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Dietary fatty acids intakes and rate of mild cognitive impairment.
The Italian Longitudinal Study on Aging
Vincenzo Solfrizzi a, Anna M. Colacicco a, Alessia D’Introno a, Cristiano Capurso a,b, Angelo
Del Parigi c, Sabrina A. Capurso a, Giovanni Argentieri a, Antonio Capurso a, Francesco Panza a,b,*
a Department of Geriatrics, Center for Aging Brain, Memory Unit, University of Bari, Bari, Italyb Department of Geriatrics, University of Foggia, Foggia, Italy
c National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, AZ, USA
Received 15 December 2005; received in revised form 29 March 2006; accepted 30 March 2006
Available online 12 May 2006
Abstract
The possible impact of diet, particularly the intake of fatty acids, on cognitive decline and dementia was addressed recently by several studies.
We investigated the role of dietary fatty acids on the rate of mild cognitive impairment (MCI) in a population-based, prospective study carried out
on 278 and 186 nondemented elderly subjects (65–84 years) at the 1st (1992–1993) and 2nd (1995–1996) survey from the cohort of Casamassima,
Bari, Italy (nZ704), one of the eight centers of the Italian Longitudinal Study on Aging. During the median follow-up of 2.6 years, 18 new events
of MCI were diagnosed, and high polyunsaturated fatty acids (PUFA) intake appeared to be a protective factor against the development of MCI
[hazard ratio (HR): 0.65, 95% confidence interval (CI): 0.43–0.98, trend-test, dfZ1, p!0.04]. However, when we controlled for the possible
confounders (age, sex, education, Charlson comorbidity index, and total energy intake), the HR slightly changed, and the highly skewed 95% CI,
while not statistically significant, may be important (HR: 0.62, 95% CI: 0.34–1.13, pZ0.12). In our population, dietary fatty acids intakes were not
associated with incident MCI in older age, only high PUFA intake evidenced a borderline nonsignificant trend for a protective effect against the
development of MCI.
q 2006 Elsevier Inc. All rights reserved.
Keywords: Mild cognitive impairment; Fatty acids; Dementia; Diet; Nutrition
1. Introduction
Mild cognitive impairment (MCI) refers to progressive
mild memory- or cognitive impairment without dementia
(Petersen et al., 1999; Panza et al., 2005a). Persons with MCI
are known to have an increased risk of progression to
dementia, but the evolution is heterogeneous, as some
persons have seen to improve over time or remain stable
(Winblad et al., 2004; Panza et al., 2005a). Recently, in the
Italian Longitudinal Study on Aging (ILSA), a population-
based study with a sample of 5632 65–84 year old subjects,
we found a progression rate of MCI to dementia of 3.8/100
0531-5565/$ - see front matter q 2006 Elsevier Inc. All rights reserved.
doi:10.1016/j.exger.2006.03.017
* Corresponding author. Address: Department of Geriatrics, Center for Aging
Brain, Memory Unit, University of Bari, Policlinico, Piazza G. Cesare, 11,
70124 Bari, Italy. Tel.: C39 080 5592685; fax: C39 080 5478633.
E-mail addresses: [email protected] (V. Solfrizzi), geriat.dot@
geriatria.uniba.it (F. Panza).
person-years and that vascular risk factors influenced incident
MCI and the rate of progression to dementia (Solfrizzi et al.,
2004). In fact, many of the risk factors for cerebrovascular
disease and vascular dementia, including serum total
cholesterol, hypertension, atherosclerosis, and apolipoprotein
E genotype have also been shown to increase the risk of AD
(Haan et al., 1999; Panza et al., 2005b). Among these
vascular-related factors, there is a recent increase in the level
of interest in the possible impact of diet (Solfrizzi et al.,
2003; Del Parigi et al., 2006), particularly the intake of fatty
acids, on cognitive decline and dementia (Conquer et al.,
2000; Kalmijn, 2000; Kalmijn et al., 1997, 2004; Morris
et al., 2003a,b, 2004; Solfrizzi et al., 1999, 2005a,c). At
present, no population-based study investigated the associ-
ation between fatty acids intake and the risk of MCI in old
age, and management of risk factors for MCI may indicate
new options for prevention of dementia. In the present study,
we evaluated the association between dietary intake of fatty
acids and the development of MCI in a prospective
population-based study.
