Review

Dietary fatty acids intake: possible role in cognitive

decline and dementia

Vincenzo Solfrizzia,*, Alessia D’Intronoa, Anna M. Colaciccoa, Cristiano Capursob,Angelo Del Parigic, Sabrina Capursoa, Annamaria Gadaletaa,

Antonio Capursoa, Francesco Panzaa

aDepartment of Geriatrics, Center for Aging Brain, Memory Unit, University of Bari-Policlinico, Piazza Giulio Cesare, 11, Bari 70124, ItalybDepartment of Geriatrics, University of Foggia, Foggia, Italy

cNational Institutes of Health—National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix AZ, USA

Received 19 November 2004; received in revised form 27 December 2004; accepted 13 January 2005

Available online 3 February 2005

Abstract

There is a recent increase in the level of interest in the possible role of dietary fatty acids in age-related cognitive decline, and cognitive

impairment of both degenerative (Alzheimer’s disease, AD) or vascular origin. At present, several studies suggested that an increase of

saturated fatty acids (SFA) could have negative effects on cognitive functions. Furthermore, a clear reduction of risk of cognitive decline has

been found in a population sample with a high intake of polyunsaturated fatty acids (PUFA) and monounsaturated fatty acids (MUFA). These

findings were confirmed by studies in which high intakes of nK6 PUFA, nK3 PUFA, MUFA, and weekly fish consumption, providing large

amount of nK3 PUFA, appear to be protective against the risk of AD. In our elderly population from Southern Italy, elevated unsaturated

fatty acids intake (MUFA and PUFA), high levels of antioxidant compounds, and very low SFA intake could act synergistically in improving

cognitive performance. Epidemiological studies on the association between diet and cognitive decline suggested a possible role of fatty acids

intake in maintaining adequate cognitive functioning and possibly in preventing or delaying the onset of dementia, both of degenerative or

vascular origin. Appropriate dietary measures or supplementation with specific micro- and macronutrients might open new ways for the

prevention and management of cognitive decline and dementia.

q 2005 Elsevier Inc. All rights reserved.

Keywords: MUFA; PUFA; Fatty acids; Dementia; Alzheimer’s disease; Vascular dementia; Mild cognitive impairment; Cognitive decline

1. Introduction

Cognitive impairment and dementia are frequent dis-

orders among elderly persons and influence the individual’s

ability to function independently. Due to the aging of the

population, the prevalence of cognitive impairment and

dementia are expected to increase. Establishing the

diagnosis at the preclinical phase of dementia would be

likely to increase the efficacy of treatment.

Mild cognitive impairment (MCI) is, at present, the most

widely used term to indicate non-demented aged persons

with a mild memory or cognitive impairment that cannot be

accounted for any recognized medical or psychiatric

0531-5565/$ - see front matter q 2005 Elsevier Inc. All rights reserved.

doi:10.1016/j.exger.2005.01.001

* Corresponding author. Tel.: C39 80 5478860; fax: C39 80 5478633.

E-mail address: v.solfrizzi@geriatria.uniba.it (V. Solfrizzi).

condition (Petersen et al., 1999; D’Introno et al., 2004).

Different diagnostic criteria have been proposed, and the

terms age-related cognitive decline (ARCD) (American

Psychiatric Association Committee on Nomenclature and

Statistics, 1994) and aging-associated cognitive decline

(AACD) (Levy, 1994) have been recently proposed to

distinguish individuals with mild cognitive disorders

associated with aging from non-affected individuals. At

present, it difficult to establish whether these entities are an

expression of a normal aging process, or are clinically

distinguishable from dementigen syndromes, or, eventually,

are a continuum with dementia (Brayne and Calloway,

1988). In fact, while MCI is assumed to be pathology-based

and therefore, amenable to interventions, ARCD and AACD

are generally considered non-progressive, a phenomenon of

normal aging. Furthermore, MCI may be a prodromal phase

Experimental Gerontology 40 (2005) 257–270

www.elsevier.com/locate/expgero

V. Solfrizzi et al. / Experimental Gerontology 40 (2005) 257–270258

of dementia, with estimates of 12% of MCI patients

developing dementia in 1 year (Wolf et al., 1998; Petersen

et al., 1999), and 20% over 3 years (Petersen et al., 2001).

Recently, in the Italian Longitudinal Study on Aging, a

population-based study with a sample of 5632 65–84 year

old subjects, we found a progression rate to dementia of

MCI of 3.8/100 person-years (Solfrizzi et al., 2004 a,b).

In contrast to MCI, a diagnosis of dementia is made when

cognitive impairment is greater than that found in normal

aging, affects two or more cognitive domains, and

the person’s ability to function (American Psychiatric

Association, 1994). In occidental countries, current

nosology indicates that the two most common dementigen

syndromes are Alzheimer’s disease (AD) and vascular

dementia (VaD), with respective frequencies of 70 and 15%

for all dementias (Whitehouse et al., 1997), while oriental

populations from Asian countries are known to be at high

risk for stroke (Kagan, 1996) and VaD (Jorm, 1991; White

et al., 1996). Therefore, AD is the most common dementia

and primary neurodegenerative disorder in the elderly. It

involves aberrant protein processing and is characterized by

the presence of both intraneuronal protein clusters

composed of paired helical filaments of hyperphosphori-

lated tau protein [neurofibrillary tangles (NFTs)], and

extracellular protein aggregates [senile plaques (SPs)].

The SPs are the result of misprocessing of the amyloid

precursor protein (APP) by b- and g-secretases to form a

toxic b-amyloid (Ab) peptide that aggregates and initiates a

pathogenic self-perpetuating cascade ultimately leading to

neuronal loss and dementia. According to the ‘amyloid

cascade hypothesis’ (Hardy and Higgins, 1992), the

development of SPs is thought to precede and precipitate

the formation of NFTs as a result of the cellular changes

invoked. This neurodegenerative disease gradually leads to

a complete psychological and physical dependency and

finally to death within one to two decades. AD can be

diagnosed with certainty at autopsy, but it can also be

diagnosed with reliable clinical criteria established in 1984

by the National Institute for Neurological and Commu-

nicative Disorders and Stroke/Alzheimer’s Disease and

Related Disorders Association (NINCDS/ADRDA)

(McKhann et al., 1984).

On the other hand, the diagnosis of certainty for VaD also

relies on pathological findings (Roman et al., 1993), but the

pathological diagnosis usually does not confirm the clinical

diagnosis (Gold et al., 2002). The clinical presentation of

VaD varies greatly depending on the causes and location of

cerebral damage (Roman, 2002). Large-vessel disease leads

commonly to multiple cortical infarcts and a multifocal

cortical dementia syndrome, whereas small-vessel disease,

usually resulting from hypertension and diabetes, causes

periventricular white matter ischemia and lacunar strokes

characterized clinically by subcortical dementia with frontal

lobe deficits, executive dysfunction, slow information

processing, impaired memory, inattention, depressive

mood changes, slowing of motor function, Parkinsonian

features, small-step gait, urinary disturbances and pseudo-

bulbar palsy (Roman and Royall, 1999).

The causes of cognitive decline and dementia are at

present unknown. However, some studies have suggested

that these conditions may be prevented (Solfrizzi et al.,

1999; Solfrizzi et al., 2003). Previous works have linked

cognitive decline to cardiovascular disease (Breteler et al.,

1994), diabetes mellitus (Naor et al., 1997), hypertension,

and high and low blood pressure (Launer et al., 1995; Guo

et al., 1997). Various genetic and non-genetic factors known

to increase the risk of vascular disease, including apolipo-

protein E (APOE) and angiotensin I converting enzyme 1

(ACE1) genotypes, total cholesterol, lipoprotein(a) [Lp(a)],

diabetes mellitus, atrial fibrillation, hypertension, serum

APOE levels, and C-reactive protein levels an inflammation

(Mazer and Rabbani, 2004), have been evaluated as risk

factors for AD and VaD (de la Torre, 2004; Panza et al.,

2004a), and cognitive decline (Tilvis et al., 2004).

The role of the diet in cognitive decline has not been

extensively investigated, with a few data available on the

role of macronutrient intake in the pathogenesis of dementia

and ARCD (Solfrizzi et al., 2003). Since several dietary

factors affect the risk of cardiovascular disease, it can be

assumed that they also influence the risk of dementia. Some

recent studies have suggested that dietary fatty acids may

play a role in the development of cognitive decline

associated with aging or dementia.

Fatty acids can be categorized briefly into saturated fatty

acids (SFA) and unsaturated fatty acids (UFA). SFA, such as

stearic acid, are present in products such as meat, dairy

products, cookies and pastries. Monounsaturated fatty acids

(MUFA) are most frequently consumed in olive oil. The

principal series of polyunsaturated fatty acids (PUFA) are

nK6 (i.e. linoleic acid) and nK3 (i.e. a-linolenic acid,

docosahexaenoic acid, and eicosapentaenoic acid). In our

Mediterranean dietary pattern the main sources of nK6

PUFA are vegetable oils, while the principal sources of nK3

PUFA are fatty fish (salmon, tuna, and mackerel). In fact,

olive oil contains 70–80% MUFA (oleic acid) and 8–10%

PUFA (6–7% linoleic acid and 1–2% a-linolenic acid).

The aim of this presentation is to examine in depth the

possible role of dietary fatty acids in modulating the risk of

age-related changes in cognitive function, and the cognitive

decline of degenerative or vascular origin, as well as the

possible mechanisms behind the observed associations. We

reviewed clinical and epidemiological studies from the

international literature through keyword and author searches

of Medline from January 1983 to July 2004.

2. Unsaturated fatty acids and age-related

cognitive decline

Only a few epidemiological and clinical studies

have addressed the link between UFA intake and

cognitive function, most being cross-sectional. In a recent

V. Solfrizzi et al. / Experimental Gerontology 40 (2005) 257–270 259

cross-sectional French study, the association among macro-

nutrient intake, functional variables, and cognitive functions

was studied in 441 free living elderly subjects aged 65 or

over. A positive relationship was found in women between

lipid intake and the Mini Mental State Examination

(MMSE) score, which evaluates global cognitive functions.

A positive relationship was also found between PUFA

intake and mobility in men, and between functional

variables and alcohol intake in the whole sample. The

response rate of this study was very low (around 50%) and

these findings, contradictory to the results of the subsequent

studies, were explained by the authors with the fact that high

intakes of these dietary factors can be considered as an

indicator of a better health status (Pradignac et al., 1995)

(Table 1).

