.7
Family history of dementia, % 20.5 20.1 19.8 20.5
Current smoker, % 16.3 16.6 15.5 12.8
Physical activity, MET-h/wk 14.4 (19.8) 16.5 (22.9) 18.3 (23.2) 18.8 (25.9)
Total calories, kcal/d 1702 (497) 1762 (501) 1907 (512) 1989 (531)
Alcohol intake, g/d 4.1 (8.6) 6 (10.2) 7.3 (11) 7.2 (10.9)
AMED score, 0-9 4.1 (1.8) 4.8 (1.8) 5.5 (1.7) 5.7 (1.7)
AHEI score, 0-110 50.8 (10.9) 53.8 (10.8) 56.8 (10.6) 58.1 (10.7)
Red and processed meat, servings/d 0.9 (0.6) 0.9 (0.6) 0.8 (0.6) 0.8 (0.6)
Fruits and vegetables, servings/d 4.8 (1.9) 5.3 (2) 6 (2.1) 6.4 (2.2)
Whole grains, servings/d 1.8 (1.5) 1.9 (1.6) 2.2 (1.7) 2.3 (1.8)
Total nuts, servings/d 0.1 (0.2) 0.1 (0.2) 0.2 (0.2) 0.2 (0.2)
Soda, servings/d 0.8 (0.9) 0.8 (0.9) 0.7 (0.8) 0.8 (0.9)
Butter, g/d 1.1 (2.9) 1.3 (3.1) 1.6 (3.3) 1.7 (3.8)
Mayonnaise, g/d 5.5 (7) 4.6 (5.5) 5.2 (6.7) 6.5 (9)
Other vegetable oils, g/d 4.6 (4.3) 4.2 (3.5) 5.1 (4.3) 6.6 (6)
Margarine, g/d 14.7 (17.1) 14.0 (16.6) 13.8 (17) 14.7 (17.6)
Total fat, % kcal [g/d] 31.5 31.0 32.1 33.5
[59.8 (21.9)] [60.8 (21.5)] [67.8 (22.1)] [74 (24.8)]
Saturated fat, % kcal [g/d] 10.9 10.5 10.2 10.1
[20.7 (8.1)] [20.6 (8)] [21.7 (8.2)] [22.5 (8.6)]
Trans-fat, % kcal [g/d] 1.6 1.4 1.3 1.3
[3.0 (1.5)] [2.8 (1.4)] [2.8 (1.4)] [2.9 (1.4)]
Polyunsaturated fat, % kcal [g/d] 5.9 5.8 6.1 6.7
[11.2 (4.6)] [11.4 (4.4)] [12.9 (4.8)] [14.7 (6.1)]
Monounsaturated fat, % kcal [g/d] 11.9 12.0 13.0 13.9
[22.6 (8.7)] [23.5 (8.6)] [27.3 (8.7)] [30.6 (10.2)]
HPFS
No. of participants 16 007 12 828 1238 1621
Total olive oil, g/d 0 (0) 1.5 (1.1) 5.8 (0.5) 9.1 (4.5)
Age, y 57 (9.7) 56.4 (9.2) 57.2 (9) 57.3 (9.1)
BMI 25.6 (3.4) 25.5 (3.2) 25.5 (3.1) 25.3 (3.2)
Hypertension, % 16.2 17.6 16.5 16.9
Hypercholesterolemia, % 19.1 20.9 21.7 23.4
Diabetes, % 2.8 2.7 2.7 2.7
Family history of dementia, % 15.9 16.0 17.4 16.9
Current smoker, % 8.2 7.3 7.4 5.3
Physical activity, MET-h/wk 36.6 (42.6) 37.8 (39.5) 40.4 (37.4) 43.6 (45.4)
Total calories, kcal/d 1897 (577) 1927 (582) 2065 (605) 2134 (605)
Alcohol intake, g/d 8.4 (13.5) 11.2 (14.6) 12.8 (15) 13.3 (15)
AMED score, 0-9 3.8 (1.8) 4.5 (1.9) 5.2 (1.8) 5.5 (1.7)
AHEI score, 0-110 51.1 (11.5) 54.8 (11.1) 58.3 (11.6) 60 (11.4)
Red and processed meat, servings/d 1.1 (0.8) 1.0 (0.8) 1.0 (0.8) 0.8 (0.7)
Fruits and vegetables, servings/d 5.2 (2.4) 5.7 (2.4) 6.6 (2.7) 7.2 (2.9)
Whole grains, servings/d 1 (0.9) 1 (0.9) 1.1 (0.9) 1.2 (1.1)
Total nuts, servings/d 0.2 (0.3) 0.3 (0.3) 0.3 (0.4) 0.3 (0.5)
(continued)