Experimental Gerontology 41 (2006) 619–627
www.elsevier.com/locate/expgero
V. Solfrizzi et al. / Experimental Gerontology 41 (2006) 619–627620
2. Methods
2.1. Study population
The subjects of this study took part in the ILSA, a study of
5632 subjects 65–84 year old, independent or institutiona-
lized, randomly selected from the electoral rolls of eight
Italian municipalities. The methods of data collection have
been described in detail elsewhere (Solfrizzi et al., 1999,
2004). Data were obtained from the 1st survey between
March 1992 and June 1993, and from the 2nd survey between
September 1995 and October 1996. The study population
included 704 randomized elderly subjects (65–84 years),
from Casamassima, Bari (Southern Italy). Participants were
278 and they were followed-up for a median period of 2.6
years, when a second evaluation of cognitive and functional
status was performed in 186 nondemented subjects. The
major causes of nonresponse among 278 elderly subjects
were death (49 subjects), refusal to take the follow-up
interview and/or to complete the neuropsychological evalu-
ation (32 subjects), removal and/or never found at home (nine
subjects), and two subjects became demented. After complete
description of the study, written informed consent was
obtained from all subjects and/or their relatives, according
to local ethical institutional guidelines.
2.2. Neuropsychological, functional, nutritional,
and clinical variables
The mini mental state examination (MMSE) was used to
evaluate global cognitive functions (Folstein et al., 1975).
Episodic memory was explored with the babcock story recall
test (BSRT). This test measures immediate and delayed recall,
and their sum, using a 21-unit story (Spinnler and Tognoni,
1987). Functional status was assessed by the activities of daily
living scale (ADL), which determines the level of indepen-
dence in six activities: bathing, dressing, toileting, transferring
from bed to chair, continence, and feeding (Katz and Akpom
1976). Ability in home management was assessed by the
instrumental activities of daily living scale (IADL) [scores
ranging from 8 (all functions preserved) to 31 (all functions
lost)], which determines the level of independence in
executing tasks such as using the telephone, shopping for
personal items, preparing meals, doing light housework (e.g.
washing dishes), managing money or drugs, and so forth
(Lawton and Brody, 1969). Dietary intakes were assessed at
baseline with a 77-item semi-quantitative food frequency
questionnaire (FFQ), previously validated (Leoci et al., 1993).
Dietary variables estimated were: energy, total lipids,
saturated fatty acids, monounsaturated fatty acids (MUFA),
polyunsaturated fatty acids (PUFA), carbohydrates, proteins,
alcohol, total, insoluble, and soluble fibers, cellulose and
noncellulosic polysaccharides. In particular, concerning the
validity and reliability of the semi-quantitative FFQ, this was
administered twice to a sample of 82 participants at a 1-year
interval. The subjects enrolled indicated how often during the
previous year, on average, they had eaten a certain food,
choosing among the pictures of three different serving sizes or
natural units, e.g. a glass of wine. Eight response categories
were offered, ranging from never to two or more times per
day. Two trained dietitians administered the semi-quantitative
FFQ in face-to-face meetings in each subject’s home. During
the 1-year interval, these subjects completed two 7-day food
records, currently considered as a ‘gold standard’ among
dietary assessment methods (Bingham and Day, 1997), spaced
approximately 6 months apart. Our semi-quantitative FFQ had
measures of validity against the criterion of the 7-day food
record and measures of reliability at a 1-year interval
approximately similar to other tools exploring the same issues
(Rimm et al., 1992). In particular, a validity from 48% for
proteins to 50–84% for lipids and alcohol (41% for PUFA and
52% for MUFA) and a reliability from about 60% for proteins
and fibers to 86–93% for lipids and alcohol (85% for PUFA
and 77% for MUFA) (Leoci et al., 1993). Nutrient intakes
were calculated from the questionnaire by multiplying the
frequency weight (once per day was equal to one) of each
food by the nutrient content of the portion size. The food
composition database used to calculate nutrient values was
primarily based on The Food Composition Tables of the
National Institute of Nutrition (Istituto Nazionale della
Nutrizione, 1989). We performed the Charlson comorbidity
index (CCI), a weighted index that takes into account the
number and the seriousness of comorbid disease (Charlson
et al., 1987). In the ILSA, we estimated the prevalence of
selected diseases [hypertension, coronary artery disease
(CAD) (e.g. myocardial infarction or angina pectoris), type
2 diabetes mellitus, and stroke] with a two-phase examination:
(a) extensive screening of all participants, including personal
interview, physician examination, and laboratory and diag-
nostic tests; and (b) for participants resulting positive in phase
one, clinical assessment by a board certified geriatrician,
internist, or neurologist, and review of medical records.
Clinical criteria used in the ILSA for the diagnosis of these
selected disease were detailed elsewhere (The Italian
longitudinal study on aging working group, 1997). Blood
samples were obtained following a 13-h overnight fast; serum
total cholesterol concentrations were determined as reported
in detail elsewhere (Solfrizzi et al., 2004).