Another cross-sectional study from Spain investigated

the association between dietary intake and global cognitive

functions, assessed the MMSE and the Pfeiffer’s Mental

State Questionnaire (PMSQ), among 260 non-institutiona-

lized and non-demented older subjects, aged 65–90 years.

Dietary intake was monitored with a weighed-food record

for 7 consecutive days. The subjects with a lower intake of

MUFA, SFA, and cholesterol, and higher intakes of total

calories, fresh fruit, carbohydrate, thiamine, foliate, vitamin

C, and minerals (iron and zinc) had the best performance in

cognitive tests (MMSE score O28 points or no errors on the

PMSQ), with a statistical significance after adjustment for

age and sex (Ortega et al., 1997) (Table 1).

The cross-sectional association between dietary macro-

nutrients and cognitive impairment was examined also in 278

non-demented elderly subjects aged 65–84 years from the

Italian Longitudinal Study on Aging. Dietary intakes were

assessed with a 77-item food frequency questionnaire. We

included MUFA, PUFA, and SFA in the analysis and found a

positive Spearman correlation coefficient between MUFA

intake and the MMSE (0.12; p!0.05) and the Digit

Cancellation Test (DCT) (0.16; p!0.01), assessing visual

selective attention. Also, the correlation coefficient between

PUFA intake and the DCT was positive (0.12; p!0.05).

After adjustment for educational level, the odds ratios (ORs)

of cognitive decline (MMSE score !24) decreased expo-

nentially with the increase of MUFA energy intakes. Despite

the lower education (%3 years), MUFA energy intake over

2400 kJ/day was associated with a reduction in OR of

cognitive impairment [OR 0.6, 95% confidence interval (CI)

0.1–4.5]. The age as a confounder of the interaction term

‘education by MUFA’ was associated with a further increase

in OR of cognitive impairment (OR 0.7, 95% CI 0.1–4.5).

Furthermore, selective attention performances evaluated by

DCT were independently associated with MUFA intake (OR

0.99, 95% CI 0.98–0.99) (Solfrizzi et al., 1999) (Table 1).

The apparently conflicting findings on MUFA intake

between our study compared to the Spanish study (Ortega

et al., 1997) could be partially due to some methodological

differences in food-frequency questionnaires and selection of

participants. Socio-economic and educational factors,

determining the choice of nutrients in different populations

and countries, might influence the strength of association of

various nutrients and cognitive function.

Finally, very recently, another Northern Italian cross-

sectional study examined whether type of dietary fats

consumed was associated with cognitive performance in a

sample of 191 subjects aged O65 years randomly selected

from a free-living population from the Progetto Veneto

Anziani (Pro.V.A. study) (Manzato et al., 2003) (Table 1).

Global cognitive functions were assessed with the MMSE,

comparing subjects with a score between 10 and 17 with

subjects with a score between 28 and 30, and plasma

phospholipid fatty acid composition was determined by

using gas chromatography. In the Pro.V.A. study, in a

multiple regression analysis, age and educational level

accounted for 29.6% of the MMSE variance, while the

contribution of the other variables considered [low-density

lipoproteins (LDL) cholesterol, diastolic blood pressure,

MUFA, and PUFA] was almost negligible (Manzato et al.,

2003). The authors acknowledged that these results were

limited by the fact that total energy intake, which is known

to be reduced in patients with cognitive impairment, was not

considered, and by the fact that the study was a cross-

sectional survey.

Moreover, 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 confounding factors, this study showed

a statistically significant lower level of nKs3 PUFA in the

plasma of subjects with cognitive impairment (Conquer

et al., 2000). Finally, in the cohort of the Etude du

Viellissement Arteriel (EVA) Study, moderate cognitive

decline (a O2-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 (OR 0.59,

95% CI 0.38–0–93) was significantly associated with a

higher risk of cognitive decline. In this study, after adjusting

for age, gender, educational level and initial MMSE score,

stearic acid [OR 1.91, 95% CI 1.16–3.15 for a 1-standard

deviation(SD) difference] and total nK6 PUFA (OR 1.59,

95% CI 1.04–2.44 for a 1-SD difference) were consistently

associated with an increased risk of cognitive decline.

Moreover, a lower content of nK3 PUFA (OR 0.59, 95% CI

0.38–0–93 for a 1-SD difference) was significantly associ-

ated with cognitive decline, but after adjustment this

association remained significant only for docosahexaenoic

acid, and not for eicosapentaenoic acid (Hende et al., 2003)

(Table 1).

Very recently, the role of fatty acids in cognitive

impaiment was investigated in a cross-sectional study

carried out in a cohort of 1613 middle-aged men and

women from the Netherlands aged 45–70 years, the

Doetinchem Cohort Study (DCS). Dietary assessment was

performed with a 178-item food frequency questionnaire,

Table 1

Principal cross-sectional and longitudinal clinical and epidemiological studies on the relationships between dietary fatty acids and cognitive functions in older

people

Reference Setting and

study design

Subjects Dietary assessment Cognitive outcomes Results and conclusions

Cross-sectional studies

Pradignac

et al., 1995

Cross-sec-

tional, popu-

lation-based

441 sub-

jects

agedO65

years

Evaluation of dietary intake Mini-Mental State Examination

(MMSE), Geronte scale for the

assessment of daily living activities

In men, alcohol intake was associ-

ated with improved functional and

cognitive parameters, while poly-

unsaturated (PUFA) intake only

with functional status. In women,

lipid intakes were related to better

cognitive performance. Overweight

in both sexes was associated with an

improvement in functional status

Ortega

et al., 1997

Cross-

sectional

260 sub-

jects aged

65–90 years

Evaluation of dietary intake with a

weighed-food record for 7 con-

secutive days, and biochemical

assays

MMSE, Pfeiffer’s mental state

questionnaire

A diet poor in fatty acids, saturated

fatty acids, and cholesterol, but rich

in carbohydrates, fibers, vitamins

(folates, vitamins C and E, and b-

carotene, and minerals [zinc and

iron) seems to improve cognitive

skills

Solfrizzi

et al., 1999

Cross-sec-

tional, popu-

lation-based

278 sub-

jects, 65–94

years old

Evaluation of dietary intake with a

77-item FFQ

MMSE, digit cancellation test

(DCT), Babcock recall story test

(BSRT)

Inverse relationship between

monounsaturated fatty acids

(MUFA) intake and cognitive

decline. Significant inverse associ-

ation between MUFA intakes and

selective attention. No association

was found between nutritional

variables and episodic memory

Manzato

et al., 2003

Cross-sec-

tional, popu-

lation-based

191 sub-

jects aged

R65 years

Evaluation of plasma phospholipid

fatty acid composition

MMSE: subjects with a score

between 10 and 17 versus subjects

with a score between 28 and 30

Cognitive functioning are affected

mainly by age and education, not by

dietary fatty acids

Kalmijn

et al., 2004

Cross-sec-

tional, popu-

lation-based

1613 sub-

jects, 45–70

years old

Evaluation of fatty fish, total fat,

cholesterol, SFA MUFA, PUFA

(nK6 and nK3) dietary intakes

with a 178-item FFQ

Concurrent to the dietary assess-

ment, the visual verbal learning test,

the concept shifting task, an abbre-

viated stroop color word test, the

letter digit substitution test, a

category fluency test were

administrated

Fatty fish and marine nK3 PUFA

consumption was associated with a

reduced risk and intake of choles-

terol and saturated fatty acids with

an increased risk of impaired cog-

nitive function in this middle-aged

population

Longitudinal studies

Kalmijn

et al., 1997a

Longitudi-

nal, popu-

lation-based

(3 years)

476 sub-

jects, aged

69–89 years

Evaluation of dietary intake with the

cross-check dietary history method

Cognitive impairment defined as a

MMSE score !25 points and

cognitive decline as a drop of O2

points of MMSE over a 3-year

period

High linoleic acid intake (PUFA)

was positively associated with cog-

nitive impaiment. High fish con-

sumption was inversely associated

with cognitive impairment

Hende

et al., 2003

Longitudi-

nal, popu-

lation-based

(4 years)

246 sub-

jects aged

63–74 years

Evaluation of fatty acid composition

in erythrocyte membranes

MMSE score with a O2-point of

decrease in a 4-year follow-up

Inverse association between cogni-

tive decline and the ratio of nK3 to

nK6 PUFA in erythrocyte mem-

branes

Capurso

et al., 2003

Longitudi-

nal, popu-

lation-based

(8.5 years)

278 sub-

jects, 65–94

years old

from a

cohort of

5632 sub-

jects

Evaluation of MUFA and PUFA

dietary intakes with a 77-item FFQ

MMSE The MMSE performance over 8.5

years follow-up due to high PUFA

(R220 kJ/day) and MUFA (O2000 kJ/day) intakes were signifi-

cantly better than that due to low

PUFA and MUFA intake, in all

subjects and completers

Morris

et al., 2004

Longitudi-

nal, popu-

lation-based

(6 years)

2560 sub-

jects, aged

65 years

and older

Evaluation of dietary intake with a

139-items FFQ

Cognitive change at 3-year and 6-

year follow-ups measured with the

East Boston tests of immediate and

delayed recall, the MMSE, and the

symbol digit modalities test

A diet high in saturated and trans-

unsaturated fat or low in non-

hydrogenated unsaturated fats may

be associated with cognitive decline

among older people

FFQ, food frequency questionnaire; MMSE, global cognitive functioning; PMSQ, global cognitive functioning; DCT, selective attention; BSRT, episodic

memory; Visual Verbal Learning Test, verbal memory; Concept Shifting Task, mental processing speed; Stroop Color Word Test, selective attention; Letter Digit

Substitution Test, perceptual-motor speed; Category Fluency Test, semantic memory; East Boston Memory test, immediate and delayed episodic memory;

Symbol Digit Modalities Test, perceptual-motor speed.

V. Solfrizzi et al. / Experimental Gerontology 40 (2005) 257–270260

V. Solfrizzi et al. / Experimental Gerontology 40 (2005) 257–270 261

while cognitive functions were assessed with the Visual

Verbal Learning Test (verbal memory), the Concept

Shifting Task (mental processing speed), an abbreviated

Stroop Color Word Test (selective attention), the Letter

Digit Substitution Test (perceptual-motor speed), a Cat-

egory Fluency Test (semantic memory) were administrated.