Table 1. Age-Standardized Baseline Characteristics of Participants by Cohortsa (continued)
Olive oil intake

Never or <1/mo >0-≤4.5 g/d >4.5-≤7 g/d >7 g/d
Soda, servings/d 0.8 (0.9) 0.7 (0.9) 0.7 (0.9) 0.7 (0.9)
Butter, g/d 1.2 (3.3) 1.4 (3.3) 1.5 (3.3) 1.6 (3.6)
Mayonnaise, g/d 4.8 (6.7) 3.9 (5.5) 4.3 (6.4) 4.3 (6.9)
Other vegetable oils, g/d 4.5 (4.3) 4.1 (3.7) 4.8 (4.3) 5.4 (5)
Margarine, g/d 12.6 (16.5) 10.8 (14.8) 10.7 (15.3) 10.1 (14.7)
Total fat, % kcal [g/d] 31.3 30.5 31.5 31.7 Abbreviations: AHEI, alternative healthy eating index;
[66.5 (26.4)] [65.9 (25.5)] [72.6 (27.2)] [75.3 (27)]
AMED, alternative Mediterranean diet index; BMI,
Saturated fat, % kcal [g/d] 10.6 10.1 9.8 9.4 body mass index (calculated as weight in kilograms
[22.5 (9.8)] [21.8 (9.4)] [22.7 (9.8)] [22.5 (9.6)]
divided by height in meters squared); HPFS, Health
Trans-fat, % kcal [g/d] 1.6 1.5 1.3 1.2
[3.5 (1.9)] [3.2 (1.7)] [3.1 (1.8)] [2.9 (1.6)] Professionals’ Follow-up Study; MET-h/wk, metabolic
Polyunsaturated fat, % kcal [g/d] 5.9 5.8 6.1 6.3 equivalent of task–hour per week; NHS, Nurses’ Health
[12.4 (5.3)] [12.5 (5)] [14.0 (5.6)] [15.0 (6.2)] Study I.
Monounsaturated fat, % kcal [g/d] 12.1 12.0 13.0 13.4 a
Values are means (SD) for continuous variables and
[25.8 (10.8)] [25.9 (10.4)] [29.8 (11.2)] [31.6 (11.3)]
No. (%) for categorical variables.
(Table1). Individuals who were homozygous for the APOE ε4 allele were 5.5 to 9.4 times more likely
to die with dementia compared with noncarriers for the APOE e4 allele (χ2 P < .001) (eTable 1 in
Supplement 1).
Olive oil intake was inversely associated with dementia-related mortality in age-stratified and
multivariable-adjusted models (Table 2). Compared with participants with the lowest olive oil intake,
the pooled HR for dementia-related death among participants with the highest olive oil intake (>7
g/d) was 0.72 (95% CI, 0.64-0.81), after adjusting for sociodemographic and lifestyle factors. The
association between each 5-g increment in olive oil consumption with dementia-related death was
also inverse and significant in the pooled analysis. The multivariable-adjusted HR for dementia-
related death for the highest compared with the lowest olive oil intake (>7 g/d) was 0.67 (95% CI,
0.59-0.77) for women and 0.87 (95% CI, 0.69-1.09) for men (Table 2). Olive oil intake in 5-g
increments was inversely associated with dementia-related mortality in women (HR, 0.88 [95% CI,
0.84-0.93]), but not in men (HR, 0.96 [95% CI, 0.88-1.04]). Analyses remained consistent when
using the composite outcome for death with dementia (eTable 2 in Supplement 2). In the genotyping
subsample, the results remained unchanged after further adjusting for the APOE ε4 allelic genotype
(multivariable-adjusted pooled HR comparing high vs low olive oil intake, 0.66 [95% CI, 0.54-0.81]; P
for trend < .001) (eTable 4 in Supplement 1). Pooled mediation analyses found that CVD,
hypercholesterolemia, hypertension, and diabetes did not significantly attenuate the association
(unchanged HRs with and without adjusting for the intermediate; data not shown).
In joint analyses, participants with the highest olive oil intake had a lower risk for dementia-
related mortality, irrespective of their AMED score (28% to 34% lower risk compared with
participants in the combined low olive oil and high AMED) (Figure 1A; eTable 3 in Supplement 1) and
of their AHEI (27% to 38% lower risk compared with participants with low olive oil and high AHEI)
(Figure 1B; eTable 3 in Supplement 1).
Replacing 5 g/d of mayonnaise with 5 g/d of olive oil was associated with a 14% (95% CI,
7%-20%) lower risk of dementia-related mortality in pooled multivariable-adjusted models
(Figure 2). As for the substitution of 5 g/d of margarine with the equivalent amount of olive oil, we
estimated an 8% (95% CI, 4%-12%) lower risk. Substitutions of other vegetable oils or butter with
olive oil were not statistically significant.
Exploratory subgroup analyses (eFigure in Supplement 1) showed associations between higher
olive oil intake and lower risk of dementia-related mortality across most subgroups. No statistically
significant associations were found in participants with a family history of dementia, living alone,
using a multivitamin, and in non–APOE ε4 carriers. Results from exploratory sensitivity analyses
(eTables 5-8 in Supplement 1) were comparable with the findings from the main analysis (eResults in
Supplement 1).

