Food groups and risk of age-related macular degeneration: A systematic review with meta-analysis

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European Journal of Nutrition (2019) 58:2123–2143
https://doi.org/10.1007/s00394-018-1771-5
ORIGINAL CONTRIBUTION
Food groups andrisk ofage-related macular degeneration:
asystematic review withmeta-analysis
MonicaDinu1,2 · GiudittaPagliai1,2· AlessandroCasini1,2· FrancescoSo1,2,3
Received: 7 February 2018 / Accepted: 28 June 2018 / Published online: 5 July 2018
© Springer-Verlag GmbH Germany, part of Springer Nature 2018
Abstract
Objective To systematically review all the available evidence from prospective cohort studies that investigated the associa-
tion between consumption of food groups and the occurrence of age-related macular degeneration (AMD).
Methods We conducted an electronic literature search through MedLine, Embase, Google Scholar, Web of Science, and
bibliographies of retrieved articles up to January, 2018. Studies were included if they analysed prospectively the association
between consumption of food groups and AMD.
Results At the end of the selection process, 26 articles were included in the meta-analysis, for a total of 211,676 subjects and
7154 cases of AMD. By comparing the highest vs. the lowest consumption, pooled analyses showed no significant association
with AMD for vegetables, fruit, nuts, grains, dairy products, as well as dietary fats such as oils, butter and margarine. Fish
determined a significant (p < 0.05) reduction of risk for total AMD (RR 0.82 95% CI 0.75–0.90), as well as for both early
(RR 0.84 95% CI 0.73–0.97), and late (RR 0.79 95% CI 0.70–0.90) AMD. On the other hand, high meat consumption was
associated with a significant increased risk of early (RR 1.17 95% CI 1.02–1.34), but not late AMD. Finally, a significant
increased risk of AMD for the highest consumption of alcohol (RR 1.20 95% CI 1.04–1.39) was reported.
Conclusions The results of the present meta-analysis show a significant 18% reduced risk for fish and a 20% increased risk
for alcohol consumption. In addition, an increased risk was observed for meat, but only in the subgroup of early AMD.
Keywords Food· Macular degeneration· Nutrition· Diet
Introduction
Age-related macular degeneration (AMD) is the leading
cause of severe visual loss and blindness, affecting about
30–50million people worldwide [1]. The prevalence of
AMD is likely to increase over the next decades, due to the
increased life expectancy [2]. AMD, in fact, affects subjects
above 50 more frequently, and more than 10% of all patients
with AMD are 80 or more years old [1, 2]. Despite recent
progress in the discovery of underlying risk factors, the exact
pathogenesis of AMD remains unresolved. Therefore, pri-
mary prevention of AMD is the most important public health
strategy.
Epidemiological studies have suggested that dietary
patterns impact on AMD development and progression
[3, 4]. Given the high susceptibility of the retina to oxida-
tive stress derived from exposures to light and oxygen,
associations between nutritional factors with antioxidant
properties and AMD are biologically plausible [5]. Several
dietary intervention studies with food supplements have
been conducted with significant and positive results [6, 7].
However, most of the studies that evaluated dietary fac-
tors and AMD have determined association with nutrients
(macro or micro) and only some of them have analysed
the association between foods and the onset of AMD. Few
meta-analyses have been conducted so far, with the aim of
investigating the association of certain food groups such
Electronic supplementary material The online version of this
article (https ://doi.org/10.1007/s0039 4-018-1771-5) contains
supplementary material, which is available to authorized users.
* Monica Dinu
mdinu@unifi.it
1 Department ofExperimental andClinical Medicine,
University ofFlorence, Largo Brambilla 3, 50134Florence,
Italy
2 Clinical Nutrition Unit, Careggi University Hospital,
Florence, Italy
3 Don Carlo Gnocchi Foundation Italy, Onlus IRCCS,
Florence, Italy