2.3. Classification of dementia and MCI
The case finding strategy for the diagnosis of dementia
consisted of a two-phase procedure as reported in details
elsewhere (Solfrizzi et al., 1999, 2004). Several recent studies
have suggested that the subjective memory impairment
criterion for MCI is of questionable additional predictive
value for the conversion to dementia (Busse et al., 2003; Fisk
et al., 2003). Furthermore, subjects classified as having MCI
could have visual, auditory, or muscoloskeletal disabilities
impairing their ADL’s, in the absence of functionally disabling
cognitive impairment (Nygard, 2003). Finally, in very early
stages of cognitive impairment we may have evidence of subtle
but important changes in everyday functional competence
(Boeve et al., 2003; Busse et al., 2003; Fisk et al., 2003;
V. Solfrizzi et al. / Experimental Gerontology 41 (2006) 619–627 621
Nygard, 2003). Therefore, while we generally adhered to the
diagnostic criteria for MCI as defined by Petersen and
colleagues (1999) we did not require subjective memory
impairment, and we allowed for the presence of noncognitive
disabilities and comorbid illnesses (Solfrizzi et al., 2004). We
retroactively applied these criteria to the data collected in this
study between 1992 and 1995: (1) no dementia; (2) normal
general cognitive functioning as assessed by MMSE using age
and education based norms (this cutoff was calculated by
subtracting 1.5 SD from the mean age- and education-adjusted
MMSE scores after excluding subjects with prevalent
dementia). Elderly subjects with MMSE adjusted scores
greater than this cutoff were considered normal in terms of
general cognitive functioning; (3) objective evidence of
memory impairment as assessed by a total BRST score
(immediate plus delayed recall) in the lowest 10th percentile
of the distribution of age- and education-adjusted scores after
exclusion of prevalent dementia at entry; and (4) independence
in the basic activities of daily living, as measured by ADL. In
summary, our inclusion criteria to assess the functional status
of MCI subjects included: (1) subjects with no functional
impairment (ADLZ6); (2) subjects who were slightly
impaired (ADLZ7 or 8) but with no IADL impairment; (3)
subjects with visual, auditory, or skeletal muscle (i.e. stroke)
disabilities compromising ADL, but not cognitive skills; (4)
subjects with ADL impaired by comorbid illnesses (presence of
two or more diseases).
2.4. Statistical analysis
Medians and quartile values have been used for dietary
variables, including intake, means plus/minus standard
deviations have been reported elsewhere (Solfrizzi et al.,
2005b). MCI failure data have modelled through Cox
proportional-hazards regression. The Cox models have been
used to asses the association between the studied food groups
and new MCI events. The variables that have modelled as
continuous were examined by quartile analysis to obtain the
correct scale in the log hazard of MCI, using the lowest
quartile as a the reference group. The Cox models tested for
the effects of socio-demographic and clinically relevant
covariates on rate of MCI: sex (coded 0 for men and 1 for
women), quartile values of age (65–68 years, 69–72 years,
73–76 years, and 77–84 years), education (illiterate coded as 0
and literate coded as 1), quartile values of CCI (0, 1, 2, and
3–7), hypertension (coded 0 for not affected and 1 for affected
by the disease), type 2 diabetes (coded 0 for not affected and 1
for affected by the disease), CAD (coded 0 for not affected
and 1 for affected by the disease), stroke (coded 0 for not
affected and 1 for affected by the disease), quartile values of
total cholesterol [91–176 mg/dL (2.35–4.55 mmol/L), 177–
201 mg/dL (4.58–5.20 mmol/L), 202–229 mg/dL (5.22–
5.92 mmol/L), and 230–237 mg/dL (5.95–6.13 mmol/L)]
calcium channel blockers (coded 0 for those not assuming
the drug and 1 for those assuming the drug), angiotensin-
converting enzyme inhibitors (coded 0 for those not assuming
the drug and 1 for those assuming the drug), lipid-lowering
drugs (coded 0 for those not assuming the drug and 1 for those
assuming the drug) and total energy intake (%7400 kJ/day,
7401–9183, 9184–11,329, and R11,330 kJ/day). In order to
check the proportional hazard assumption over time for the
covariates of interest we included in the Cox model each
covariate by time as a predictor variable. Univariate and
multivariate Cox proportional hazard models are presented in
the form of point estimates of the hazard rate, with 95%
confidence intervals. In order to compare the effect of PUFA
intake (in ordered quartiles) on rate of MCI between age
categories (76–84 years vs 65–75 years), controlling for
education levels (coded 0 for illiterate and 1 literate subjects)
and variation of rates on a time scale by breaking up time into
very short intervals (clicks) and, on the other hand, to
compare the effect of PUFA intake (in ordered quartiles)
between education levels (literate vs illiterate), controlling for
age categories (coded 0 for 65–75 and 76–84 years subjects)
and for time (by clicks) we used the Mantel–Cox analysis. To
avoid to overfit the Cox model for confounding effect
evaluation we limited the number of parameters in the
multivariate model to the only significant variables in the
univariate models and evaluate the effect of PUFA intake on
incident MCI as independent of total caloric intake. The
statistical significance threshold was set at 0.05.