Compound scores for psychomotor or simple speed,

memory function, cognitive flexibility, and global cognitive

function were calculated by averaging the z-scores of the

above-mentioned neuropsychological tests. After adjusting

for age, gender, education, alcohol consumption, smoking,

and energy intake, higher dietary cholesterol was associated

with an increased risk of impaired memory function (OR,

1.27) and cognitive flexibility cognitive function (OR,

1.26), whereas higher SFA intake was associated with an

increased risk of impairment in memory function, psycho-

motor speed, and cognitive flexibility by 15–19%, although

not significantly. Fatty fish and marine nK3 PUFA

consumption were significantly associated with a decreased

risk of global cognitive function impairment and psycho-

motor speed by 19–28%. These associations appeared to be

independent of differences in cardiovascular risk factors

(Kalmijn et al., 2004).

To our knowledge, only three epidemiological studies on

the association between fatty acids and cognitive function-

ing were longitudinal (Kalmijn et al., 1997a; Capurso et al.,

2003; Morris et al., 2004), indicating a crucial need for

prospective studies that could confirm initial observations.

In fact, subjects with cognitive impairment or dementia may

have altered their diet as a consequence of the disease.

Moreover, the report of the dietary intake can be altered by

cognitive impairment, suggesting an investigation to

identify any possible associations between diet and

cognitive functioning using longitudinal observations.

Nonetheless, the amount of evidence coming from the

above-mentioned cross-sectional studies must not be

dismissed because these are hypothesis-generating studies

that need to be confirmed in prospective assessments. In

fact, among the macronutrients, fatty acids were suggested

to play a role in modulating the risk of cognitive impairment

and dementia based on cross-sectional observations.

Furthermore, subjects investigated in longitudinal studies

may still have been cognitively impaired at baseline.

However, it does not appear very likely that subjects with

cognitive impairment or in a preclinical phase of dementia

like MCI consistently over-reported the consumption of

certain foods or under-reported the consumption of other

food intakes. In fact, in these cross-sectional studies

dementia patients were excluded, while all studies with

dementia as an outcome were prospective.

In particular, one of these prospective studies, the

Zutphen Study of 476 men aged 69–89 years, defined

cognitive impairment as a MMSE score !25 points and

cognitive decline as a drop of O2 points of MMSE over a

3-year period. Dietary assessment was performed with the

cross-check dietary history method. In this study, it was

found that high linoleic acid intake was positively

associated with cognitive impairment in elderly subjects

only in cross-sectional study after an adjustment for age,

education, cigarette smoking, alcohol consumption,

and energy intake. High fish consumption, an important

source of long-chain nK3 PUFA, tended to be inversely

associated with cognitive impairment and cognitive decline

at 3-year follow-up, but not significantly (Kalmijn et al.,

1997a) (Table 1).

Furthermore, on the basis of the previous significant

suggestions (Solfrizzi et al., 1999), we tested further the

hypothesis that high MUFA and PUFA intakes may protect

against the development of cognitive impairment over time

in a median follow-up of 8.5 years of the Italian

Longitudinal Study on Aging. The major finding of this

recent study was that the MMSE performance over the

course of an 8.5 years follow-up due to high PUFA

(R220 kJ/day) and MUFA (O2000 kJ/day) intakes were

significantly better than those due to low PUFA (!220 kJ/

day) and MUFA (%2000 kJ/day) intake, in all subjects and

completers (Capurso et al., 2003) (Table 1). Furthermore,

although higher PUFA and MUFA intakes could be

protective on cognitive functions, the mean predicted

MMSE score over 8.5 years of follow-up, adjusted for

cohort effect and education, were impaired in comparison of

their respective values at baseline. Finally, it was confirmed

in this longitudinal study that at baseline a low educational

level (%3 years) modified the protective effect of higher

MUFA intake on MMSE performance observed in the cross-

sectional analysis (Solfrizzi et al., 1999). However, the role

of education could be important in modifying dietary intake

habits in cognitively impaired subjects. In particular, in a

very mild cognitive impairment this change could be

difficult to estimate by MMSE which could remain normal

for a long time with a high level of education suggesting that

dietary intake modification may precede the decline. We did

not estimate this subtle difference because 83% of our

cohort of subjects attended primary school and only three

subjects had a degree. Some limitations of our study should

be considered, in particular the small size of the cohort and

the nature of the missing value mechanism and its

implications for statistical inference.

Finally, recent findings from the Chicago Health and

Aging Project (CHAP) showed that in a large population-

based sample of 2560 persons, aged 65 years and older, a

high intake of saturated and trans-unsaturated fat were

associated with a greater cognitive decline over a 6-year

follow-up. Intake of MUFA was inversely associated with

cognitive change among persons with good cognitive

function at baseline and among those with stable long-

term consumption of margarine, a major food-source.

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. Finally, cognitive

V. Solfrizzi et al. / Experimental Gerontology 40 (2005) 257–270262

change was not associated with intakes of total fat, animal

fat, vegetable fat, or cholesterol (Morris et al., 2004).

Therefore, several studies suggested that an increase of

SFA could have negative effects on cognitive functions.

Furthermore, a clear reduction of risk of cognitive

impairment in cross-sectional studies and cognitive decline

in longitudinal studies have been found in population-base

samples with high intakes of PUFA and MUFA. Although

these findings are promising, further investigations are

needed in larger samples of elderly subjects with longer

follow-up periods to determine the role of UFA intake in

protecting against ARCD in relation to other environmental

and genetic factors. Furthermore, in these studies, cognitive

functioning was assessed by simple neuropsychological

tests in non-demented people while, at present, there was

any study with a focus on predementia syndromes,

identifying with this term all conditions with age-related

deficits in cognitive function and operational clinical

criteria, including a mild stage of cognitive impairment

based more on a normality model (ARCD or AACD) and

concepts considered as a pathological condition and there-

fore, a risk state for dementia (MCI)

3. Dietary fatty acids and dementia

Recent findings showed that older African-Americans

(Hendrie et al., 1995) and Japanese living in the United

States (White et al., 1996) have a much higher prevalence of

AD (6.24 and 4.1%, respectively) than those still living in

their ethnic homelands (!2%), suggesting that the

prevalence of AD is more strongly influenced by diet and

nutrition, environment, and/or lifestyle, than by genetics.

However, the simple comparison of prevalence data might

be misleading, since there is a large difference in selective

survival and cultural effects. A more valuable comparison

would be that of the overall dementia rate among different

countries, culturally adjusted.

The first paper establishing a strong dietary link to AD

was published in 1997 (Grant, 1997). In this cross-sectional

ecological study, regression analyses have been performed

in the 65C age population of 11 countries-including the

USA, European countries, and China-obtained from 18

community-wide studies versus components of the national

diets (Table 2). The primary finding is that fat and total

caloric supply have the highest correlations with AD

prevalence rates. In addition, a combination of fat and fish

consumption is found to reduce the prevalence of AD in the

European and North American countries, i.e. one calorie of

fish was found to counter the effects of approximately 4.3

calories of fat (Grant, 2000). These findings were supported

in an editorial comment (Smith et al., 1999), and have been

reviewed and updated in several subsequent publications

(Grant, 1999; Grant, 2000; Grant et al., 2002). As with most

studies of this type, there are a number of potential caveats.

In particular, the results of analyses of food supply data with

prevalence data that are applied to specific populations

should be viewed with caution (Smith et al., 1999).

However, these ecological evidences are in agreement

with various recent epidemiologic studies (Grant, 1999).

In fact, the finding that total dietary fat is a possible risk

factor for the development of AD, has been reported in the

Rotterdam Study with 5386 participants !55 years of age,

although not at a statistically significant level. In the

same study, fish consumption was confirmed to reduce AD

risk and linoleic acid was inversely correlated with AD.

This study suggested that an elevated intake of lipids

and saturated fat increased the risk for dementia with

a cerebrovascular component (Kalmijn et al., 1997b)

(Table 2).

One of the most interesting findings of a recent study on

VaD risk factors conducted on the cohort of the Honolulu-

Asia Aging Study (HAAS), in 3385 older Japanese subjects,

was the protective effect of a Western diet against the

development of VaD (Ross et al., 1999) (Table 2). As

reported above, oriental populations from Asian countries

are known to be more prone to stroke (Kagan, 1996) and

VaD (Jorm, 1991; White et al., 1996). A traditional Western

diet is high in animal fat and protein and low in complex

carbohydrates (Berrino, 2002), compared to the traditional

Japanese diet, which is high in complex carbohydrates and

low in animal fat and protein. This is an interesting approach

in which dietary patterns, not only single micro- or

macronutrients, are considered in explaining the possible

role of diet in cognitive decline. The mechanism by which

an oriental diet leads to VaD remains speculative. The

higher risk of stroke could probably be referred to the lower

intake of animal fat and protein. As these findings do not

allow analysis of separate nutrients, a hypotheses could be

that more fat intake may stabilize the integrity of smaller

intracranial arterioles, while the quantity and quality of

dietary protein may affect small vessel pathology. Further-

more, the increased risk of VaD and stroke in Japan may

well be due to the high sodium intake, in the form of soy

sauce, pickled fish, etc (Nagata et al., 2004). In a recent

study conducted in Japan on 27 AD patients, 15 patients

with VaD, and 49 age-matched healthy controls, a

significant difference was found in the profile of dietary

fatty acids intake. AD male patients took more SFA and

MUFA than VaD male patients, probably reflecting

Westernization of dietary habits in Japan in recent years.

Furthermore, the nK6/nK3 ratios were consistently

increased in all dementia groups versus controls, although

nK6 PUFA was increased in male patients and nK3 PUFA

was decreased in female patients (Otsuka et al., 2002).