2124 European Journal of Nutrition (2019) 58:2123–2143
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as fish and alcohol and AMD [8, 9], but a comprehensive
evaluation of all dietary groups that make up a diet has not
been conducted yet.
The aim of this study was to systematically review all
prospective cohort studies available that have evaluated the
consumption of different food groups and alcohol in relation
to occurrence and progression of AMD.
Methods
Selection ofstudies
Studies that investigated the possible association between
food groups’ consumption and AMD in clinically healthy
adults were identified through a search in the following
electronic databases according to the PRISMA (Preferred
Reporting Items for Systematic Reviews and Meta-Analyses)
statement [10]: MedLine (source: PubMed, 1966 to January
2018), Embase (1980 to January 2018), Web of Science,
and Google Scholar. Relevant keywords relating to food and
food groups in combination as MeSH terms and text words:
“diet”, “dietary factor”, “fish”, “nut”, “vegetables”, “dairy”,
“fruit”, “grain”, “cereal”, “legumes”, “meat”, “oil”, and
“alcohol” were used in combination with words relating to
AMD: “age-related macular degeneration”, “maculopathy”,
“retinal degeneration”, “drusen”, and “geographic atrophy”,
and their variants. No language limitations were applied.
The references list of all retrieved articles was reviewed
manually. The most recent publication was used when mul-
tiple articles for a single-cohort study were present.
Two investigators (M.D., F.S.) independently evaluated
relevant articles for eligibility. The decision to include or
exclude studies was hierarchical and on the study title, the
study abstract, and finally on the complete study manuscript.
In the event of conflicting opinions, resolution of the disa-
greement was resolved through discussion with a third inves-
tigator (G.P.).
Prospective cohort studies that assessed the consump-
tion of food groups and alcohol as the exposure variable,
reported the occurrence of AMD as the outcome, and pro-
vided risk estimates with confidence intervals or standard
errors (or sufficient data to calculate them) were eligible
for inclusion. Disagreements on eligibility were resolved by
consensus. Only prospective cohort studies were included
to minimize recall and selection biases that are common in
cross-sectional studies.
Eligible studies were included if they evaluated subjects
aged ≥ 18years at baseline; if they reported clear definitions
of method used to evaluate the food consumption; and if
they reported data on food groups’ consumption in relation
to early and/or late AMD.
Data extraction
Two reviewers (M.D., F.S.) independently extracted data
from all the studies fulfilling the inclusion criteria. Disagree-
ments were resolved by consensus, or by a third investigator
(G.P.) if consensus could not be reached. The following data
were extracted from the original articles using a standard-
ized form: lead author, year of publication, cohort, number
of participants, age of the study cohort, length of follow-
up (years), sex, definition of the outcome of interest, com-
parison, effect size measurements and confidence intervals,
adjustment for confounding factors at the multivariate model
and study quality.
Assessment ofmethodological quality
Two reviewers (M.D., F.S.) assessed the methodological
quality independently, and any incongruity was discussed
and resolved with a third investigator (G.P.). The methodo-
logical quality of the included studies was appraised using
the Newcastle–Ottawa Scale, which ranges from 0 to 9
points [11]. This scale assesses each study in three domains:
the selection of the participants for each group, the compa-
rability between the study groups, and the ascertainment of
exposure in each group. We considered high-quality studies
as those that achieved ≥ 7 points, medium-quality studies
as those with 4–6 points, and poor-quality studies as those
with ≤ 3 points.
Statistical analysis
Studies were grouped according to the different food groups
(vegetables, fruit, nuts, grain, meat, dairy products, fish, but-
ter, margarine, oils, and alcohol). We used Review Manager
(RevMan; version 5.3 for Macintosh; Copenhagen, Den-
mark) to combine the multivariable adjusted RRs or ORs
of the highest compared with the lowest consumption. A
random effects model using DerSimonian and Laird method,
which incorporated both within and between study variabil-
ity, was implemented. Pooled results were reported as RRs
and were presented with 95% confidence intervals (CIs) with
two-sided P values. A P value less than 0.05 was considered
statistically significant.
Statistical heterogeneity was estimated using the Chi-
square Cochran Q test with the I2 statistic, which provides an
estimate of the amount of variance across studies due to the
heterogeneity, rather than sampling error (≥ 75% indicates
substantial heterogeneity) [12]. Subgroup analyses were per-
formed according to AMD stage (early/late). To establish the
robustness of our results, we conducted a sensitivity analysis
by removing each study one by one from the meta-analyses

2125European Journal of Nutrition (2019) 58:2123–2143
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and recalculating the summary estimate (the “leave one out”
approach). If ≥ 10 studies were available, we explored the
possibility of publication bias by visual inspection of funnel
plot of effect size against standard error.
Results
Literature search
The flow chart of the identification and selection of studies
is shown in Fig.1. A total of 3365 records were identified in
the initial search strategy, with additional three records iden-
tified through other sources (reference lists of retrieved arti-
cles). After screening of title and abstracts, 77 records were
selected for full-text evaluation. At the end of the selection
process, 26 articles were included in the meta-analysis, for
a total of 211,676 subjects. Characteristics of the studies are
summarized in Tables1, 2 and 3.
Seven prospective cohort studies investigated plant prod-
uct’s consumption and incidence of AMD [3, 4, 13–17], 12
animal products [3, 4, 14, 15, 18–25], 3 dietary fats [18, 21,
26], and 12 alcohol [4, 14, 27–36]. The follow-up period
ranged from 4 to 27years. The majority of the studies were
conducted in the US [4, 13, 15, 18, 22, 25, 27, 28, 31, 33].
and Australia [3, 16, 17, 19–21, 24, 26, 34, 36], while the
others were conducted in northern Europe [14, 23, 29, 32]
and eastern Asia [30, 35]. All the studies, except for the
study by Miyazaky etal. [30] reported separated results
for early and late AMD. The diagnosis of AMD was self-
reported and confirmed by medical record review in six
studies [13, 18, 22, 25, 27, 28]. In the remaining 20 studies,
Fig. 1 PRISMA flow diagram for search strategy

2126 European Journal of Nutrition (2019) 58:2123–2143
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Table 1 Characteristics of included cohort studies investigating plant product’s consumption and occurrence of AMD
Author, year Country (cohort) n/NFollow up Age Sex Outcome Comparison RR (95% CI) Adjustment Study quality
Vegetables
Cho etal. 2004 [13]US (NHS + HPFS) 464/110,232 18 30–75 M/F Early AMD ≥ 4/day vs. <2/day 1.11 (0.69–1.77) Age, pack-years of smoking,
energy and fish intake, body
mass index, postmenopausal
hormone use, moderate to
vigorous activities, history
of hypertension, history of
high blood cholesterol level,
alcohol intake, profession,
physical activity
High
Cho etal. 2004 [13]US (NHS + HPFS) 316/110,232 18 30–75 M/F Late AMD ≥ 4/day vs. <2/day 1.06 (0.73–1.56)
Arnarsson etal. 2006
(fiber-rich) [14]
Iceland (RES) 126/1379 5 ≥ 50 M/F Early AMD 4–7/week vs. <1/month 0.46 (0.21–1.03) Age, smoking, and sex High
Islam etal. 2014 [3] Australia (MCCS) 2508/19,768 13 40–69 M/F Early AMD Q4 vs. Q1 0.97 (0.85–1.11) Age, sex, country of origin,
smoking status, education
level, multivitamin supple-
ment use, total energy intake
High
Islam etal. 2014 [3] Australia (MCCS) 108/19,768 13 40–69 M/F Late AMD Q4 vs. Q1 0.84 (0.45–1.59)
Merle etal. 2015 [4] US (AREDS) 744/2525 8.7 55–80 M/F Late AMD Q2 vs. Q1 0.85 (0.73–0.99) Age, sex, AREDS treatment,
AMD grade at baseline
for both eyes, total energy
intake, educational level,
smoking, BMI, supplement
use, 10 genetic variants, 9
alternate Mediterranean diet
components
High
Fruit
Cho etal. 2004 [13]US (NHS + HPFS) 464/110,232 18 30–75 M/F Early AMD ≥ 3/day vs. <1.5/day 0.86 (0.64–1.15) Age, pack-years of smoking,
energy and fish intake, body
mass index, postmenopausal
hormone use, moderate to
vigorous activities, history
of hypertension, history of
high blood cholesterol level,
alcohol intake, profession,
physical activity
High
Cho etal. 2004 [13]US (NHS + HPFS) 316/110,232 18 30–75 M/F Late AMD ≥ 3/day vs. <1.5/day 0.64 (0.44–0.93)
Islam etal. 2014 [3] Australia (MCCS) 2508/19,768 13 40–69 M/F Early AMD Q4 vs. Q1 0.93 (0.82–1.05) Age, sex, country of origin,
smoking status, education
level, multivitamin supple-
ment use, total energy intake
High
Islam etal. 2014 [3] Australia (MCCS) 108/19,768 13 40–69 M/F Late AMD Q4 vs. Q1 0.81 (0.47–1.40)