Table 2. Risk of Dementia-Related Mortality According to Categories of Total Olive Oil
Category of cumulative average olive oil intake, HR (95% CI) HR (95% CI)
for 5 g increase
Never or <1/mo >0 to ≤4.5 g/d >4.5 to ≤7 g/d >7 g/d P for trend in olive oil intake
NHS
Total olive oil, mean (SD) 0 1.5 (1.2) 5.6 (0.7) 11.9 (5.8) NA NA
No. of cases/person-years 1088/438 566 1829/739 116 250/125 884 306/182 726 NA NA
Age-adjusted model 1 1 [Reference] 0.69 (0.64-0.75) 0.66 (0.57-0.75) 0.53 (0.47-0.60) <.001 0.84 (0.80-0.88)
Multivariable model 2 1 [Reference] 0.86 (0.80-0.93) 0.85 (0.74-0.98) 0.69 (0.60-0.79) <.001 0.89 (0.85-0.94)
HPFS
Total olive oil, mean (SD) 0 1.5 (1.2) 5.6 (0.7) 11.4 (5.5) NA NA
No. cases/person-years 407/226 931 681/381 397 86/57 337 104/72 138 NA NA
Age-adjusted model 1 1 [Reference] 0.84 (0.74-0.95) 0.71 (0.56-0.90) 0.65 (0.52-0.80) <.001 0.87 (0.80-0.95)
Multivariable model 2 1 [Reference] 0.97 (0.85-1.10) 0.87 (0.69-1.11) 0.84 (0.67-1.05) .09 0.95 (0.87-1.03)
Multivariable model 3 1 [Reference] 0.98 (0.86-1.12) 0.90 (0.71-1.15) 0.87 (0.69-1.09) .17 0.96 (0.88-1.04)
Pooled data
Meta-analysis
Abbreviations: NHS, Nurses’ Health Study I; HPFS, Health Professionals Follow-up Study. intake (kcal/d), family history of dementia (yes/no), history of depression (yes/no),
All Cox proportional hazards models were stratified by age and calendar time. census socioeconomic status (9-variable score, in quintiles), and body mass index
Multivariable model 2 was adjusted for Southern European/Mediterranean ancestry calculated as weight in kilograms divided by height in meters squared (<23, 23-25, 25-30,
(yes/no), married (yes/no), living alone (yes/no), smoking status (never, former, current 30-35, ⱖ35). Multivariable model 3 was additionally adjusted for red meat, fruits and
smoker 1-14 cigarettes/d, 15-24 cigarettes/d, or ⱖ25 cigarettes/d), alcohol intake (0, vegetables, nuts, soda, whole grains intake (in quintiles), and trans-fat (% kcal). Pooled
0.1-4.9, 5.0-9.9, 10.0-14.9, and ⱖ15.0 g/d), physical activity (<3.0, 3.0-8.9, 9.0-17.9, 18.0- results were obtained by pooling the datasets of the cohorts, and Cox proportional
26.9, ⱖ27.0 metabolic equivalent of task–h/wk), multivitamin use (yes/no), history of hazards model 3 was further stratified by cohort (sex). No significant cohort by olive oil
hypertension (yes/no), history of hypercholesterolemia (yes/no), history of diabetes intake interaction was found. In a secondary analysis, results were meta-analyzed using a
(yes/no), in women postmenopausal status and menopausal hormone use fixed-effect inverse variance-weighted approach. No significant heterogeneity between
(premenopausal, postmenopausal [no, past, or current hormone use]), total energy cohorts was found.
Figure 1. Joint Associations of Olive Oil Intake and Alternative Mediterranean Diet Index (AMED) and Alternative Healthy Eating Index (AHEI)
With Dementia-Related Mortality
A AMED B AHEI
1.2 1.2
a a
1.0 1.0
b b
0.8 0.8 b b
b b b
b b
HR
0.6 0.6
HR
0.4 0.4
0.2 0.2
0 0
Low olive oil Medium olive oil High olive oil Low olive oil Medium olive oil High olive oil
High AMED Medium AHED Low AHED High AHEI Medium AHEI Low AHEI
Models were stratified by age, cohort (sex), and calendar time, and adjusted for Southern status (9-variable score, in quintiles), and body mass index calculated as weight in
European/Mediterranean ancestry (yes/no), married (yes/no), living alone (yes/no), kilograms divided by height in meters squared (<23, 23-25, 25-30, 30-35, ⱖ35). Pooled
smoking status (never, former, current smoker 1-14 cigarettes/d, 15-24 cigarettes/d, or results were obtained by pooling the datasets of the cohorts. AMED score is without
ⱖ25 cigarettes/d), physical activity (<3.0, 3.0-8.9, 9.0-17.9, 18.0-26.9, ⱖ27.0 metabolic monounsaturated:saturated fats intake ratio component. AHEI score is without
equivalent of task–h/wk), multivitamin use (yes/no), history of hypertension (yes/no), polyunsaturated fats intake component. HR indicates hazard ratio.
history of hypercholesterolemia (yes/no), history of diabetes (yes/no), in women a
Reference value.
postmenopausal status and menopausal hormone use (premenopausal, b
P < .05.
postmenopausal [no, past, or current hormone use]), total energy intake (kcal/d), family
history of dementia (yes/no), history of depression (yes/no), census socioeconomic