3. Results
Socio-demographic, clinical characteristics, and dietary
intake of fatty acids of nondemented subjects at baseline are
shown in Table 1. During the median follow-up period, 622
person-years were accrued, and 18 new events of MCI were
diagnosed. Out of 704 subjects of original cohort of the
study, 278 elderly subjects completed both MMSE and the
semi-quantitative food frequency questionnaire at the 1st
survey and 186 elderly people at the 2nd survey (40%). At
the 2nd survey, differences on age (72.5G5.4 vs 74.0G5.6,
p!0,05 evaluated by separate variance t test) but not on
gender (Pearson c2Z1.07, p!0.30) were shown between the
186 completers and the nonparticipants at the same survey,
respectively [186 participants: 99 (64.3%) men and 87
women (70.2%); 92 nonparticipants: 55 (35.7%) men and 37
(29.8%) women]. Moreover, there was a significant
difference on age (72.5G5.4 vs 74.2G5.7, p!0,01 evaluated
by separate variance t-test) but not on gender [186
participants: 99 (28.4%) men and 87 women (24.4%); 518
nonparticipants: 249 (71.6%) men and 269 (75.6%) women]
between the completers at 2nd survey and the 518
nonparticipants of the original cohort (Pearson c2Z1.46,
p!0.25). Furthermore, among the 278 elderly subjects who
completed both MMSE and the semi-quantitative dietary
questionnaire at the 1st survey we assessed the cognitive
status of the completers elderly people (no. 186) respect to
nonparticipants at the 2nd survey (no. 92). They were
characterized by an higher education (4G2.8 vs 2.9G2.2,
p!0.01, participants and nonparticipants, respectively), and,
as we observed before, younger compared to the nonparti-
cipants, while no difference in MMSE performance (24.1G
Table 1
Demographic, clinical, and dietary intake of fatty acids, Italian Longitudinal
Study on Aging (1992–1996)
Variable 1st Survey [1992–1993]
No. 278
Age (years) 73.01G5.52
Sex (m/w) 154/124
Education (years) 3.96G2.76
Charlson comorbidity index 1.81G1.63
Mini mental state examination 23.62G4.03
Babcock story recall test 6.19G4.93
Activities of daily living 6.88G1.37
Instrumental activities of daily living 8.48G3.96
Hypertension 187 (67.3%)
Coronary artery disease 42 (15.1%)
Stroke 18 (6.5%)
Type 2 diabetes 35 (12.6%)
Calcium channel blockers 53 (19.1%)
Angiotensin-converting enzyme inhibitors 62 (22.3%)
Lipid-lowering drugs 14 (5.0%)
Total cholesterol
Median score [interquartile range]
(mg/dL) 202 [177–230]
(mmol/L) 5.22 [4.58–5.98]
MUFA dietary Intake (g/day)
Median score [interquartile range] 42.87 [32.83–51.82]
PUFA dietary Intake (g/day)
Median score [interquartile range] 7.19 [5.78–8.92]
SFA dietary Intake (g/day)
Median score [interquartile range] 19.24 [15.56–24.20]
MUFA/SFA ratio
Median score [interquartile range] 2.11 [1.70–2.58]
PUFA/MUFA ratio
Median score [interquartile range] 0.17 [0.15–0.20]
UFA/SFA ratio
Median score [interquartile range] 2.48 [2.03–2.99]
Total energy intake [kJ/day]a
Median score [interquartile range] 9281.37 [7405.79–11334.33]
Values are mean [SD] or numbers unless stated otherwise. MUFA,
monounsaturated fatty acids; PUFA, polyunsaturated fatty acids; SFA,
saturated fatty acids; UFA, unsaturated fatty acids [MUFA plus PUFA].a To convert values for energy intake to kilocalories, divide by 4.184.
V. Solfrizzi et al. / Experimental Gerontology 41 (2006) 619–627622
4.2 vs 22.9G3.9, p!0.24, participants and nonparticipants,
respectively) was found.
Demographic and clinical characteristics at baseline and
associated rate of MCI are shown in Table 2. The rate risk of
development of MCI was inversely associated with high
PUFA [hazard ratio (HR): 0.65, 95% confidence interval
(CI): 0.43–0.98, trend-test p!0.04] (Table 3). Adding age,
education, and total energy intake to the model, the HR
slightly changed, and the highly skewed 95% CI, while not
statistically significant, may be important (HR: 0.62, 95% CI:
0.34–1.13, p!0.12) (Table 4). On the other hand, age
categories, as well as on education levels, the only significant
variables in the univariate models (Table 2), showed no
significant effect modification on rate of MCI for a one unit
increase in PUFA intake controlling for education and age
strata, respectively (Table 4). Furthermore, we did not found
any significant association between other dietary fatty acids
intakes and the rate of MCI (Table 3).