2127European Journal of Nutrition (2019) 58:2123–2143
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Table 1 (continued)
Author, year Country (cohort) n/NFollow up Age Sex Outcome Comparison RR (95% CI) Adjustment Study quality
Merle etal. 2015 [4] US (AREDS) 744/2525 8.7 55–80 M/F Late AMD Q2 vs. Q1 0.99 (0.85–1.15) Age, sex, AREDS treatment,
AMD grade at baseline
for both eyes, total energy
intake, educational level,
smoking, BMI, supplement
use, 10 genetic variants, 9
alternate Mediterranean diet
components
High
Grain
Kaushik etal. 2008 [16] Australia (BMES) 208/1810 10 ≥ 49 M/F Early AMD 376g/day vs. 82.6g/day 0.67 (0.44–1.02) Age, sex, mean arterial blood
pressure, BMI, smoking,
HDL cholesterol, qualifica-
tion level, history of myo-
cardial infarction or stroke,
fish consumption, and total
vegetable, fruit, and total fat
(energy-adjusted) intakes
High
Merle etal. 2015 [4] US (AREDS) 744/2525 8.7 55–80 M/F Late AMD Q2 vs. Q1 0.93 (0.80–1.07) Age, sex, AREDS treatment,
AMD grade at baseline
for both eyes, total energy
intake, educational level,
smoking, BMI, supplement
use, 10 genetic variants, 9
alternate Mediterranean diet
components
High
Nuts
Seddon etal. 2003 [15] US (PAMDS) 51/261 4.6 ≥ 60 M/F Late AMD ≥ 1/week vs. never 0.60 (0.32–1.02) Age–sex group, education,
body mass index, systolic
blood pressure, cardiovascu-
lar disease, log energy, pro-
tein intake, energy-adjusted
log beta-carotene intake,
alcohol intake, physical
activity, and initial age-
related macular degeneration
grade, total intake of energy-
adjusted log zinc, vitamin C,
and vitamin E
High
Tan etal. 2009 [17] Australia (BMES) 220/1925 10.5 ≥ 49 M/F Early AMD ≥ 3/week vs. <1/week 0.73 (0.51–1.06) Age, sex, smoking High
Tan etal. 2009 [17] Australia (BMES) 344/1813 10.5 ≥ 49 M/F Late AMD ≥ 3/week vs. <1/week 0.75 (0.56–1.02)

2128 European Journal of Nutrition (2019) 58:2123–2143
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ophthalmologic data were collected by ocular examination
and fundus photographs of the macula [3, 4, 14–17, 19–21,
23, 24, 26, 29–36].
Plant products
Characteristics of the studies that investigated plant prod-
uct’s consumption and incidence of AMD are summarized
in Table1. Four studies evaluated vegetables (133,904 par-
ticipants), three fruits (n = 132,525), two grain (n = 4335),
and three nuts (n = 4711). By comparing the highest vs. the
lowest consumption, pooled analyses indicated a non-signif-
icant reduction of risk for either vegetables (RR 0.92 95% CI
0.82–1.03; p = 0.33) (I2 = 13%; p = 0.15), fruit (RR 0.91 95%
CI 0.82–1.01; p = 0.08) (I2 = 19%; p = 0.29), nuts (RR 0.81;
95% CI 0.64–1.02; p = 0.08) (I2 = 58%; p = 0.07) or grain
(RR 0.84 95% CI 0.62–1.13; p = 0.25) (I2 = 52%; p = 0.15)
(Fig.2). Similarly, no significant results were obtained in
subgroup analysis by AMD stage.
Animal products
Characteristics of the studies that investigated animal prod-
uct’s consumption and incidence of AMD are summarized
in Table2. Six studies evaluated meat (n = 101,011), 3
dairy products (n = 73,772), and 8 fish (n = 237,464). As
depicted in Fig.3, pooled analyses indicated a non-signif-
icant increase of AMD risk for the group with the highest
consumption of meat (RR 1.11 95% CI 0.96–1.27; p = 0.16)
(I2 = 65%; p = 0.16). The result reached the statistical sig-
nificance when only early AMD was considered (RR 1.17
95% CI 1.02–1.34; p = 0.03) (I2 = 66%; p = 0.01). A non-
significant association was found for dairy products (RR
1.07 95% CI 0.68–1.70; p = 0.77) (I2 = 77%; p = 0.004). On
the other hand, fish determined a significant reduction of
risk for total AMD (RR 0.82 95% CI 0.75–0.90; p < 0.001)
(I2 = 33%; p = 0.14), as well as for both early (RR 0.84 95%
CI 0.73–0.97; p = 0.02) (I2 = 50%; p = 0.09), and late (RR
0.79 95% CI 0.70–0.90; p < 0.001) (I2 = 10%; p = 0.35)
AMD.
Fats andalcohol
Characteristics of the studies that investigated fats, alcohol
consumption and incidence of AMD are summarized in
Table3. Two studies evaluated oils (n = 77,078), two butter
(n = 7862), three margarine (n = 79,336), and twelve alco-
hol consumption (n = 120,440). Pooled analyses indicated a
non-significant association for either oils (RR 1.10 95% CI
0.98–1.23; p = 0.12) (I2 = 1%; p = 0.36), butter (RR 1.04 95%
CI 0.93–1.16; p = 0.49) (I2 = 0%; p = 0.52), or margarine
(RR 1.05 95% CI 0.91–1.21; p = 0.54) (I2 = 7%; p = 0.36)
(Fig.4). As showed in Fig.5, there was a significant increase
Table 1 (continued)
Author, year Country (cohort) n/NFollow up Age Sex Outcome Comparison RR (95% CI) Adjustment Study quality
Merle etal. 2015 [4]US (AREDS) 744/2525 8.7 55–80 M/F Late AMD Q2 vs. Q1 1.00 (0.87–1.16) Age, sex, AREDS treatment,
AMD grade at baseline
for both eyes, total energy
intake, educational level,
smoking, BMI, supplement
use, 10 genetic variants, 9
alternate Mediterranean diet
components
High
NHS Nurses’ Health, HPFS Health Professionals Follow-up Study, RES Reykjavik Eye Study, MCCS Melbourne Collaborative Cohort Study, AREDS Age-Related Eye Disease Study, PAMDS
The Progression of Age-Related Macular Degeneration Study, BMES Blue Mountains Eye Study