The cohort of the Rotterdam Study was re-examined in a

6.0-year follow-up, and a high intake of total fat, saturated

fat, trans fat, and cholesterol and low intake of MUFA,

PUFA, nK6 PUFA, and nK3 PUFA were not associated

with an increased risk of dementia or its subtypes (Engelhart

et al., 2002). The discrepancy with the results of the first

study were explained by the authors by the shorter follow-up

Table 2

Principal ecological, clinical and epidemiological studies on the relationships between dietary fatty acids and dementia, vascular dementia (VaD), and

Alzheimer’s disease (AD)

Reference Setting and

study design

Subjects Dietary assessment Dementia diagnosis Results and conclusions

Cross-sectional studies

Grant, 1997 Ecological

cross-sec-

tional

18 commu-

nity-wide

studies con-

ducted after

1979 (R65

years old)

Evaluation of the components of the

national diets

Prevalence of AD The primary finding is that fat and total

caloric supply have the highest corre-

lations with AD prevalence rates. In

addition, fish consumption is found to

reduce the prevalence of AD in the

European and North American

countries

Ross et al.,

1999

Cross-sec-

tional, popu-

lation-based

3734 Japa-

nese Ameri-

can men

aged 71–93

Evaluation of vascular risk factors,

dietary habits, and questionnaire on

supplementary vitamin E and C use

and alcohol intake

Diagnosis of dementia,

VaD (ADDTC criteria),

and stroke without

dementia

The antioxidant vitamin E and

unknown factors related to a Western

diet, high in animal fat and protein and

low in complex carbohydrates, as

opposed to an Oriental diet may be

protective against developing VaD

Longitudinal studies

Kalmijn

et al., 1997b

Longitudi-

nal, popu-

lation-based

(2.1 years)

5386 sub-

jects aged 55

and older

Evaluation of dietary intakes with a

170-item FFQ

Diagnosis of AD

(NINCDS-ADRDA

criteria), VaD (NINDS-

AIREN criteria), or

dementia with a vascular

component

High intakes of total fat, saturated fat,

and cholesterol were associated with

an increased risk of dementia Demen-

tia with a vascular component was

most strongly related to total fat and

saturated fat. Fish consumption was

inversely related to incident dementia,

and in particular to AD

Engelhart

et al., 2002

Longitudi-

nal,popula-

tion-based

(6 years)

5395 sub-

jects aged 55

and older

Evaluation of dietary intakes with a

100-item FFQ

Diagnosis of dementia

(DSM-III-R criteria),

AD (NINCDS-ADRDA

criteria), and VaD

(NINCDS-AIREN

criteria)

High intakes of total fat, saturated fat,

trans fat, and cholesterol and low

intake of MUFA, PUFA, nK6 PUFA,

and nK3 PUFA were not associated

with an increased risk of dementia,

AD, or VaD

Luchsinger

et al., 2002

Longitudi-

nal, popu-

lation-based

(4 years)

980 sub-

jects, mean

age:75.3G

5.8 years

Evaluation of dietary intake with a

61-item FFQ

Diagnosis of prevalent

dementia (DSM-IV

criteria) and incident

AD(NINCDS-ADRDA

criteria)

Higher intake of calories and fats may

be associated with higher risk of AD in

subjects carrying the apolipoprotein E

34 allele

Barbeger-

Gateau

et al., 2002

Longitudi-

nal, popu-

lation-based

(7 years)

1674 sub-

jects aged 68

years and

over

Evaluation of frequency of consump-

tion of meat and fish and seafood: from

daily to never

Diagnosis of incident

dementia, including AD

(DSM-III-R criteria)

Elderly people who consumed fish

[rich in PUFA] or seafood at least once

a week are at lower risk of dementia,

including AD

Morris et al.,

2003a

Longitudi-

nal, popu-

lation-based

(3.9 years)

815 sub-

jects, aged

65 years and

older

Evaluation of dietary intake with a

154-item FFQ

Incident diagnosis of AD

(NINCDS-ADRDA

criteria)

High intake of saturated and trans-

unsaturated fats may be associated

with higher risk of AD; while high

intake of nK6 PUFA and MUFA may

be protective against AD

Morris et al.,

2003b

Longitudi-

nal, popu-

lation-based

(3.9 years)

815 sub-

jects, aged

65 years and

older

Evaluation of dietary intake with a

154-item FFQ

Incident diagnosis of AD

(NINCDS-ADRDA

criteria)

Higher intake of nK3 PUFA and

weekly fish consumption may reduce

the risk of incident AD

FFQ, food frequency questionnaire; ADDTC, California Alzheimer’s Disease Diagnostic and Treatment Centers; NINCDS-ADRDA, National Institute of

Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association; NINCDS-AIREN, National Institute

of Neurological and Communicative Disorders and Stroke and the Association Internationale pour la Recherche at l’Enseignement en Neurosciences; DSM-

III-R, Diagnostic and Statistical Manual of Mental Disorders, third edition revised; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, fourth

edition.

V. Solfrizzi et al. / Experimental Gerontology 40 (2005) 257–270 263

(2.1 years) and a consequent smaller number of incident

cases of dementia. Moreover, this study considered fat

normalized to total energy. In a recent study, Grant, to check

on the validity of this approach, grouped in regression

analyses the data from the Rotterdam study with those of a

recent study from India (Chandra et al., 2001). The adjusted

r2 for total fat was 0.94, FZ179, p!0.001; for normalized

fat, the adjusted r2 was 0.90, FZ97, p!0.001. For fat and

fish, the adjusted r2 was 0.95, FZ111, p!0.001; for

fish and normalized fat, the adjusted r2 was 0.91, FZ57,

p!0.001. The conclusions were that it seemed inappropri-

ate to use normalized fat in the analysis (Grant, 2003).

V. Solfrizzi et al. / Experimental Gerontology 40 (2005) 257–270264

Moreover, other limitations of the Rotterdam study include

the potential for counfounding by intake of other types of fat

(e.g. intake of trans fat is associated with both intakes of

MUFA and SFA), and the potential for non-linear

associations, with associations of the extremes of intake.

Finally, the findings of the re-examined cohort of the

Rotterdam Study are at odds with several recent studies

(Giem et al., 1993; Luchsinger et al., 2002; Barbeger-

Gateau et al., 2002; Morris et al., 2003a; Morris et al.,

2003b) (Table 2). In fact, a 4-year cohort study in New

York, the Washington Heights-Inwood Columbia Aging

Project, found that dietary fat was an important risk factor

for AD for those with the APOE 34 allele [hazard ratio of

fourth quartile with respect to the first 2.31 (95% CI 1.09–

4.89), p value for trendZ0.02] but not for those without that

allele [hazard ratio of fourth to first 1.15 (95% CI 0.07–

1.93), p value for trendZ0.02] (Luchsinger et al., 2002).

Luchsinger et al. did not find associations with individual

types of fat, but like the Rotterdam study, failed to control

for other types of fat which may have confounded the

observed findings. They also confirmed previous ecological

findings on the possible role of cereals as a risk reduction

factor (Grant, 1997).

Furthermore, findings coming from the PAQUID study, a

population-based study conducted in France on 1674

subjects aged 68 years and over with no apparent dementia

at baseline, showed that participants who ate fish or seafood

at least once a week had a significantly lower risk of

dementia (age and sex adjusted hazard ratio of 0.66, 95%

CI: 0.47–0.93) in the 7 subsequent years. After adjusting for

education, the hazard ratio was almost unchanged (0.73),

but the 95% CI (0.52–1.03), slightly overlapping 1.00,

indicated that higher education of regular consumption

explains in part the protective effect against dementia of

weekly fish or seafood consumption. Moreover, in this study

no significant association between meat consumption and

the risk of dementia was found for weekly consumers with

only a borderline significance for developing AD (hazard

ratio: 0.68, 95% CI: 0.47–1.01) (Barbeger-Gateau et al.,

2002) (Table 2). Preliminary findings from the Adventist

Heart Study reported an increased risk of AD for meat eaters

(but including poultry and fish) compared to vegetarians

(relative risk 2.18, pZ0.065) in 272 California residents and

2984 unmatched subjects who resided within the California

area (Giem et al., 1993). The discrepancy was further

widened (relative risk 2.99, pZ0.048) when past meat

consumption was taken into account. There was a trend

towards delayed onset of dementia in vegetarians in both

sub studies (Giem et al., 1993; Barbeger-Gateau et al.,

2002).

Finally, very recently, two studies from the cohort of the

CHAP, increased the evidence of a strict linkage between

dementia and fatty acid intake (Morris et al., 2003a,b). In

fact, in this cohort of 815 subjects, aged 65 years and older,

after a mean follow-up of 3.9 years, 131 persons developed

AD. A high intake of saturated fat and trans-unsaturated fat

may be associated with a higher risk of AD; while a high

intake of nK6 PUFA and MUFA may be protective against

AD (Morris et al., 2003a). Furthermore, in the same cohort,

a higher intake of nK3 PUFA and weekly fish consumption

may reduce the risk of incident AD. In fact, in this study

people who ate fish once or more weekly had a relative risk

for AD of 0.4: the absolute risk reduction was about 9.5%

(Morris et al., 2003b). These results confirmed our findings

on a possible protective role of MUFA and PUFA intakes

against ARCD (Solfrizzi et al., 1999; Capurso et al., 2003).

Comparing the approach of the re-analysis of the

Rotterdam Study (Engelhart et al., 2002), with those of

the ecological study by Grant (1997) the Washington

Heights-Inwood Columbia Aging Project (Luchsinger et al.,

2002), the PAQUID study (Barbeger-gateau et al., 2002),

and the CHAP (Morris et al., 2003a,b), we could draw

possible explanations of these conflicting findings. In

particular, some methodological issues, i.e. the normal-

ization of fat to energy, omitted patients with early onset of

dementia (those who did not respond to the invitation to

participate), a population with low fish consumption, and,

finally, no genetic analysis (presence of APOE 34 allele),

may help to explain why the findings from the Rotterdam

study are at odds with the other studies considered

(Luchsinger et al., 2002; Barbeger-gateau et al., 2002;

Morris et al., 2003a,b) (Table 2). Therefore, despite these

contrasting findings, there is now considerable evidence

suggesting that diet, and particularly fatty acid intake, may

influence AD risk, but the direction (protection or risk) and

the level of this effect remain unclear. In fact, based on the

current evidences from human and animal studies, Friedland

(2003) concluded that, currently, it is not possible to make

definitive dietary recommendations in relation to the AD

risk on fish consumption and the lower intake of saturated

fat from meat and dairy products. Furthermore, individuals

who consume a diet high in fruits and vegetables as well as

nuts or fish would probably have other lifestyle character-

istics that might be effective in reducing AD or VaD risk

(e.g. physical activity) (Fratiglioni et al., 2004). However, a

high consumption of fats from fish, vegetable oils,

vegetables, and nuts should be encouraged because this

dietary advice is in accordance with recommendations for

lowering the risk of cardiovascular disease, obesity,

diabetes, and hypertension (Friedland, 2003).