4. Discussion
Our findings showed in a community defined Italian cohort
that dietary fatty acids intakes were not associated with
incident MCI. However, high PUFA intake appeared to have
borderline nonsignificant trend for a protective effect against
the development of MCI that may be important.
To the best of our knowledge, this is the first population-
based study that prospectically evaluated the effect of dietary
intakes of fatty acids on incident MCI in old age. Several
epidemiological studies have addressed the link between
PUFA intake and cognitive decline and dementia (Kalmijn
et al., 1997, 2004; Morris et al., 2003a,b, 2004; Solfrizzi et al.,
1999, 2005c). In particular, a prospective study, the Zutphen
Study of 476 men aged 69–89 years, found that high linoleic
acid intake (nK6 PUFA) was positively associated with
cognitive impairment in elderly subjects only cross-sectionally,
while high fish consumption, an important source of long-chain
nK3 PUFA, tended to be inversely associated with cognitive
impairment and cognitive decline at a 3-year follow-up, but not
significantly (Kalmijn et al., 1997). In a cohort of 1613 middle-
aged men and women aged 45–70 years from the Netherlands,
the Doetinchem Cohort Study, fatty fish and marine nK3
PUFA consumption was significantly associated with a
decreased risk of global cognitive function impairment and
psychomotor speed by 19–28%. These associations appeared to
be independent of differences in cardiovascular risk factors
(Kalmijn et al., 2004). Recent findings from the Chicago
Health and Aging Project showed that in a large population-
based sample of 2560 persons, aged 65 years and older, high
intakes of saturated and trans-unsaturated fat were associated
with a greater cognitive decline over a 6-year follow-up.
Slower decline in cognitive function was associated with
higher intake of PUFA, but the association appeared to be due
largely to its high content of vitamin E, which shares vegetable
oil as a primary food source and which is inversely related to
cognitive decline (Morris et al., 2004).
Furthermore, our findings on a possible protective effect
of PUFA intake against MCI confirmed other recent studies
that showed that high dietary intake of MUFA, nK6 and nK3
PUFA, and weakly consumption of fish may reduce the risk
of incident AD (Morris et al., 2003a,b). Finally, the PAQUID
study, a population-based study conducted in France on 1674
nondemented subjects aged 68 years and over, showed
that participants eating fish or seafood, which are a source of
nK3 PUFA, at least once a week had a significantly lower
risk of dementia in the seven subsequent years (Barberger-
Gateau et al., 2002).
In an earlier report on the same ILSA cohort, we found a
positive Spearman correlation coefficient between MUFA
intake and the MMSE and the digit cancellation test (DCT),
assessing visual selective attention. Also, the correlation
coefficient between PUFA intake and the DCT was positive.
After adjustment for educational level, the odds ratios of
cognitive decline (MMSE score !24) decreased exponentially
with the increase of MUFA energy intakes (Solfrizzi et al.,
1999). Very recently, high MUFA and PUFA energy intakes
Table 2
Demographic and clinical characteristics at baseline and associated rate of mild cognitive impairment (MCI), Italian Longitudinal Study on Aging (1992–1996)
Variable Study participants no. 278 Crude hazard
ratio (95% Cl)
Test for trend p
New events (MCl) Total subjects
Age (years)
65–68 1 –
69–72 0.44 0.04–4.87
73–76 3.01 0.58–15.59
77–84 5.90 1.28–27.16
Test for trend 2.05 1.35–3.12
Sex
Men 8 154 1 –
Women 10 124 1.67 0.65–4.25 0.29
Education (years)
0 9 28 1 –
R1 9 250 0.09 0.03–0.23 0.01
Charlson comorbidity index
0 3 62 1 –
1 6 86 1.09 0.26–4.63
2 5 49 2.13 0.53–8.53
O2 4 81 1.08 0.24–4.83
Test for trend 1.08 0.70–1.65 0.71
Total cholesterol mg/dL (mmol/L)
91–176 (2.35–4.55) 8 71 1 –
177–201 (4.58–5.20) 4 69 0.61 0.18–2.11
202–229 (5.22–5.92) 3 69 0.48 0.12–1.86
230–237 (5.95–6.13) 3 69 0.44 0.11–1.71
Test for trend 0.40 0.11–1.52 0.14
Hypertension
No 7 91 1 –
Yes 11 187 0.76 0.29–1.76 0.57
Coronary artery disease
No 15 236 1 –
Yes 3 42 1.17 0.33–4.09 0.81
Type 2 diabetes
No 17 243 1 –
Yes 1 35 0.48 0.062–3.66 0.48
Stroke
No 16 260 1 –
Yes 2 18 1.96 0.45–8.57 0.37
Calcium channel blockers
No 14 225 1 –
Yes 4 53 0.99 0.33–3.04 0.99
Angiotensin-converting enzyme inhibitors
No 14 216 1 –
Yes 4 62 1.01 0.33–3.07 0.99
Lipid-lowering drugs
No 17 264 1 –
Yes 1 14 0.91 0.12–6.90 0.93
V. Solfrizzi et al. / Experimental Gerontology 41 (2006) 619–627 623
and total energy intake were significantly associated with a
better cognitive performance in a 8.5-year follow-up of the
ILSA (Solfrizzi et al., 2005c). The apparently conflicting
findings on MUFA intake between these previous reports
compared to the present study showing no significant
relationship to incident MCI could be partially due to some
differences in the outcome examined. In fact, in the previous
reports we evaluated cross-sectionally and prospectically
dietary macronutrient intakes and some neuropsychological
tests (Solfrizzi et al., 1999, 2005c), while in the present study
the outcome was a clinical entity as MCI, with well-defined
clinical criteria (Petersen et al., 1999; Solfrizzi et al., 2004).