2129European Journal of Nutrition (2019) 58:2123–2143
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Table 2 Characteristics of included cohort studies investigating animal product’s consumption and occurrence of AMD
Author, year Country (cohort) n/NFollow
up
Age Sex Outcome Comparison RR (95%
CI)
Adjustment Study
quality
Meat
Cho etal. 2001 (beef,
pork or lamb) [18]
US (NHS + HPFS) 567/71,474 12 30–75 M/F Early AMD > 4–6/week vs. ≤3/month 1.35
(1.07–
1.69)
2-year period, age,
smoking, energy and
lutein and zeaxan-
thin intakes, BMI,
profession, physical
activity (metabolic
equivalent quintiles),
and alcohol intake
High
Seddon etal. 2003
[15]
US (PAMDS) 51/261 4.6 ≥ 60 M/F Late AMD Q4 vs. Q1 2.09
(0.98–
4.47)
Age–sex group,
education, body
mass index, systolic
blood pressure,
cardiovascular
disease, log energy,
protein intake,
energy-adjusted log
beta-carotene intake,
alcohol intake,
physical activity, and
initial age-related
macular degeneration
grade, total intake of
energy-adjusted log
zinc, vitamin C, and
vitamin E
High
Arnarsson etal. 2006
[14]
Iceland (RES) 126/1379 5 ≥ 50 M/F Early AMD 4–7/week vs. <1/month 1.54
(0.56–
4.17)
Age, sex, smoking High
Chong etal. 2009
(fresh) [19]
Australia (MCCS) 2590/5604 13 66–85 M/F Early AMD ≥ 6.5/week vs. ≤2.5/week 1.33
(1.14–
1.56)
Age, sex, smoking
(current, past, never),
energy intake,
vitamin C, vitamin
E, b-carotene, zinc,
lutein/zeaxanthin,
body mass index,
and energy-adjusted
protein intake
High
Chong etal. 2009
(fresh) [19]
Australia (MCCS) 77/5604 13 66–85 M/F Late AMD ≥ 6.5/week vs. ≤2.5/week 1.48
(0.69–
3.19)

2130 European Journal of Nutrition (2019) 58:2123–2143
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Table 2 (continued)
Author, year Country (cohort) n/NFollow
up
Age Sex Outcome Comparison RR (95%
CI)
Adjustment Study
quality
Chong etal. 2009
(processed) [19]
Australia (MCCS) 2590/5604 13 66–85 M/F Early AMD ≥ 4/week vs. ≤1/week 1.13
(0.89–
1.41)
Age, sex, smoking
(current, past, never),
energy intake,
vitamin C, vitamin
E, b-carotene, zinc,
lutein/zeaxanthin,
body mass index,
and energy-adjusted
protein intake
High
Chong etal. 2009
(processed) [19]
Australia (MCCS) 77/5604 13 66–85 M/F Late AMD ≥ 4/week vs. ≤1/week 0.98
(0.47–
2.05)
Chong etal. 2009
(chicken) [19]
Australia (MCCS) 2590/5604 13 66–85 M/F Early AMD ≥ 3.5/week vs. ≤1/week 1.15
(0.99–
1.32)
Age, sex, smoking
(current, past, never),
energy intake, vita-
min C, vitamin E,
beta-carotene, zinc,
lutein/zeaxanthin,
body mass index,
and energy-adjusted
protein intake
High
Chong etal. 2009
(chicken) [19]
Australia (MCCS) 77/5604 13 66–85 M/F Late AMD ≥ 3.5/week vs. ≤1/week 0.43
(0.20–
0.91)
Islam etal. 2014
(red) [3]
Australia (MCCS) 2508/19,768 13 40–69 M/F Early AMD Q4 vs. Q1 0.95
(0.84–
1.08)
Age, sex, country of
origin, smoking
status, education
level, multivitamin
supplement use, total
energy intake
High
Islam etal. 2014
(red) [3]
Australia (MCCS) 108/19,768 13 40–69 M/F Late AMD Q4 vs. Q1 0.97
(0.49–
1.95)
Merle etal. 2015
(red) [4]
US (AREDS) 744/2525 8.7 55–80 M/F Late AMD Q2 vs. Q1 0.88
(0.75–
1.04)
Age, sex, AREDS
treatment, AMD
grade at baseline
for both eyes, total
energy intake, edu-
cational level, smok-
ing, BMI, supple-
ment use, 10 genetic
variants, 9 alternate
Mediterranean diet
components
High