4. Fatty acids and cognitive decline: possible

mechanisms

The mechanisms by which high UFA intake could be

protective against cognitive decline and dementia in healthy

older people are, at present, unknown. In the elderly subjects

of the Italian Longitudinal Study on Aging, which fulfilled a

Mediterranean dietary pattern, total fat is 29% of energy,

with a high consumption of olive oil (46 g/d), a MUFA

energy intake of 17.6% of total energy, 85% of which

V. Solfrizzi et al. / Experimental Gerontology 40 (2005) 257–270 265

derived from olive oil, and a SFA intake of only 6%

(Solfrizzi et al., 1999). The Mediterranean diet model

included diets consumed in olive-producing Mediterranean

regions. In our population, the prolonged protection of

MUFA intake against age-related changes in cognitive

functions, may be linked to the relevant quota of antioxidant

compounds in olive oil, including low molecular weight

phenols (Briante et al., 2003). In fact, animal studies

suggested that diets high in antioxidant-rich foods, such as

spinach, strawberries, and blueberries, rich in anthocyanins

and other flavonoids may be beneficial in slowing age-

related cognitive decline (Joseph et al., 1999). These

findings were confirmed by the Rotterdam Study, in which

were found a cross-sectional inverse relation of b-carotene

to cognitive impairment (MMSE%25) (Jama et al., 1996).

The possible role of antioxidant compounds from olive oil

do not diminish or otherwise alter the argument concerning

the fatty acids, because this is only a possible explanation of

the role of MUFA on age-related cognitive changes in our

population, in which MUFA intake derived for a large part

from olive oil.

Furthermore, an increase in oxidative stress has been

demonstrated in AD (Deschamps et al., 2001). This disease

is characterized by the presence of both intraneuronal

protein clusters composed of paired helical filaments of

hyperphosphorilated tau protein (neurofibrillary tangles),

and extracellular protein aggregates (senile plaques). The

senile plaques are the result of misprocessing of the APP by

b- and g-secretases to form a toxic Ab peptide that

aggregates and initiates a pathogenic self-perpetuating

cascade ultimately leading to neuronal loss and dementia

(Panza et al., 2004a). There is evidence that oxidative stress

might be directly involved in development of the senile

plaques. The relation between deposition of Ab peptide and

the oxidative stress in AD was shown in several studies

(Deschamps et al., 2001). Antioxidant compounds may

protect the brain against oxidative stress and the accumu-

lation of Ab in aging and AD.

The protective effect of dietary UFA could be related to

the role of fatty acids in maintaining the structural integrity

of neuronal membranes, determining the fluidity of

synaptosomal membranes and thereby regulating neuronal

transmission (Solfrizzi et al., 2003; Panza et al., 2004b).

Furthermore, essential fatty acids can modify the activity of

certain membrane-bound enzymes (phospholipase A2,

protein kinese C, and acetyltranferase), and the function

of the neurotransmitters’ receptors. Finally, free fatty acids,

lipid metabolites, and phospholipids modify the function of

membrane proteins including ion channels (Solfrizzi et al.,

2003; Panza et al., 2004b). Moreover, fatty acid compo-

sition of neuronal membranes in advancing age demon-

strated an increase in MUFA content and a decrease in

PUFA content (Favrelere et al., 2000). In fact, rats

administered diets high in SFA or PUFA were impaired

on various tests of learning and memory (Solfrizzi et al.,

2003). In rats, dietary oleic acid deficiency leads to

a reduction of the oleic acid concentration in many tissues,

including the sciatic nerve, but not in the brain (Bourre,

2004). In many organs, endogenous synthesis therefore,

does not compensate for the absence of oleic acid in food

(Bourre et al., 1997). This fatty acid is therefore, not

synthesized in sufficient quantities, at least in rats and

especially during pregnancy-lactation, implying a need for

dietary intake. It must be remembered that organization of

the neurons is almost complete several weeks before birth,

and that these neurons remain for the subject’s life time.

Consequently, any disturbance of these neurons, an

alteration of their connections, and impaired turnover of

their constituents at any stage of life, will tend to accelerate

aging (Bourre, 2004).

There are several published studies on human infant

subjects in which breastfeeding, which leads to higher

nK3 PUFA docosahexaenoic acid concentrations in the

brain, or nK3 PUFA supplementation, is related to better

cognitive performance at later age (Williams et al., 1998).

There is also evidence associating a dietary deficiency of

nK3 PUFA with changes in cortical dopoaminergic

function (Delion et al., 1994). The nK3 PUFA from fish

may be inversely associated with dementia because it

lowers the risk of thrombosis (Horrocks and Yeo, 1999),

stroke (Keli et al., 1994), cardiovascular disease (Marchioli

et al., 2002), and cardiac arrhythmia (Horrocks and Yeo,

1999), reducing the risk of thromboembolism in the brain

and consequently of lacunar and large infarcts that can lead

to VaD and AD (Panza et al., 2004a). Furthermore, the

nK3 PUFA may be important as lipids in the brain,

particularly for the possible influence of docosahexaenoic

acid on the physical properties of the brain that are

essential for its function (Crawford et al., 1999). Further-

more, fish oil was a better source than a-linolenic acid for

the incorporation of nK3 PUFA into rat brain phospholipid

subclasses (Alsted and Hoy, 1992).

Finally, very recently, the reduction of dietary nK3

PUFA in an AD mouse model resulted in 80–90% losses of

the p85a subunit of phosphatidyl-inositol 3 kinase (PI-3K)

and the postsynaptic actin-regulating protein drebrin, as in

AD brain. The loss of postsynaptic proteins was associated

with increased oxidation, without concomitant neuron or

presynaptic protein loss. Treatment of nK3 PUFA-

restricted mice with docosahexaenoic acid protected against

these effects and behavioral symptoms. Since nK3 PUFA

are essential for p85-mediated central nervous system

insulin signaling and selective protection of postsynaptic

proteins, these findings may have implications for neuro-

degenerative diseases where synaptic loss is critical,

especially AD (Calon et al., 2004). Furthermore, a novel

intracellular pathway that increases the rate of secretion of

non-amyloidogenic a-secretase form of soluble APPsoluble

APPa (sAPPa) through the activity of PI3-K was demon-

strate. This pathway does not involve either the activation of

protein kinase C (PKC) or the mitogen-activated protein

kinase (MAP-K) pathway (Solano et al., 2000).

V. Solfrizzi et al. / Experimental Gerontology 40 (2005) 257–270266

In fact, stimulation of sAPPa release is highly regulated

through activation of various second messenger pathways,

including PKC, MAP-K, and tyrosine kinase cascades

(Caporaso et al., 1992; Cobb and Goldsmith, 1995). This is

not due to the phosphorylation of APP, but may result from

protein phosphorylation that modulates the activity of

a-secretase or the trafficking of APP. Other signaling

systems shown to stimulate sAPPa release include calcium

(Nitsch et al., 1992), cAMP (Hu et al., 1996), growth factors

(Fukuyama et al., 1993), cytokines (Buxbaum et al., 1992),

and estrogen (Jaffe et al., 1994). Several reports showed a

reduction of sAPPa secretion via inhibition of MAP-K for

different cell lines (Mills et al., 1997; Desdouits-Magnen

et al., 1998). Induced sAPPa secretion might have

additional advantages, since a considerable body of

evidence strongly suggest that sAPPa has potent neuro-

trophic and protective activities against excitotoxic and

oxidative insults.

On the contrary, high linoleic acid intake (nK6 PUFA)

may increase the susceptibility of LDL cholesterol to

oxidation, which makes it more atherogenic (Reaven et al.,

1994), even if the association between linoleic acid and

atherosclerosis is controversial (Blankenhorn et al., 1990).

Therefore, the ratio of dietary nK3/nK6 PUFA intake may

influence the potential role of PUFA on cognitive

decline and dementia, the optimal ratio of nK6:nK3

should be !5:1 (de Lorgeril et al., 1998).

Furthermore, clinical and epidemiological data have

shown that chronic inflammation appears as a precursor of

symptomatic AD (McGeer and McGeer, 1995), suggesting

another possible link between dietary fatty acids and

cognitive decline. In fact, iinflammation also arises from

prostaglandins derived from fatty acids (Grant, 1997).

Series 1 prostaglandins (PGE1) derived from linoleic acid

(nK6 PUFA) with linoleic acid as the starting point,

decrease inflammation response (Grant, 1997). Series 2

prostaglandins (PGE2) derived from arachidonic acid found

in meats and other animal products, as well as from linoleic

acid, lead to salt retention by the kidneys, leading to high

blood pressure and inflammation (Grant, 1997; Bayorh

et al., 2001). Series 3 prostaglandins, derived from

eicosapentaenoic acid found in fish oils, prevent arachidonic

acid from being released from membranes, thus preventing

PGE2 formation (Grant, 1997). Finally, the production of

proinflammatory cytokines in humans can be decreased by

the nK3 PUFA from fish (Horrocks and Yeo, 1999) and

MUFA from olive oil (Capurso et al., 2004). In fact, MUFA

have been demonstrated to influence tissue inflammatory

mechanisms, decreasing tissue responsiveness to inflamma-

tory cytokines, reducing the expression of the adhesion

molecules vascular cell adhesion molecule 1 (VCAM1) and

intercellular adhesion molecule 1 (ICAM1) from mono-

nuclear and endothelial cells, respectively (Capurso et al.,

2004).

Finally, a high dietary intake of SFA and cholesterol

increases the risk for cardiovascular disease, and therefore,

for cognitive decline, VaD, and AD (Panza et al., 2004a).