Discussion
In 2 large US prospective cohorts of men and women, we found that participants who consumed
more than 7 g/d of olive oil had 28% lower risk of dying from dementia compared with participants
who never or rarely consumed olive oil. This association remained significant after adjustment for
diet quality scores including adherence to the Mediterranean diet. We estimated that substituting 5
g/d of margarine and mayonnaise with olive oil was associated with significantly lower dementia-
related death risk, but not when substituting butter and other vegetable oils. These findings provide
evidence to support dietary recommendations advocating for the use of olive oil and other vegetable
oils as a potential strategy to maintain overall health and prevent dementia.
In the NHS and HPFS, a lower risk of neurodegenerative disease mortality, including dementia
mortality, was observed with higher olive oil consumption (HR, 0.81 [95% CI, 0.78-0.84]).11 Evidence
that pertains to cognitive decline or incident dementia is more widely available than it is for dementia
mortality.6,22 In the French Three-City Study (n = 6947), participants with the highest olive oil intake
were 17% (95% CI, 1%-29%) less likely to experience a 4-year cognitive decline related to visual
memory, but no association was found for verbal fluency (odds ratio [OR], 0.85 [95% CI,
0.70-1.03]).22 Furthermore, participants with a higher intake of olive oil (moderate or intensive vs
never) had a lower risk of verbal fluency and visual memory cognitive impairment. Potential sex
differences were not investigated. In the PREDIMED trial, which supplemented a Mediterranean-
style diet with extra-virgin olive oil (1 L/wk/household) or nuts (30 g/d),23 the authors investigated
cognitive effects and status in 285 and 522 cognitively healthy participants using global and in-depth
neuropsychological battery testing. Although the study was not originally designed for cognitive
outcomes and the effect of olive oil cannot be isolated, after 6.5 years, the olive oil group exhibited
improved cognitive performance in verbal fluency and memory tests compared with a low-fat diet
(control), and they were less prone to develop mild cognitive impairment (OR, 0.34 [95% CI,
0.12-0.97]; n = 285).6 Global cognitive performance was higher in both the olive oil and the nut
Figure 2. Substitution of Olive Oil for Other Fats Associated With Dementia-Related Mortality Risk in Pooled Cohorts, Nurses’ Health Study (NHS),
and Health Professionals’ Follow-Up Study (HPFS)
A Pooled cohorts B NHS cohort