These contrasting findings about the impact of dietary fatty
acids on cognitive function evaluated with neuropsychological
testing or MCI may suggest an approach not confined only to
cognitive skills but extended to functional status and
comorbidity. Furthermore, these differences could be question
of lack of power, given the relatively small sample examined.
Conquer et al. measured the plasma fatty acid composition
of various phospholipids in blood samples from 84 subjects
with different degrees of cognitive impairment, including
AD and other types of dementia. Without considering
Table 3
Daily dietary intake of fatty acids and associated rate of mild cognitive impairment (MCI), Italian Longitudinal Study on Aging (1992–1996)
Variable Study participants no. 278 Crude hazard ratio
(95% Cl)
Test for trend p
New events (MCl) Total subjects
MUFA intake (g/day)
%32.7 6 69 1 –
32.8–42.8 5 70 0.88 0.27–2.92
42.9–51.8 4 70 0.55 0.15–1.95
R51.9 3 69 0.43 0.11–1.75
Test for trend 0.75 0.49–1.13 0.17
PUFA intake (g/day)
%5.8 7 69 1 –
5.9–7.2 5 69 0.70 0.22–2.23
7.2–8.9 4 71 0.50 0.14–1.71
R9 2 69 0.22 0.05–1.09
Test for trend 0.65 0.43–0.98 0.04
SFA intake (g/day)
%15.5 4 69 1 –
15.6–19.2 5 70 1.13 0.30–4.21
19.3–24.2 5 70 1.16 0.31–4.31
R24.3 4 69 0.86 0.21–3.49
Test for trend 0.96 0.63–1.46 0.85
MUFA/SFA ratio
!1.70 6 69 1 –
1.70–2.11 5 70 0.61 0.18–2.01
2.12–2.58 3 70 0.45 0.11–1.83
O2.58 4 69 0.57 0.16–2.01
Test for trend 0.81 0.53–1.24 0.33
PUFA/MUFA ratio
!0.15 6 69 1 –
0.15–0.16 4 70 0.66 0.18–2.33
0.17–0.20 4 70 0.53 0.15–1.90
O0.20 4 69 0.61 0.17–2.18
Test for trend 0.83 0.54–1.27 0.39
UFA/SFA ratio
!2.0 4 69 1 –
2.0–2.5 3 70 0.86 0.19–3.87
2.5–3 4 70 0.84 0.21–3.38
O3 7 69 2.23 0.65–7.68
Test for trend 1.31 0.85–2.00 0.22
Total energy intake (kJ/day)a
%7400 6 67 1 –
7401–9150 5 69 0.70 0.21–2.30
9150–11320 4 72 0.51 0.14–1.82
R11321 3 70 0.35 0.09–1.42
Test for trend 0.71 0.47–1.08 0.11
CI, confidence interval; MUFA, monounsaturated fatty acids; PUFA, polyunsaturated fatty acids; SFA, saturated fatty acids; UFA, unsaturated fatty acids [MUFA
plus PUFA].a To convert values for energy intake to kilocalories, divide by 4.184.