On the contrary, treatment for four weeks with a

Mediterranean-inspired diet rich in nK3 PUFA decreased

blood lipids in healthy individuals with a low-risk profile for

cardiovascular disease, with a beneficial effect also on

vascular function and oxidative stress (Ambring et al.,

2004). High serum total cholesterol during middle age or

early old age seems to confer an increased risk of AD in old

age (Notkola et al., 1998). Epidemiological studies showed

that the onset of AD occurs earlier in APOE 34-carriers with

high serum total cholesterol (Jarvik et al., 1995). On the

contrary, a cross sectional study reported an association

between AD and lower total cholesterol (Kuusisto et al.,

1997) which has been supported by work by our group

(Solfrizzi et al., 2002). Furthermore, in our recent study we

analyzed the relationship between sporadic AD and Lp(a),

a LDL-like particle with apolipoprotein[a], that is believed

to have atherogenic and thrombotic properties and has been

associated with cerebrovascular disease as well as VaD

(Urakami et al., 2000; Panza et al., 2004a). We found that

Lp(a) serum levels were significantly associated, according

to a non-linear relationship, with an increased risk for AD,

independently of APOE genotypes, and dependent on age

(Solfrizzi et al., 2002). A high saturated fat intake increases

LDL cholesterol showing that AD patients have higher LDL

cholesterol and lower high-density lipoproteins cholesterol

than non-demented controls (Kuo et al., 1998). Moreover,

Lp(a) is a LDL-like particle, and a recent study found

increased levels of serum LDL cholesterol in AD patients

correlate with brain Ab N-42 levels, suggesting that LDL

cholesterol may influence the expression of AD-related

pathology (Kuo et al., 1998).

5. Conclusions

At present, several studies suggested that an increase of

SFA could have negative effects on cognitive functions.

Furthermore, a clear reduction of risk for cognitive decline

has been found in a population sample with a high intake of

PUFA and MUFA. These findings were confirmed by

studies in which high intakes of nK6 PUFA, nK3 PUFA,

and MUFA appear to be protective against the risk of AD.

Furthermore, weekly fish consumption, providing nK3

PUFA, may reduce the risk of incident AD. High MUFA

intake may be a marker for other dietary factors responsible

for the protection against cognitive disorders, i.e. the great

amount of tocopherol and polyphenols, the antioxidant

compounds of olive oil, and the low intake of SFA. In our

elderly population from Southern Italy, elevated UFA intake

(MUFA and PUFA), high levels of antioxidant compounds,

and very low SFA intake could act synergistically in

improving cognitive performance.

Several hypotheses could explain the association between

fatty acids and cognitive functioning, including mechanisms

through the co-presence of antioxidant compounds in food

V. Solfrizzi et al. / Experimental Gerontology 40 (2005) 257–270 267

groups rich in fatty acids, via atherosclerosis and thrombosis,

inflammation, accumulation of b-amyloid, or via an effect in

maintaining the structural integrity of neuronal membranes,

determining the fluidity of synaptosomal membranes that

thereby regulate neuronal transmission.

Nonetheless, at present, no definitive dietary recommen-

dations on fish and UFA consumption or lower intake of

saturated fat in relation to the risk for dementia and

cognitive decline are possible. In fact, these recommen-

dations have not yet been tested with a double-blind, clinical

trial. However, high levels of consumption of fats from fish,

vegetable oils, and vegetables should be encouraged

because this dietary advice is in accordance with rec-

ommendations for lowering the risk of cardiovascular

disease, obesity, diabetes, and hypertension. In conclusion,

epidemiological studies on the association between diet and

cognitive decline suggested a possible role of fatty acids

intake in maintaining adequate cognitive functioning and

possibly in preventing or delaying the onset of dementia,

both of degenerative or vascular origin. Appropriate dietary

measures or supplementation with specific macronutrients

might open new ways for the prevention and management of

cognitive decline and dementia.

Acknowledgements

This study was supported by the Italian Longitudinal

Study on Ageing [ILSA] [Italian National Research

Council-CNR-Targeted Project on Ageing-Grants

9400419PF40 and 95973PF40], by MURST 40 and 60%,

and by AFORIGE [‘Associazione per la FOrmazione e la

RIcerca in Geriatria’]. The authors wish to thank Dr Adriana

Rafaschieri, Dr Mauro Vilardi, Dr Amalia Terralavoro,

Pfizer Inc. for skilful assistance, and Ms Maria Mann for

editing the manuscript.

References

Alsted, A.L., Hoy, C.E., 1992. Fatty acid profiles of brain phospholipid

subclasses of rats fed nK3 polyunsaturated fatty acids of marine or

vegetable origin. A two generation study. Biochim. Biophys. Acta

1125, 237–244.

American Psychiatric Association Committee on Nomenclature and

Statistics, 1994. Diagnostic and Statistical Manual of Mental Disorders,

fourth ed. [DSM-IV]. American Psychiatric Association, Washington,

DC.

Ambring, A., Friberg, P., Axelsen, M., Laffrenzen, M., Taskinen, M.R.,

Basu, S., Johansson, M., 2004. Effects of a Mediterranean-inspired diet

on blood lipids, vascular function and oxidative stress in healthy

subjects. Clin. Sci. 106, 519–525.

Barberger-Gateau, P., Letenneur, L., Deschamps, V., Peres, K.,

Dartigues, J.F., Renaud, S., 2002. Fish, meat, and risk of dementia:

cohort study. BMJ 325, 932–933.

Bayorh, M.A., Socci, R.R., Eatman, D., Wang, M., Thierry-Palmer, M.,

2001. The role of gender in salt-induced hypertension. Clin. Exp.

Hypertens. 23, 241–255.

Berrino, F., 2002. Western diet and Alzheimer’s disease. Epidemiol. Prev.

26, 107–115 (Italian).

Blankenhorn, D.H., Johnson, R.L., Mack, W.J., el Zein, H.A., Vailas, L.I.,

1990. The influence of diet on the appearance of new lesions in human

coronary arteries. JAMA 263, 1646–1652.

Bourre, J.M., 2004. Roles of unsaturated fatty acids (especially omega-3

fatty acids) in the brain at various ages and during ageing. J. Nutr.

Health Aging 8, 163–174.

Bourre, J.M., Dumont, O.L., Clement, M.E., Durand, G.A., 1997.

Endogenous synthesis cannot compensate for absence of dietary oleic

acid in rats. J. Nutr. 127, 488–493.

Brayne, C., Calloway, P., 1988. Normal ageing, impared cognitive

function and senile dementia of Alzheimer type: A continuum? Lancet

1, 1265–1267.

Breteler, M.M., Claus, J.J., Grobbee, D.E., Hofman, A., 1994. Cardiovas-

cular disease and distribution of cognitive function in elderly people:

the Rotterdam Study. BMJ 308, 1604–1608.

Briante, R., Febbraio, F., Nucci, R., 2003. Antioxidant properties of low

molecular weight phenols present in the Mediterranean diet. J. Agric.

Food Chem. 51, 6975–6981.

Buxbaum, J.D., Oishi, M., Chen, H.I., Pinkas-Kramarski, R., Jaffe, E.A.,

Gandy, S.E., Greengard, P., 1992. Cholinergic agonists and interleukin

1 regulate processing and secretion of the Alzheimer beta/A4 amyloid

protein precursor. Proc. Natl Acad. Sci. USA 89, 10075–10078.

Calon, F., Lim, G.P., Yang, F., Morihara, T., Teter, B., Ubeda, O.,

Rostaing, P., Triller, A., Salem Jr.., N., Ashe, K.H., Frautschy, S.A.,

Cole, G.M., 2004. Docosahexaenoic acid protects from dendritic

pathology in an Alzheimer’s disease mouse model. Neuron 43,

633–645.

Caporaso, G.L., Gandy, S.E., Buxbaum, J.D., Ramabhadran, T.V.,

Greengard, P., 1992. Protein phosphorylation regulates secretion of

Alzheimer /A4 amyloid precursor protein. Proc. Natl Acad. Sci. USA

89, 3055–3059.

Capurso, A., Panza, F., Capurso, C., Colacicco, A.M., D’Introno, A.,

Torres, F., Solfrizzi, V., 2003. Olive oil consumption and health. Ann.

Nutr. Metab. 47, 243–244.

Capurso, A., Panza, F., Solfrizzi, V., Capurso, C., D’Introno, A.,

Capurso, S., Colacicco, A.M., 2004. Monounsaturated fatty acids and

neuroprotection. The results of a study of cognitive decline in old age. Is

there a case for this treatment in multiple sclerosis?, In: Hommes, O.R.,

Comi, G. (Eds.), Early Indicators, Early Treatments Neuroprotection in

Multiple Sclerosis Series Topics in Neuroscience. Springer, New York,

pp. 97–107.

Chandra, V., Pandav, R., Dodge, H.H., Johnston, J.M., Belle, S.H.,

DeKosky, S.T., Ganguli, M., 2001. Incidence of Alzheimer’s disease in

a rural community in India: the Indo-US study. Neurology 57, 985–989.

Cobb, M.H., Goldsmith, E.J., 1995. How MAP kinases are regulated.

J. Biol. Chem. 270, 14843–14846.

Conquer, J.A., Tierney, M.C., Zecevic, J., Bettger, W.J., Fisher, R.H., 2000.

Fatty acid analysis of blood plasma of patients with Alzheimer disease,

other types of dementia, and cognitive impairment. Lipids 35,

1305–1312.

Crawford, M.A., Bloom, M., Broadhurst, C.L., Schmidt, W.F.,

Cunnane, S.C., Galli, C., Gehbremeskel, K., Linseisen, F., Lloyd-

Smith, J., Parkington, J., 1999. Evidence for the unique function of

docosahexaenoic acid during the evolution of the modern hominid brain.

Lipids 34, S39–S47.

de la Torre, J.C., 2004. Is Alzheimer’s disease a neurodegenerative or a

vascular disorder? Data, dogma, and dialectics. Lancet Neurol. 3,

184–190.

de Lorgeril, M., Salen, P., Martin, J.L., Monjaud, I., Boucher, P.,

Mamelle, N., 1998. Mediterranean dietary pattern in a randomized

trial: prolonged survival and possible reduced cancer rate. Arch. Intern.

Med. 158, 1181–1187.

Delion, S., Chalon, S., Hearault, J., Guilloteau, D., Besnard, J-C.,

Durand, G., 1994. Chronic dietary-linolenic acid deficiency alters

V. Solfrizzi et al. / Experimental Gerontology 40 (2005) 257–270268

dopaminergic and serotoninergic neurotransmission in rats. J. Nutr.

124, 2466–2476.

Deschamps, V., Barberger-Gateau, P., Peuchant, E., Orgogozo, J.M.,

2001. Nutritional factors in cerebral aging and dementia: epidemio-

logical arguments for a role of oxidative stress. Neuroepidemiology

20, 7–15.