Other fats HR (95% CI) Other fats HR (95% CI)
Margarine 0.90 (0.86-0.94) Margarine 0.91 (0.86-0.95)
Mayonnaise 0.90 (0.86-0.95) Mayonnaise 0.86 (0.78-0.94)
Butter 0.88 (0.84-0.93) Butter 0.98 (0.89-1.08)
Other vegetable oils 0.93 (0.86-1.00) Other vegetable oils 0.98 (0.88-1.10)
0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3 1.4 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3 1.4
HR (95% CI) HR (95% CI)
C HPFS cohort
Other fats HR (95% CI)
Margarine 0.92 (0.85-1.00)
Mayonnaise 0.87 (0.75-0.99)
Butter 1.05 (0.90-1.22)
Other vegetable oils 1.03 (0.86-1.22)
0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3 1.4

HR (95% CI)
Substitution analysis of 5 g/d intake of olive oil for the equivalent amount of butter, other women postmenopausal status and menopausal hormone use (premenopausal,
vegetable oils, mayonnaise, and margarine. All Cox proportional hazards models were postmenopausal [no, past, or current hormone use]), total energy intake (kcal/d), family
stratified by age and calendar time. Models were adjusted for Southern European/ history of dementia (yes/no), history of depression (yes/no), census socioeconomic
Mediterranean ancestry (yes/no), married (yes/no), living alone (yes/no), smoking status status (9-variable score, in quintiles), body mass index calculated as weight in kilograms
(never, former, current smoker 1-14 cigarettes/d, 15-24 cigarettes/d, or ⱖ25 cigarettes/d), divided by height in meters squared (<23, 23-25, 25-30, 30-35, ⱖ35), red meat, fruits
alcohol intake (0, 0.1-4.9, 5.0-9.9, 10.0-14.9, and ⱖ15.0 g/d), physical activity (<3.0, and vegetables, nuts, soda, whole grains intake (in quintiles), and trans-fat. Pooled
3.0-8.9, 9.0-17.9, 18.0-26.9, ⱖ27.0 metabolic equivalent of task–h/wk), multivitamin use results were obtained by pooling the data sets of the cohorts and Cox proportional
(yes/no), history of hypertension (yes/no), history of hypercholesterolemia (yes/no), in hazards model 3 was further stratified by cohort (sex). HR indicates hazard ratio.