V. Solfrizzi et al. / Experimental Gerontology 41 (2006) 619–627624
counfounding factors, this study showed a statistically
significant lower level of nK3 PUFA in the plasma of subjects
with cognitive impairment (Conquer et al., 2000). Moreover, in
the cohort of the Etude du Viellissement Arteriel (EVA) Study,
moderate cognitive decline (aO2-point of MMSE decrease)
and erythrocyte membrane fatty acid composition were
evaluated in 264 elderly subjects aged 63–74 years, during a
4-year follow-up. In this study, a lower content of nK3 PUFA
was significantly associated with a higher risk of cognitive
decline, and, after adjusting for age, gender, educational
level and initial MMSE score, stearic acid and total nK6 PUFA
were consistently associated with an increased risk of cognitive
decline. Moreover, a lower content of nK3 PUFA was
significantly associated with cognitive decline, but after
adjustment this association remained significant only for
docosahexaenoic acid (DHA), and not for eicosapentaenoic
acid (EPA) (Hende et al., 2003). Nonetheless, the findings from
the Canadian Study of Health and Aging do not support
the hypothesis that nK3 PUFA play a protective role in
cognitive function and dementia. In fact, in the prospective
analysis, a higher EPA concentration was found in cognitively
impaired cases compared to controls while higher DHA, nK3
Table 4
Effects of polyunsaturated fatty acids intake (in ordered quartiles) on incident mild cognitive impairment adjusted by socio-demographic risk factors, Italian
Longitudinal Study on Aging (1992–1996)
Rate ratio (RR) (95% CI) Overall estimate (95% CI) Test for unequal RR (effect modification),
Asymptotic
c2 p!
Age (years)a 0.69 (0.43–1.12) 0.42 0.52
65–76 0.80 (0.41–1.57)
77–84 0.59 (0.30–1.17)
Education (years)b 0.69 (0.43–1.12) 1.93 0.17
0 0.54 (0.22–1.29)
R1 0.77 (0.44–1.36)
PUFA intake (g/day)Zc 1
%5.8 (K)
5.9–7.2 0.77 (0.22–2.62)
7.2–8.9 0.35 (0.08–1.60)
R9 0.25 (0.03–1.86)
Test for trend 0.62 (0.34–1.13)
CI, confidence interval; PUFA, polyunsaturated fatty acids.a Approximate estimate of the rate ratio for a one unit increase in PUFA intake (in ordered quartiles) controlling for time (by clicks) and education (coded 0 for
unlettered and 1 for littered) by age (coded 0 for 65–76 years and 1 for 77–84 years).b Approximate estimate of the rate ratio for a one unit increase in PUFA intake (in ordered quartiles) controlling for time (by clicks) and age (coded 0 for 65–76
years and 1 for 77–84 years) by education (coded 0 for unlettered and 1 for littered).c Adjusted model: age (coded 0 for 65–76 years and 1 for 77–84 years), education (coded 0 for unlettered and 1 for littered), and total energy intake (in ordered
quartiles).
V. Solfrizzi et al. / Experimental Gerontology 41 (2006) 619–627 625
and total PUFA concentrations were found in dementia
cases (Laurin et al., 2003). However, dietary supplements
of EPA in rats attenuated the inflammation-induced
impairment of spatial memory by centrally administered
interleukin-1b. By contrast, rats fed with the soybean oil
(contained mainly nK6 PUFA) diet showed no effect on the
changes induced by the interleukin-1b administration
(Song and Horrobin, 2004).
Finally, data from 1049 men aged 70–91 in five cohorts
from the seven countries study (two cohorts from Finland, one
from the Netherlands, and two from Italy) suggested that there
was a tendency towards a lower prevalence of cognitive
impairment in association with increased score on the healthy
diet indicator (HDI) (Huijbregts et al., 1995), that indicates a
diet more in accordance with the World Health Organization
(WHO) (Huijbregts et al., 1998), in four out of five cohorts
(except East Finland). In particular, in Finnish cohorts and in
The Netherlands, most men scored well within the borders of
the WHO guidelines for PUFA and fibres, but in the Dutch
cohort most men scored well on dietary cholesterol too.
Finally, in Italy the score was mainly built up by a favourable
consumption of saturated fatty acids, vegetables, fruits, and
dietary cholesterol.
Moreover, in case–control and cohort studies, concen-
trations of nK3 PUFAs were lower in participants with
unipolar and postpartum depression, and infrequent fish
consumption was associated with depression in epidemiologi-
cal studies. The relationship between nK3 PUFA and
depression is biologically plausible and is consistent across
study designs, study groups, and diverse populations, which
increases the likelihood of a causal relationship (Sontrop and
Campbell, 2006).