Desdouits-Magnen, J., Desdouits, F., Takeda, S., Syu, J., Saltiel, A.R.,

Buxbaum, J.D., Czernik, A.J., Nairn, A.C., Greengard, P., 1998.

Regulation of secretion of Alzheimer amyloid precursor protein by the

mitogen-activated protein kinase cascade. J. Neurochem. 70, 524–530.

D’Introno, A., Panza, F., Colacicco, A.M., Capurso, A., Solfrizzi, V., 2004.

Mild Cognitive Impairment and related entities: role of vascular risk

factors, In: Panza, F., Solfrizzi, V., Capurso, A. (Eds.), Diet and

Cognitive Decline. Nova Science Publishers, Inc, New York, USA,

pp. 1–33.

Engelhart, M.J., Geerlings, M.I., Ruitenberg, A., Van Swieten, J.C.,

Hofman, A., Witteman, J.C., Breteler, M.M., 2002. Diet and risk of

dementia: does fat matter? The Rotterdam study. Neurology 59, 1915–

1921.

Favrelere, S., Stadelmann-Ingrand, S., Huguet, F., De Javel, D., Piriou, A.,

Tallineau, C., Durand, G., 2000. Age-related changes in ethanolamine

glycerophospholipid fatty acid levels in rat frontal cortex and

hippocampus. Neurobiol. Aging 21, 653–660.

Fratiglioni, L., Paillard-Borg, S., Winblad, B., 2004. An active and socially

integrated lifestyle in late life might protect against dementia. Lancet

Neurol. 3, 343–353.

Friedland, R.P., 2003. Fish consumption and the risk of Alzheimer disease:

is it time to make dietary recommendations?. Arch. Neurol. 60,

923–924.

Fukuyama, R., Chandrasekaran, K., Rapoport, S.I., 1993. Nerve growth

factor induced neuronal differentiation is accompanied by differentiated

induction and localization of the amyloid precursor protein (APP) in

PC12 cells and variant PC12S cells. Mol. Brain Res. 17, 17–22.

Giem, P., Beeson, W.L., Fraser, G.E., 1993. The incidence of dementia and

intake of animal products: preliminary findings from the Adventist

health study. Neuroepidemiology 12, 28–36.

Gold, G., Bouras, C., Canuto, A., Bergallo, M.F., Herrmann, F.R.,

Hof, P.R., Mayor, P.A., Michel, J.P., Giannakopoulos, P., 2002.

Clinicopathological validation study of four sets of clinical criteria for

vascular dementia. Am. J. Psychiatry 159, 82–87.

Grant, W.B., 1997. Dietary links to Alzheimer’s disease. Alzheimers Dis.

Rev. 2, 42–55.

Grant, W.B., 1999. Dietary links to Alzheimer’s disease: 1999 Update.

J. Alzheimers Dis. 1, 197–201.

Grant, W.B., 2000. Fish consumption, cancer, and Alzheimer’s disease.

Am. J. Clin. Nutr. 71, 599–600.

Grant, W.B., 2003. Diet and risk of dementia: Does fat matter? The

Rotterdam study. Neurology 60, 2020–2021.

Grant, W.B., Campbell, A., Itzhaki, R.F., Savory, J., 2002. The significance

of environmental factors in the etiology of Alzheimer’s disease.

J. Alzheimers Dis. 4, 179–189.

Guo, Z., Viitanen, M., Winblad, B., 1997. Low blood pressure and five-year

mortality in a Stockholm cohort of the very old: possible confounding

by cognitive impairment and other factors. Am. J. Public Health 87,

623–628.

Hardy, J.A., Higgins, G.A., 1992. Alzheimer’s disease: The amyloid

cascade hypothesis. Science 256, 184–185.

Hende, B., Ducimitiere, P., Berr, C., 2003. Cognitive decline and fatty acid

composition of erythrocyte membranes-The EVA study. Am. J. Clin.

Nutr. 77, 803–808.

Hendrie, H.C., Osuntokun, B.O., Hall, K.S., Ogunniyi, A.O., Hui, S.L.,

Unverzagt, F.W., Gureje, O., Rodenberg, C.A., Baiyewu, O.,

Musick, B.S., 1995. Prevalence of Alzheimer’s disease and dementia

in two communities: Nigerian Africans and African Americans. Am.

J. Psychiatry 152, 1485–1492.

Horrocks, L.A., Yeo, Y.K., 1999. Health benefits of docosahexaenoic acid

[DHA]. Pharmacol. Res. 40, 211–225.

Hu, H., Sweeney, D., Greengard, P., Gandy, S., 1996. Metabolism of

Alzheimer -amyloid precursor protein: regulation by protein kinase A in

intact cells and in a cell-free system. Proc. Natl Acad. Sci. USA 93,

4081–4084.

Jaffe, A.B., Toran-Allerand, C.D., Greengard, P., Gandy, S.E., 1994.

Estrogen regulates metabolism of Alzheimer amyloid precursor protein.

J. Biol. Chem. 269, 13065–13068.

Jama, J.W., Launer, L.J., Witteman, J.C., den Breeijen, J.H.,

Breteler, M.M., Grobbee, D.E., Hofman, A., 1996. Dietary

antioxidants and cognitive function in a population-based

sample of older persons. The Rotterdam study. Am. J. Epidemiol.

144, 275–280.

Jarvik, G.P., Wijsman, E.M., Kukull, W.A., Schellenberg, G.D., Yu, C.,

Larson, E.B., 1995. Interactions of apolipoprotein E genotype, total

cholesterol level, age, and sex in prediction of Alzheimer’s disease: a

case-control study. Neurology 45, 1092–1096.

Jorm, A.F., 1991. Cross-national comparisons of the occurrence of

Alzheimer’s and vascular dementias. Eur. Arch. Psychiatry Clin.

Neurosci. 240, 218–222.

Joseph, J.A., Shukitt-Hale, B., Denisova, N.A., Bielinski, D., Martin, A.,

McEwen, J.J., Bickford, P.C., 1999. Reversals of age-related declines in

neuronal signal transduction, cognitive and motor behavioral deficits

with blueberry, spinach or strawberry dietary supplementation.

J. Neurosci. 19, 8114–8121.

Kagan, A., 1996. Stroke. In: Kagan, A. (Ed.), The Honolulu Heart Program

An epidemiological study of coronary heart disease and stroke.

Harwood Academic Publishers, Amsterdam, pp. 111–126.

Kalmijn, S., Feskens, E.J., Launer, L.J., Kromhout, D., 1997a. Poly-

unsaturated fatty acids, antioxidants, and cognitive functions in very old

men. Am. J. Epidemiol. 145, 33–41.

Kalmijn, S., Launer, L.J., Ott, A., Witteman, J.C., Hofman, A.,

Breteler, M.M., 1997b. Dietary fat intake and the risk of

incident dementia in the Rotterdam study. Ann. Neurol. 42,

776–782.

Kalmijn, S., van Boxtel, M.P., Ocke, M., Verschuren, W.M.,

Kromhout, D., Launer, L.J., 2004. Dietary intake of fatty acids

and fish in relation to cognitive performance at middle age.

Neurology 62, 275–280.

Keli, S.O., Feskens, E.J., Kromhout, D., 1994. Fish consumption and risk of

stroke. The Zutphen study. Stroke 25, 328–332.

Kuo, Y.M., Emmerling, M.R., Bisgaier, C.L., Essenburg, A.D.,

Lampert, H.C., Drumm, D., Roher, A.E., 1998. Elevated low-density

lipoprotein in Alzheimer’s disease correlates with brain Ab 1-42 levels.

Biochem. Biophys. Res. Commun. 252, 711–715.

Kuusisto, J., Koivisto, K., Mykkanen, L., Helkala, E.L., Vanhanen, M.,

Hanninen, T., Kervinen, K., Kesaniemi, Y.A., Riekkinen, P.J.,

Laakso, M., 1997. Association between features of the insulin

resistance syndrome and Alzheimer’s disease independently of

apolipoprotein E4 phenotype: cross sectional population based study.

BMJ 315, 1045–1049.

Launer, L.J., Masaki, K., Petrovitch, H., Foley, D., Havlik, R.J., 1995. The

association between midlife blood pressure levels and late-life

cognitive function. The Honolulu-Asia aging study. JAMA 274,

1846–1851.

Levy, R., 1994. Aging-associated cognitive decline. Working Party

of the international Psychogeriatric association in collaboration

with the World Health Organization. Int. Psychogeriatr. 6,

63–368.

Luchsinger, J.A., Tang, M.X., Shea, S., Mayeux, R., 2002.

Caloric intake and the risk of Alzheimer disease. Arch. Neurol.

59, 1256–1263.

Manzato, E., Roselli, della Rovere, G., Zambon, S., Romanato, G.,

Corti, M.C., Sartori, L., Baggio, G., Crepaldi, G., 2003. Cognitive

functions are not affected by dietary fatty acids in elderly in the Pro.V.

A. study population. Aging Clin. Exp. Res. 15, 83–86.

Marchioli, R., Barzi, F., Bomba, E., Chieffo, C., Di Gregorio, D., Di

Mascio, R., Franzosi, M.G., Geraci, E., Levantesi, G.,

V. Solfrizzi et al. / Experimental Gerontology 40 (2005) 257–270 269

Maggioni, A.P., Mantini, L., Marfisi, R.M., Mastrogiuseppe, G.,

Mininni, N., Nicolosi, G.L., Santini, M., Schweiger, C., Tavazzi, L.,

Tognoni, G., Tucci, C., Valagussa, F., 2002. , GISSI-Prevenzione

Investigators, Early protection against sudden death by n2K3

polyunsaturated fatty acids after myocardial infarction: time-course

analysis of the results of the Gruppo Italiano per lo Studio della

Sopravvivenza nell’Infarto Miocardico [GISSI]-Prevenzione. Circu-

lation 105, 1897–1903.

Mazer, S.P., Rabbani, L.E., 2004. Evidence for C-reactive protein’s role in

(CRP) vascular disease: atherothrombosis, immuno-regulation and

CRP. J. Thromb. Thrombolysis 17, 95–105.

McGeer, P.L., McGeer, E.G., 1995. The inflammatory response system of

brain: Implications for therapy of Alzheimer and neurodegenerative

diseases. Brain Res. Rev. 21, 195–218.