2131European Journal of Nutrition (2019) 58:2123–2143
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Table 2 (continued)
Author, year Country (cohort) n/NFollow
up
Age Sex Outcome Comparison RR (95%
CI)
Adjustment Study
quality
Dairy products
Cho etal. 2001
(cheese) [18]
US (NHS + HPFS) 567/71,474 12 30–75 M/F Early AMD > 4–6/week vs. ≤3/month 1.14
(0.86–
1.51)
2-year period, age,
smoking, energy and
lutein and zeaxan-
thin intakes, BMI,
profession, physical
activity (metabolic
equivalent quintiles),
and alcohol intake
High
Seddon etal. 2003
[15]
US (PAMDS) 51/261 4.6 ≥ 60 M/F Late AMD Q4 vs. Q1 1.91
(0.98–
3.73)
Age, sex, smoking,
energy, vitamin
C, vitamin E,
β-Carotene, zinc,
lutein, zeaxanthin,
and supplements
(vitamin C, vitamin
E, cod liver oil, and
fish oil [yes/no])
High
Gopinath etal. 2014
[20]
Australia (BMES) 268/2037 15 ≥ 49 M/F Early AMD ≥ 2.75 serv/day vs. ≤0.78 serv/day 1.30
(0.83–
2.04)
Age, sex, current
smoking, white cell
count, fish consump-
tion
High
Gopinath etal. 2014
[20]
Australia (BMES) 84/2037 15 ≥ 49 M/F Late AMD ≥ 2.75 serv/day vs. ≤0.78 serv/day 0.36
(0.33–
0.83)
Fish
Cho etal. 2001 [18]US (NHS + HPFS) 567/71,474 12 30–75 M/F Early AMD ≥ 4/week vs. ≤1/month 0.65
(0.46–
0.91)
2-year period, age,
smoking, energy and
lutein and zeaxan-
thin intakes, BMI,
profession, physical
activity (metabolic
equivalent quintiles),
and alcohol intake
High
Seddon etal. 2003
[15]
US (PAMDS) 51/261 4.6 ≥ 60 M/F Late AMD ≥ 2/week vs. ≤1/week 0.88
(0.49–
1.60)
Age, sex, smoking,
energy, vitamin
C, vitamin E,
β-carotene, zinc,
lutein, zeaxanthin,
and supplements
(vitamin C, vitamin
E, cod liver oil, and
fish oil [yes/no])
High

2132 European Journal of Nutrition (2019) 58:2123–2143
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Table 2 (continued)
Author, year Country (cohort) n/NFollow
up
Age Sex Outcome Comparison RR (95%
CI)
Adjustment Study
quality
Chong etal. 2009
[21]
Australia (MCCS) 2590/5604 13 66–85 M/F Early AMD ≥ 2/week vs. 0-0.5/week 0.90
(0.79–
1.03)
Age, sex, smoking,
energy, vitamin
C, vitamin E,
β-carotene, zinc,
lutein, zeaxanthin,
and supplements
(vitamin C, vitamin
E, cod liver oil, and
fish oil [yes/no])
High
Chong etal. 2009
[21]
Australia (MCCS) 77/5604 13 66–85 M/F Late AMD ≥ 2/week vs. 0-0.05/week 0.76
(0.42–
1.38)
Christen etal. 2011
[22]
US (WHS) 235/38,022 10 ≥ 45 F Early AMD ≥ 1/week vs. <1/month 0.58
(0.38–
0.87)
Age, randomized treat-
ment assignment,
smoking, alcohol
use, BMI, menopau-
sal status and use of
hormonal therapy,
history of hyperten-
sion, history of high
cholesterol, history
of diabetes multivi-
tamin use, history of
eye exam in the last
2years
High
Wang etal. 2014 [23]Australia + Holland
(BMES + RS)
1074/3579 15 ≥ 55 M/F Early AMD ≥ 1/week vs. <1/week 0.93
(0.82–
1.07)
Age, sex High
Wang etal. 2014 [23]Australia + Holland
(BMES + RS)
200/3579 15 ≥ 55 M/F Late AMD ≥ 1/week vs. <1/week 0.72
(0.52–
0.99)
Joachim etal. 2015
[24]
Australia (BMES) 173/1149 15 ≥ 49 M/F Early AMD ≥ 1/week vs. never 0.92
(0.68–
1.24)
Age, sex, smoking,
CFH, ARMS2 poly-
morphisms
High
Joachim etal. 2015
[24]
Australia (BMES) 47/1149 15 ≥ 49 M/F Late AMD ≥ 1/week vs. never 0.48
(0.29–
0.79)

2133European Journal of Nutrition (2019) 58:2123–2143
1 3
Table 2 (continued)
Author, year Country (cohort) n/NFollow
up
Age Sex Outcome Comparison RR (95%
CI)
Adjustment Study
quality
Merle etal. 2015 [4] US (AREDS) 744/2525 8.7 55–80 M/F Late AMD Q2 vs. Q1 0.86
(0.74–
0.99)
Age, sex, AREDS
treatment, AMD
grade at baseline
for both eyes, total
energy intake, edu-
cational level, smok-
ing, BMI, supple-
ment use, 10 genetic
variants, 9 alternate
Mediterranean diet
components
High
Wu etal. 2017 [25]US (NHS + HPFS) 1356/114,850 27 50–90 M/F Late AMD ≥ 5/week vs. never 0.80
(0.59–
1.08)
Age, race, body mass
index, pack/years of
smoking, physical
activity, current
aspirin use, history
of hypertension
and hypercholes-
terolemia, dietary
variables including
alternative healthy
eating index,
a-linolenic acid, and
total energy intake,
postmenopausal
status, menopausal
hormone use
High
NHS Nurses’ Health, HPFS Health Professionals Follow-up Study, PAMDS The Progression of Age-Related Macular Degeneration Study, RES Reykjavik Eye Study, MCCS Melbourne Collabo-
rative Cohort Study, AREDS Age-Related Eye Disease Study, BMES Blue Mountains Eye Study, WHS Women’s Health Study, RS Rotterdam Study