The mechanism by which high PUFA intake could be
protective against cognitive decline in healthy elderly people
is, at present, unknown. This effect could be related to the role
of fatty acids in maintaining the structural integrity of neuronal
membranes, determining the fluidity of synaptosomal mem-
branes and thereby regulate neuronal transmission (Solfrizzi
et al., 2003, 2005a). Furthermore, the protective effect of
PUFA could be related to antinflammatory effects and vascular
protection exercised by these fatty acids (Solfrizzi et al., 2003,
2005a). There are several published studies on human infant
subjects in which breastfeeding, which leads to higher nK3
PUFA (DHA) concentrations in the brain, or nK3 PUFA
supplementation, is related to better cognitive performance at
later age (Willatts et al., 1998). The PUFA nK3 arachidonic
acid (AA) and DHA are essential, structural, and functional
constituents of cell membranes. They are especially required
for the growth and function of the brain and vascular systems,
which are the primary biofocus of human fetal growth
(Crawford et al., 2003). Very preterm babies are born with
minimal fat stores and suboptimal circulating levels of these
nutrients (Crawford et al., 2003). The biochemistry implies that
the expansion of the human brain required a plentiful source of
preformed DHA. The richest source of DHA is the marine food
chain, and recent fossil evidence indicates that the lacustrine
and marine food chain was being extensively exploited at the
time cerebral expansion took place and suggests the alternative
that the transition from the archaic to modern humans took
place at the land/water interface (Crawford, 2002). Both AA
and DHA would have been freely available from such habitats
providing the double stimulus of preformed acyl components
for the developing blood vessels and brain (Crawford et al.,
1999). It has suggested that the evolution of the large human
V. Solfrizzi et al. / Experimental Gerontology 41 (2006) 619–627626
brain depended on a rich source of DHA from the land/water
interface (Crawford et al., 1999, 2001).
Finally, there is also evidence associating a dietary
deficiency of nK3 PUFA with changes in cortical dopoami-
nergic function (Delion et al., 1994). Therefore, while there are
biologically plausible mechanisms between nK3 and cognitive
functioning, findings on the possible role of nK6 PUFA are
controversial (Delion et al., 1994). In fact, high nK6 PUFA
intake may increase the susceptibility of low-density lipopro-
teins cholesterol to oxidation, which makes it more atherogenic
(Reaven et al., 1994; Khor, 2004). Therefore, the ratio of
dietary nK6/nK3 PUFA intake may influence the potential
role of PUFA on MCI, the optimal ratio of nK6/nK3 should be
!5:1 (de Lorgeril et al., 1998). The parent fatty acid alpha-
linolenic acid (ALA), found in vegetable oils such as flaxseed
or rapeseed oil, is used by the human organism partly as a
source of energy, partly as a precursor of the metabolites, but
the degree of conversion appears to be unreliable and
restricted. More specifically, most studies in humans have
shown that whereas a certain, though restricted, conversion of
high doses of ALA to EPA occurs, conversion to DHA is
severely restricted. The use of ALA labelled with radioisotopes
suggested that with a background diet high in saturated fat
conversion to long-chain metabolites is approximately 6% for
EPA and 3.8% for DHA. With a diet rich in nK6 PUFA,
conversion is reduced by 40–50%. It is thus reasonable to
observe an nK6/nK3 PUFA ratio not exceeding 4–6 (Gerster,
1998). A recent study demonstrated the efficacy of the
conversion of ALA–EPA and docosapentaenoic acid in a
minority population with chronic disease, suggesting that ALA
may be an alternative to fish oil (Harper et al., 2006).
The major strengths of the present study are our study
design, a population-based prospective study, and that MCI
was diagnosed not only by neuropsychological categories, but
also by assessing the functional status, a criterion that was not
well defined in previous studies (Fisk et al., 2003; Nygard,
2003). In particular, our criteria place in question the category
of normal ‘ADL/IADL’ criterion in MCI (Petersen et al.,
1999), suggesting that the diagnosis of MCI should include
subtle functional changes in everyday life activities (Nygard,
2003). Nonetheless, some limitations of our study should be
considered, in particular the small size of the cohort and the
length of the follow-up. The small sample size makes it
difficult to detect significant associations. The nonsignificant
findings may be due to lack of power and not due to lack of
existing association. Furthermore, the follow-up time of the
study was fairly short. Therefore, it is possible that the persons
that were diagnosed with MCI at the follow-up had changed
their diet due to cognitive problems already at the time of
baseline examination. So the causal implications of the results
of the present study should be cautiously interpreted. More-
over, the nonparticipation rate was high. In fact, at baseline 278
out of 704 persons (39.4%) participated, although at the follow-
up the situation was better, with 186 out of the 227 people
evaluated (81.9%) who were still alive and nondemented.
The low participation at baseline raises the concern of the
generalizability of the results. Finally, the attrition rate of this
longitudinal study is quite high, which is plausible given the
characteristics of this elderly population-based sample. There-
fore, our findings, although interesting, warrant further
investigation in larger population-based samples of elderly
subjects, with a longer follow-up.
Acknowledgements
This group is supported by Italian longitudinal study on
aging [ILSA] [Italian National Research Council-CNR-
Targeted Project on Ageing-Grants 9400419PF40 and
95973PF40], by AFORIGE [‘Associazione per la FOrmazione
e la RIcerca in Geriatria’]. The authors thank Ms Maria Mann
for editing the manuscript, and Dr Giovanni Castellaneta,
Pfizer, Inc., and Dr Adriana Rafaschieri for their assistance
with bibliographic sources.
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