McKhann, G., Drachman, D., Folstein, M., Katzman, R., Price, D.,

Stadlan, E.M., 1984. Clinical diagnosis of Alzheimer’s disease: Report

of the NINCDS-ADRDA Work Group under the auspices of

Department of Health and Human Services Task Force on Alzheimer’s

Disease. Neurology 34, 939–944.

Mills, J., Laurent Charest, D., Lam, F., Beyreuther, K., Ida, N., Pelech, S.L.,

Reiner, P.B., 1997. Regulation of amyloid precursor protein catabolism

involves the mitogen-activated protein kinase signal transduction

pathway. J. Neurosci. 17, 9415–9422.

Morris, M.C., Evans, D.A., Bienias, J.L., Tangney, C.C., Bennett, D.A.,

Aggarwal, N., Schneider, J., Wilson, R.S., 2003a. Dietary fats

and the risk of incident Alzheimer disease. Arch. Neurol. 60,

194–200.

Morris, M.C., Evans, D.A., Bienias, J.L., Tangney, C.C., Bennett, D.A.,

Wilson, R.S., Aggarwal, N., Schneider, J., 2003b. Consumption of fish

and nK3 fatty acids and risk of incident Alzheimer disease. Arch.

Neurol. 60, 940–946.

Morris, M.C., Evans, D.A., Bienias, J.L., Tangney, C.C., Bennett, D.A.,

Wilson, R.S., 2004. Dietary fat intake and 6-year cognitive change in an

older biracial community population. Neurology 62, 1573–1579.

Nagata, C., Takatsuka, N., Shimizu, N., Shimizu, H., 2004. Sodium intake

and risk of death from stroke in Japanese men and women. Stroke 35,

1543–1547.

Naor, M., Steingruber, H.J., Westhoff, K., Schottenfeld-Naor, Y.,

Gries, A.F., 1997. Cognitive function in elderly non-insulin-dependent

diabetic patients before and after inpatient treatment for metabolic

control. J. Diabetes Complications 11, 40–46.

Nitsch, R.M., Slack, B.E., Wurtman, R.J., Growdon, J.H., 1992. Release of

Alzheimer amyloid precursor derivatives stimulated by activation of

muscarinic acetylcholine receptors. Science 258, 304–307.

Notkola, I.L., Sulkava, R., Pekkanen, J., Erkinjuntti, T., Ehnholm, C.,

Kivinen, P., Tuomilehto, J., Nissinen, A., 1998. Serum total cholesterol,

apolipoprotein E (4 allele, and Alzheimer’s disease. Neuroepidemiol-

ogy 17, 14–20.

Ortega, R.M., Requejo, A.M., Andres, P., Lopez-Sobaler, A.M.,

Quintas, M.E., Redondo, M.R., Navia, B., Rivas, T., 1997. Dietary

intake and cognitive function in a group of elderly people. Am. J. Clin.

Nutr. 66, 803–809.

Otsuka, M., Yamaguchi, K., Ueki, A., 2002. Similarities and differences

between Alzheimer’s disease and vascular dementia from the viewpoint

of nutrition. Ann. NY Acad. Sci. 977, 155–161.

Panza, F., D’Introno, A., Colacicco, A.M., Basile, A.M., Capurso, C.,

Kehoe, P.G., Capurso, A., Solfrizzi, V., 2004a. Vascular risk and

genetics of sporadic late-onset Alzheimer’s disease. J. Neural. Transm.

111, 69–89.

Panza, F., Solfrizzi, V., Colacicco, A.M., D’Introno, A., Capurso, C.,

Torres, F., Del Parigi, A., Capurso, S., Capurso, A., 2004b.

Mediterranean diet and cognitive decline. Public Health Nutr. 7,

959–963.

Petersen, R.C., Smith, G.E., Waring, S.C., Ivnik, R.J., Tangalos, E.G.,

Kokmen, E., 1999. Mild cognitive impairment: clinical characterization

and outcome. Arch. Neurol. 56, 303–308.

Petersen, R.C., Doody, R., Kurz, A., Mohs, R.C., Morris, J.C., Rabins, P.V.,

Ritchie, K., Rossor, M., Thal, L., Winblad, B., 2001. Current concepts

in mild cognitive decline. Arch. Neurol. 58, 1985–1992.

Pradignac, A., Schlienger, J.L., Velten, M., Mejean, L., 1995.

Relationships between macronutrient intake, handicaps, and cogni-

tive impairments in free living elderly people. Aging Clin. Exp. Res.

7, 67–74.

Reaven, P.D., Grasse, B.J., Tribble, D.L., 1994. Effects of linoleate-

enriched and oleate-enriched diets in combination with alpha-toco-

pherol on the susceptibility of LDL and LDL subfractions

to oxidative modification in humans. Arterioscler. Thromb. 14,

557–566.

Roman, G.C., 2002. Defining dementia: clinical criteria for the diagnosis of

vascular dementia. Acta Neurol. Scand. Suppl. 178, 6–9.

Roman, G.C., Royall, D.R., 1999. Executive control function: a rational

basis for the diagnosis of vascular dementia. Alzheimer Dis. Assoc.

Disord. 13 (Suppl. 3), S69–S80.

Roman, G.C., Tatemichi, T.K., Erkinjuntti, T., Cummings, J.L.,

Masdeu, J.C., Garcia, J.H., Amaducci, L., Brun, A., Hofman, A.,

Moody, D.M., O’Brien, M.D., Yamaguchi, T., Grafman, J.,

Drayer, B.P., Bennett, D.A., Fisher, M., Ogata, J., Kokmen, E.,

Bermejo, F., Wolf, P.A., Gorelick, P.B., Bick, K.L., Pajeau, A.K.,

Bell, M.A., DeCarli, C., Culebras, A., Korczyn, A.D.,

Bogousslavsky, J., Hartmann, A., Scheinberg, P., 1993. Vascular

dementia: diagnostic criteria for research studies. Report of the NINDS-

AIREN International Workshop. Neurology 43, 250–260.

Ross, G.W., Petrovitch, H., White, L.R., Masaki, K.H., Li, C.Y., Curb, J.D.,

Yano, K., Rodriguez, B.L., Foley, D.J., Blanchette, P.L., Havlik, R.,

1999. Characterization of risk factors for vascular dementia: the

Honolulu-Asia aging study. Neurology 53, 337–343.

Smith, M.A., Petot, G.J., Perry, G., 1999. Diet and oxidative stress: a novel

synthesis of epidemiological data on Alzheimer’s disease.

J. Alzheimers Dis. 1, 203–206.

Solano, D.C., Sironi, M., Bonfini, C., Solerte, S.B., Govoni, S., Racchi, M.,

2000. Insulin regulates soluble amyloid precursor protein release via

phosphatidyl inositol 3 kinase-dependent pathway. FASEB 14,

1015–1022.

Solfrizzi, V., Panza, F., Torres, F., Mastroianni, F., Del Parigi, A.,

Venezia, A., Capurso, A., 1999. High monounsaturated fatty acids

intake protects against age-related cognitive decline. Neurology 52,

1563–1569.

Solfrizzi, V., Panza, F., D’Introno, A., Colacicco, A.M., Capurso, C.,

Basile, A.M., Capurso, A., 2002. Lipoprotein(a), apolipoprotein E

genotype, and risk of Alzheimer’s disease. J. Neurol. Neurosurg.

Psychiatry 72, 732–736.

Solfrizzi, V., Panza, F., Capurso, A., 2003. The role of diet in cognitive

decline. J. Neural. Transm. 110, 95–110.

Solfrizzi, V., Panza, F., Colacicco, A.M., Torres, F., Del Parigi, A.,

Capurso, A., 2004a. Dietary fatty acids, cognitive decline, and

dementia. In: Panza, F., Solfrizzi, V., Capurso, A. (Eds.), Diet and

Cognitive Decline. Nova Science Publishers, Inc, New York, USA,

pp. 91–106.

Solfrizzi, V., Panza, F., Colacicco, A.M., D’Introno, A., Capurso, C.,

Torres, F., Grigoletto, F., Maggi, S., Del Parigi, A., Reiman, E.R.,

Caselli, R.J., Scafato, E., Farchi, G., Capurso, A., Italian Longitudinal

Study on Aging Working Group, 2004b. Vascular risk factors,

incidence of MCI, and rates of progression to dementia. Neurology

63, 1882–1891.

Tilvis, R.S., Kahonen-Vare, M.H., Jolkkonen, J., Valvanne, J.,

Pitkala, K.H., Strandberg, T.E., 2004. Predictors of cognitive decline

and mortality of aged people over a 10-year period. J. Gerontol. A Biol.

Sci. Med. Sci. 59, 268–274.

Urakami, K., Wada-Isoe, K., Wakutani, Y., Ikeda, K., Ji, Y., Yamagata, K.,

Kowa, H., Okada, A., Adachi, Y., Nakashima, K., 2000. Lipoprotein[a]

phenotypes in patients with vascular dementia. Dement. Geriatr. Cogn.

Disord. 11, 135–138.

V. Solfrizzi et al. / Experimental Gerontology 40 (2005) 257–270270

White, L., Petrovitch, H., Ross, G.W., Masaki, K.H., Abbott, R.D.,

Teng, E.L., Rodriguez, B.L., Blanchette, P.L., Havlik, R.J.,

Wergowske, G., Chiu, D., Foley, D.J., Murdaugh, C., Curb, J.D.,

1996. Prevalence of dementia in older Japanese-American men in

Hawaii. JAMA 276, 955–960.

Whitehouse, P.J., Sciulli, C.G., Mason, R.M., 1997. Dementia drug

development: use of information systems to harmonize global drug

development. Psychopharmacol Bull 33, 129–133.

Williams, P., Forsyth, J.S., DiMondugno, M.K., Varma, S., Colvin, M.,

1998. Effects of long-chain polyunsaturated fatty acids in

infant formula on problem solving at 10 months of age. Lancet 352,

688–691.

Wolf, H., Grunwald, M., Ecke, G.M., Zedlick, D., Bettin, S.,

Dannenberg, C., Dietrich, J., Eschrich, K., Arendt, T., Gertz, H.J.,

1998. The prognosis of mild cognitive impairment in the elderly. J

Neural Suppl 54, 31–50.