2134 European Journal of Nutrition (2019) 58:2123–2143
1 3
Table 3 Characteristics of included cohort studies investigating dietary fats, alcohol consumption and occurrence of AMD
Author, year Country (cohort) n/NFolow up Age Sex Outcome Comparison RR (95% CI) Adjustment Study quality
Oils
Cho etal. 2001 [18]US (NHS + HPFS) 567/71,474 12 30–75 M/F Early AMD > 4–6/week vs. ≤3/month 1.29 (1.00–1.66) 2-year period, age, smok-
ing, energy and lutein
and zeaxanthin intakes,
BMI, profession, physi-
cal activity (metabolic
equivalent quintiles),
and alcohol intake
High
Chong etal. 2009a (olive
oil) [21]
Australia (MCCS) 1680/5604 13 66–85 M/F Early AMD ≥ 100mL/week vs.
0.05mL/week
1.05 (0.92–1.20) Age, sex, smoking,
energy, vitamin C, vita-
min E, β-carotene, zinc,
lutein, zeaxanthin, and
supplements (vitamin C,
vitamin E, cod liver oil,
and fish oil [yes/no])
High
Chong etal. 2009a (olive
oil) [21]
Australia (MCCS) 77/5,604 13 66–85 M/F Late AMD ≥ 100mL/week vs.
0.05mL/week
1.05 (0.53–2.07)
Butter
Chua etal. 2006 [26] Australia (BMES) 130/2258 5.1 ≥ 49 M/F Early AMD ≥ 3/week vs. <1/month 0.77 (0.48–1.24) Medium
Chua etal. 2006 [26] Australia (BMES) 22/2258 5.1 ≥ 49 M/F Late AMD ≥ 3/week vs. <1/month 0.85 (0.27–2.66)
Chong etal. 2009a [21] Australia (MCCS) 1680/5604 13 66–85 M/F Early AMD ≥ 7/week vs. 0/week 1.07 (0.95–1.21) Age, sex, smoking,
energy, vitamin C, vita-
min E, β-carotene, zinc,
lutein, zeaxanthin, and
supplements (vitamin C,
vitamin E, cod liver oil,
and fish oil [yes/no])
High
Chong etal. 2009a [21] Australia (MCCS) 77/5604 13 66–85 M/F Late AMD ≥ 7/week vs. 0/week 0.85 (0.45–1.58)
Margarine
Cho etal. 2001 [18]US (NHS + HPFS) 567/71,474 12 30–75 M/F Early AMD > 6/week vs. ≤3/month 1.42 (1.01–2.00) 2-year period, age, smok-
ing, energy and lutein
and zeaxanthin intakes,
BMI, profession, physi-
cal activity (metabolic
equivalent quintiles),
and alcohol intake
High
Chua etal. 2006 [26] Australia (BMES) 130/2258 5.1 ≥ 49 M/F Early AMD ≥ 3/week vs. <1/month 0.87 (0.58–1.29) Medium
Chua etal. 2006 [26] Australia (BMES) 22/2258 5.1 ≥ 49 M/F Late AMD ≥ 3/week vs. <1/month 0.85 (0.33–2.22)
Chong etal. 2009a [21] Australia (MCCS) 1680/5604 13 66–85 M/F Early AMD ≥ 7/week vs. 0/week 1.01 (0.88–1.17) Age, sex, smoking,
energy, vitamin C, vita-
min E, β-carotene, zinc,
lutein, zeaxanthin, and
supplements (vitamin C,
vitamin E, cod liver oil,
and fish oil [yes/no])
High
Chong etal. 2009a [21] Australia (MCCS) 77/5604 13 66–85 M/F Late AMD ≥ 7/week vs. 0/week 1.05 (0.53–2.07)

2135European Journal of Nutrition (2019) 58:2123–2143
1 3
Table 3 (continued)
Author, year Country (cohort) n/NFolow up Age Sex Outcome Comparison RR (95% CI) Adjustment Study quality
Alcohol
Ajani etal. 1999 [27] US (PHS) 451/21,052 12.5 40–84 M Early AMD ≥ 1/day vs. <1/week 1.14 (0.89–1.46) Age, randomized treat-
ment assignment,
diabetes, hypertension,
obesity, physical activ-
ity, parental history of
myocardial infarction
before age 60, smoking
status, multivitamin use
High
Ajani etal. 1999 [27] US (PHS) 68/21,052 12.5 40–84 M Late AMD ≥ 1/day vs. <1/week 1.14 (0.62–2.09)
Cho etal. 2000 [28]US (HPFS + NHS) 451/62,252 11 ≥ 50 M/F Early AMD ≥ 30g/day vs. 0g/day 1.60 (0.94–2.73) Age, smoking, energy,
body mass index, exer-
cise, hormone replace-
ment therapy
Hypertension, occupation
High
Cho etal. 2000 [28]US (HPFS + NHS) 180/62,252 11 ≥ 50 M/F Late AMD ≥ 30g/day vs. 0g/day 0.78 (0.42–1.47)
Buch etal. 2005 [29] Denmark (CCES) 94/301 14.5 60–80 M/F Early AMD > 250g/week vs. 0g/day 2.90 (1.00–9.20) Age, gender Medium
Buch etal. 2005 [29] Denmark (CCES) 52/301 14.5 60–80 M/F Late AMD > 250g/week vs. 0g/day 2.80 (0.80–9.90)
Miyazaky etal. 2005
[30]
Japan (Hisayama) 75/961 5 ≥ 50 M/F AMD ≥ 1/week vs. never 1.25 (0.81–1.91) Age, sex, hypertension,
diabetes, hyperlipi-
demia, smoking habit,
body mass index, white
blood cells
High
Arnarsson etal. 2006
[14]
Iceland (RES) 126/1379 5 ≥ 50 M/F Early AMD >monthly vs. never 1.98 (1.13–3.49) Age, smoking, and sex High
Knudtson etal. 2007
[31]
US (BDES) 391/3509 15 43–86 M/F Early AMD ≥ 44g/day vs. never 1.42 (0.69–2.92) Age, smoking, vitamin
use, systolic blood pres-
sure, gender
High
Knudtson etal. 2007
[31]
US (BDES) 102/3509 15 43–86 M/F Late AMD ≥ 44g/day vs. never 4.56 (1.54–13.50)
Boekhoorn etal. 2008
[32]
Holland (RS) 519/4229 8 ≥ 50 M/F Early AMD > 20g/day vs. 0g/day 1.10 (0.80–1.51) Smoking, body mass
index, systolic and
diastolic blood pres-
sures, complement
factor H genotype status,
and total cholesterol,
high-density lipoprotein
cholesterol levels
High
Boekhoorn etal. 2008
[32]
Holland (RS) 81/4229 8 ≥ 50 M/F Late AMD > 20g/day vs. 0g/day 1.01 (0.46–2.21)
Coleman etal. 2010 [33] US (SOF) 286/1194 15 ≥ 65 M/F Early AMD any alcohol in last 30
days: yes vs. no
1.57 (1.18–2.11) Current smoking, age,
race, hypertension,
walks for exercise, study
sites
High
Coleman etal. 2010 [33] US (SOF) 94/1710 15 ≥ 65 M/F Late AMD any alcohol in last 30
days: yes vs. no
0.79 (0.51–1.23)
Adams etal. 2012 [34] Australia (MCCS) 2662/20,963 4 48–86 M/F Early AMD ≥ 20g/day vs. 0g/day 1.21 (1.06–1.38) Age, sex, country of birth,
physical activity, energy
from food
High