groups compared with the control post trial (n = 522).8 These studies were conducted in Europe, in
populations with typically higher olive oil intake compared with US populations.
Observational studies and some trials have consistently found associations between following
diets such as the Mediterranean, DASH, MIND, and AHEI, and prudent patterns to healthier brain
structure,24 reduced cognitive impairment and Alzheimer risk, and improved cognitive function.4 In
our study, those with the highest olive oil intake (>7 g/d) had the lowest dementia-related death risk
compared with those with minimal intake (never or less than once per month), regardless of diet
quality. This highlights a potentially specific role for olive oil. Still, the group with both high AHEI
scores and high olive oil intake exhibited the lowest dementia mortality risk (HR, 0.68 [95% CI, 0.58-
0.79]; reference: low AHEI score and low olive oil intake), suggesting that combining higher diet
quality with higher olive oil intake may confer enhanced benefit.
Olive oil consumption may lower dementia mortality by improving vascular health.18 Several
clinical trials support the effect of olive oil in reducing CVD via improved endothelial function,
coagulation, lipid metabolism, oxidative stress, platelet aggregation and decreased inflammation.25
Nonetheless, the results of our study remained independent of hypertension and
hypercholesterolemia. Mild cognitive impairment, Alzheimer disease, and related dementias were
associated with abnormal blood brain barrier permeability, possibly allowing the crossing of
neurotoxic molecules into the brain.26 Mechanistical evidence from animal27-29 and human
studies9,30 have shown that phenolic compounds in olive oil, particularly extra-virgin olive oil, may
attenuate inflammation, oxidative stress and restore blood brain barrier function, thereby reducing
brain amyloid-β and tau-related pathologies and improving cognitive function. However, incident
CVD, hypercholesterolemia, hypertension, and diabetes were not significant mediators of the
association between olive oil intake and dementia-related death in our study.
The association was significant in both sexes but did not remain in men after full adjustment of
the model. Some previous research has reported cognitive-related sex differences. Evidence from
trials also showed sex- and/or gender-specific responses to lifestyle interventions for preventing
cognitive decline, possibly due to differences in brain structure, hormones (sex) and social factors
(gender).31 Olive oil intake may be protective of dementia and related mortality, particularly in
women. Nonetheless, we did not observe significant heterogeneity or interaction of cohort by olive
oil intake on the risk of fatal dementia. Sex and gender differences should be carefully considered in
future studies examining the association or effect of olive oil on cognitive-related outcomes to
improve our understanding.
We found that using olive oil instead of margarine and mayonnaise, but not butter and other
vegetable oils, was associated with a lower risk of dementia-related death. At the time of the study,
margarine and mayonnaise contained considerable levels of hydrogenated trans-fats. The latter were
strongly associated with all-cause mortality, CVD, type 2 diabetes, and dementia,32,33 which may
explain the lower dementia-related death risk observed when replacing it with olive oil. The US Food
and Drug Administration banned manufacturers from adding partially hydrogenated oils to foods in
2020.34 Future studies examining intake of trans-fat–free margarine will be informative. Although
the substitution of butter with olive oil was found to be associated with a lower risk of type 2
diabetes, CVD, and total mortality,11 we did not find an association with the risk of dementia mortality.
Although these previous studies did not examine the associations for butter per se, intake of regular
fat dairy products, including cheese, yogurt, and milk, was reported to be either not associated or
inversely associated with lower cognitive function, cognitive decline, and dementia.35-37
Our cohort analyses include several strengths, namely the long follow-up period and large
sample size with a high number of dementia death cases. Also, we included genotyping of the APOE
ε4 allele in a large subsample of participants to reduce potential confounding attributed to this
well-known risk factor for Alzheimer disease. Additionally, our repeated diet measurements, weight,
and lifestyle variables permitted us to account for long-term olive oil intake and confounding factors.
Furthermore, the use of dietary cumulative average updates reduced random measurement error
by considering within-person variations in intake.

Limitations
This study has limitations. The possibility of reverse causation cannot be excluded due to the
observational nature of our study. However, the 4-year lagged analysis results, consistent with the
primary analysis, suggest that olive oil intake is predictive of dementia mortality rather than a
consequence of premorbid dementia. While it is plausible that higher olive oil intake could be
indicative of a healthier diet and higher SES, our results remained consistent after accounting for the
latter. Despite adjusting for key covariates, residual confounding may remain due to unmeasured
factors. Also, our study was conducted among health professionals. While this minimizes the
potential confounding effects of socioeconomic factors and likely increases reporting due to a high
level of education, this may also limit generalizability. Our population was predominantly of
non-Hispanic White participants, limiting generalizability to more diverse populations. Additionally,
we could not differentiate among various types of olive oil that differ in their polyphenols and other
nonlipid bioactive compounds content.
Conclusions
This study found that in US adults, particularly women, consuming more olive oil was associated with
lower risk of dementia-related mortality, regardless of diet quality. Substituting olive oil intake for marga-
rine and mayonnaise was associated with lower risk of dementia mortality and may be a potential strat-
egy to improve longevity free of dementia. These findings extend the current dietary recommendations
of choosing olive oil and other vegetable oils to the context of cognitive health and related mortality.
ARTICLE INFORMATION
Accepted for Publication: March 6, 2024.
Published: May 6, 2024. doi:10.1001/jamanetworkopen.2024.10021
Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2024 Tessier AJ
et al. JAMA Network Open.
Corresponding Authors: Anne-Julie Tessier, RD, PhD (ajtessier@hsph.harvard.edu), and Marta Guasch-Ferré,
PhD (mguasch@hsph.harvard.edu), Department of Nutrition, Harvard T.H. Chan School of Public Health,
655 Huntington Ave, Bldg 2, Boston, MA 02115.
Author Affiliations: Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
(Tessier, Cortese, Yuan, Bjornevik, Wang, Chavarro, Stampfer, Hu, Willett, Guasch-Ferré); School of Public Health,
the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China (Yuan); Department of
Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts (Bjornevik, Ascherio, Wang,
Chavarro, Stampfer, Hu, Willett); Channing Division of Network Medicine, Department of Medicine, Brigham and
Women’s Hospital and Harvard Medical School, Boston, Massachusetts (Ascherio, Chavarro, Stampfer, Hu, Willett);
Department of Public Health and Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health
and Medical Sciences, University of Copenhagen, Copenhagen, Denmark (Guasch-Ferré).
Author Contributions: Drs Tessier and Guasch-Ferré had full access to all of the data in the study and take
responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Tessier, Chavarro, Hu, Willett, Guasch-Ferré.
Acquisition, analysis, or interpretation of data: Tessier, Cortese, Yuan, Bjornevik, Ascherio, Wang, Chavarro,
Stampfer, Willett, Guasch-Ferré.
Drafting of the manuscript: Tessier.
Critical review of the manuscript for important intellectual content: Tessier, Cortese, Yuan, Bjornevik, Ascherio,
Wang, Chavarro, Stampfer, Hu, Willett, Guasch-Ferré.
Statistical analysis: Tessier, Cortese, Wang, Willett, Guasch-Ferré.
Obtained funding: Chavarro, Stampfer, Hu, Guasch-Ferré.
Administrative, technical, or material support: Cortese, Yuan, Stampfer, Hu.
Supervision: Chavarro, Hu, Guasch-Ferré.