2136 European Journal of Nutrition (2019) 58:2123–2143
1 3
of AMD risk for the group with the highest consumption of
alcohol (RR 1.20 95% CI 1.04–1.39; p = 0.01) (I2 = 55%;
p = 0.002). However, by analyzing subgroup analyses of
AMD stage, only early AMD was statistically significant
(RR 1.29 95% CI 1.16–1.43; p < 0.001) (I2 = 8%; p = 0.37).
Study quality, sensitivity analysis andpublication
bias
On the basis of the Newcastle–Ottawa Scale assessment,
almost all studies (93%) resulted of relatively high qual-
ity. The mean NOS score was 7.96 ± 0.93. The detailed
description of the quality rating of the studies is shown in
Supplementary Table1. A leave-one-out sensitivity analysis
was performed by iteratively removing one study at a time
to confirm that our findings were not driven by any single
study. There was little change in the quantitative summary
measures of RR or the 95% CI, with no studies influencing
results for almost all the food groups. The only exception
were nuts, where the removal of the study by Merle etal. [4]
changed the relative effect from non-significant (in the main
analysis) to significant in the sensitivity analysis (RR 0.72
95% CI 0.58–0.89; p = 0.002) (I2 = 0%; p = 0.77).
Publication bias was assessed for alcohol consumption
(Supplementary Fig.1). The shape of the funnel plot showed
no obvious asymmetry, suggesting little evidence of publi-
cation bias. In particular, two studies appeared as outliers
[4, 31].
Discussion
The present study systematically explored the possible asso-
ciation existing between food groups and AMD in a compre-
hensive analysis of 26 prospective cohort studies, including
a total of 211,676 subjects and 7154 cases of AMD. Com-
paring the highest and the lowest consumption of different
food groups, we found a significant 18% reduced risk of
AMD for fish (1–5 servings/week vs. <1 serving/week) and
a 20% increased risk for alcohol (1–2 servings/day vs. <1
serving/day). Furthermore, an increased risk for meat (3.5-7
servings/week vs. 1-2.5 servings/week) was observed, but
only in the subgroup of early AMD. With regard to the other
food groups (fruit, vegetables, nuts, grain, dairy products,
oils, butter and margarine), no significant associations were
found for either the early or late AMD phases.
AMD is the most important cause of visual loss, with a
prevalence that increases with age [2]. Despite many efforts
of the scientific community and pharmaceutical companies,
effective treatments for AMD are not yet available [37].
The pathogenesis of AMD is complex and involves many
mechanisms such as endothelial dysfunction, inflamma-
tion and oxidative stress, which are in common with other
Table 3 (continued)
Author, year Country (cohort) n/NFolow up Age Sex Outcome Comparison RR (95% CI) Adjustment Study quality
Merle etal. 2015 [4] US (AREDS) 744/2525 8.7 55–80 M/F Late AMD Q2 vs. Q1 0.88 (0.74–1.04) Age, sex, AREDS treat-
ment, AMD grade at
baseline for both eyes,
total energy intake, edu-
cational level, smoking,
BMI, supplement use,
10 genetic variants, 9
alternate Mediterranean
diet components
High
Shim etal. 2016 [35] South Korea 34/172 4.4 50–79 M/F Late AMD ≥ 20g/day vs. 0g/day 0.6 (0.1–1.4) Age, smoking status,
alcohol consumption,
BMI, blood pressure,
total cholesterol, HDL
cholesterol
High
Gopinath etal. 2017 [36] Australia (BMES) 248/1903 15 ≥ 49 M/F Early AMD > 2/day vs. ≤2/day 1.39 (1.01–1.91) Age, sex, white cell count,
fish consumption
High
Gopinath etal. 2017 [36] Australia (BMES) 76/1903 15 ≥ 49 M/F Late AMD > 2/day vs. ≤2/day 0.93 (0.49–1.74)
NHS Nurses’ Health, HPFS Health Professionals Follow-up Study, RES Reykjavik Eye Study, MCCS Melbourne Collaborative Cohort Study, BMES Blue Mountains Eye Study, AREDS Age-
Related Eye Disease Study, PHS Physician Health Study, CCES Copenhagen City Eye Study, BDES Beaver Dam Eye Study, RS The Rotterdam Study, SOF Study of Osteoporotic Fractures

2137European Journal of Nutrition (2019) 58:2123–2143
1 3
Fig. 2 Forest plot summary of
plant product’s consumption
and occurrence of AMD

2138 European Journal of Nutrition (2019) 58:2123–2143
1 3
Fig. 3 Forest plot summary of
animal product’s consumption
and occurrence of AMD

2139European Journal of Nutrition (2019) 58:2123–2143
1 3
chronic degenerative diseases [37]. This supports biological
plausibility to explore the possible beneficial role of some
nutritional factors such as antioxidants, carotenoids, vita-
mins and essential fatty acids towards the development and
progression of AMD. Several studies have reported benefi-
cial effects for some nutrients and food supplements. The
AREDS trial clearly identified a multi-integrator strategy,
including beta-carotene, vitamins E and C, zinc and copper,
as an effective nutritional strategy to reduce the progres-
sion of AMD [6]. Furthermore, in the AREDS2 study, par-
ticipants with low dietary intake of lutein and zeaxanthin at
baseline, but who took an AREDS formulation with lutein
Fig. 4 Forest plot summary of
fat consumption and occurrence
of AMD

2140 European Journal of Nutrition (2019) 58:2123–2143
1 3
and zeaxanthin during the study, had a 25% reduced risk
of developing advanced AMD compared with participants
with similar dietary intake, but who were not taking lutein
and zeaxanthin [7].
While subjects with moderate or advanced AMD should
be advised to use supplements based on AREDS [38], there
is no evidence that healthy subjects should take antioxidants,
omega-3 or vitamin supplements to prevent the development
of AMD [39, 40]. Improving the overall diet quality, how-
ever, could be effective in reducing its incidence [41–43].
Numerous cross-sectional and prospective cohort studies
suggested that healthy diets rich in fruit, vegetables, fish and
nuts are protective against AMD [3, 43]. A greater adherence
to the Mediterranean food model has been associated with
a significant reduced risk of AMD and progression [4, 44],
perhaps with a decrease in oxidative stress and inflamma-
tion. In contrast, the typical Western diet with a high content
of fats and a high glycemic index, or a diet that includes
heavy alcohol consumption, has been associated with an
increasing risk [8, 45].
In the present meta-analysis, we found that the fish con-
sumption is able to determine a beneficial effect on the
development of AMD. This result is consistent with previous
results, in which a linear association between dose of fish
consumed and risk of AMD has been demonstrated [9]. The
protective effect can be explained by different components
of fish such as docosahexaenoic acid, which is required for
the regeneration of photoreceptor outer segments, and meso-
zeaxanthin, which has been shown to improve the optical
density of the macular pigment [46].
In line with previous studies that reported red meat as a
potential risk factor for AMD [19, 47], our pooled analysis
suggested a detrimental effect of high meat intake on early
AMD. It has been suggested that a high fat content in red
meat may increase the risk of AMD [48]. Recently, how-
ever, interest has been focused on other components such
as heme iron, nitrites, nitrous compounds, and advanced
glycated end products (AGEs) that can act independently
or in combination to determine AMD. In particular, heme
iron seems to cause an increase in levels of N-nitroso
Fig. 5 Forest plot summary of alcohol consumption and occurrence of AMD

2141European Journal of Nutrition (2019) 58:2123–2143
1 3
compounds [49], which have been reported to damage
the retina [50]. Furthermore, there is evidence that the
progression of AMD is exacerbated by AGEs through an
increase in oxidative stress and inflammation, impair-
ment of normal cellular functions, and alteration of cel-
lular function through receptor-mediated activation [51].
AGEs have also been found within soft drusen and the
retinal pigment epithelial cells in the eyes of AMD [52].
As for alcohol, our analysis confirmed that high con-
sumption has a detrimental effect on AMD. This result is
consistent with the adverse effects observed in all studies
including alcohol, when consumption was higher than the
recommended intake [53]. In fact, consumed in modera-
tion and during meals, alcohol reduces the risk of cardio-
vascular and other diseases, but high consumption has
always been associated with an increased risk, probably
because of its pro-oxidant effect [54]. Besides increasing
ROS levels, DNA, protein and lipid oxidation directly,
alcohol exposure also modifies the mechanisms that pro-
tect against oxidative stress [55]. It has been reported,
moreover, that alcohol enhances angiogenesis and exac-
erbation of choroidal neovascularization [56].
In the present meta-analysis, no significant association
with AMD was found for all the other food groups such
as fruit, vegetables, nuts, grain, dairy products and fats. It
is possible that the limited number of prospective cohort
studies evaluating such food groups and AMD reduced
the statistical power of the analysis. For example, it has
been postulated that high intake of fruit and vegetables
has a protective effect against the onset and development
of AMD, but most evidence comes from cross-sectional
studies [47, 57–59]. Further prospective cohort studies
or randomized clinical trials are needed to increase the
strength of the evidence.
Several limitations are present in this meta-analysis
and should be addressed. First of all, the included studies
assessed food groups’ consumption through self-reported
instruments which are susceptible to recall bias. Second, the
number of the studies investigating several food groups is
very limited, making it difficult to reach a definitive conclu-
sion. Finally, variables for adjustment differ across studies,
increasing the risk of residual confounding. Nevertheless,
despite these limitations, our meta-analysis identified dif-
ferent associations between food groups and AMD, empha-
sizing the importance of dietary habits in AMD prevention.
There are also several strengths that should be mentioned.
To begin with, we have included only prospective cohort
studies, which are less prone to bias with respect to cross-
sectional and case–control studies. Furthermore, all included
studies had a high methodological quality, with an adequate
follow-up, and relatively high participation rates. Finally,
aggregated studies evaluated risk estimates adjusted for at
least age, sex and smoking.
To the best of our knowledge, this is the first meta-
analysis that assessed the relationship between different
food groups and AMD. Our results suggest a protective
effect for high consumption of fish on both early and late
AMD, and a detrimental effect of high consumption of
meat on early AMD. We also detected a detrimental effect
of high alcohol intake. Although further studies are needed
to confirm these results, our findings may stimulate the
development of preventive strategies that include nutri-
tional recommendations to reduce the risk of development
and progression of AMD.
Author contributions Conception and design: MD, FS. Analysis and
interpretation of the data: MD, GP, FS. Drafting of the article: MD, FS.
Critical revision of the article for important intellectual content: GP,
AC, FS. Final approval of the article: AC, FS. Statistical expertise: MD.
Funding Nothing to declare.
Compliance with ethical standards
Conflict of interest All authors declare that there are no conflicts of
interest.
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