Conflict of Interest Disclosures: Dr Cortese reported a speaker honorarium from Roche outside the submitted
work. Dr Ascherio reported receiving speaker honoraria from WebMD, Prada Foundation, Biogen, Moderna,
Merck, Roche, and Glaxo-Smith-Kline. No other disclosures were reported.
Funding/Support: This study is supported by the research grant R21 AG070375 from the National Institutes of
Health to Dr Guasch-Ferré. The NHS, NHSII and HPFS are supported by grants from the National Institutes of
Health (UM1 CA186107, P01 CA87969, U01 CA167552, P30 DK046200, HL034594, HL088521, HL35464,
HL60712). Dr Tessier is supported by the Canadian Institutes of Health Research (CIHR) Postdoctoral Fellowship
Award. Dr Guasch-Ferré is supported the Novo Nordisk Foundation grant NNF23SA0084103.
Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection,
management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and
decision to submit the manuscript for publication.
Data Sharing Statement: See Supplement 2.
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2023.100160
SUPPLEMENT 1.
eMethods.
eResults.
eTable 1. Odds Ratios for Dementia-Related Mortality by APOE4 Allelic Dosage

eTable 2. Risk of Death With Dementia (Composite Outcome) According to Categories of Total Olive Oil
eTable 3. Joint Associations of Olive Oil Intake and AMED (A), and AHEI (B) With Dementia-Related Mortality Risk
eTable 4. Risk of Dementia-Related Mortality According to Categories of Total Olive Oil in the Genomic DNA
Subsample
eFigure. Subgroup Analyses for 5g/d Increase in Olive Oil Intake With Dementia-Related Mortality Risk
eTable 5. Risk of Dementia-Related Mortality According to Categories of Total Olive Oil Without Stopping Diet
Update Upon Report of Intermediate Non-Fatal Events
eTable 6. Risk of Dementia Mortality According to Categories of Total Olive Oil Applying a 4-Year Lag Period
Between Dietary Intake and Dementia Mortality
eTable 7. Risk of Dementia-Related Mortality According to Categories of Total Olive Oil Adjusting for Other
Covariates
eTable 8. Risk of Mortality From Dementia and Other Causes of Death According to Categories of Total Olive Oil
Applying a Competing Risk Model
eReferences
SUPPLEMENT 2.
Data Sharing Statement

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Original Investigation | Nutrition, Obesity, and Exercise

Abstract Key Points

JAMA Network Open. 2024;7(5):e2410021. doi:10.1001/jamanetworkopen.2024.10021

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Ascertainment of Dementia-Related Death

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Table 1. Age-Standardized Baseline Characteristics of Participants by Cohortsa

Olive oil intake

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Table 1. Age-Standardized Baseline Characteristics of Participants by Cohortsa (continued)

Olive oil intake

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Table 2. Risk of Dementia-Related Mortality According to Categories of Total Olive Oil

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A Pooled cohorts B NHS cohort

0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3 1.4

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