Whalley LJ, Fox HC, Wahle KW, et al. Cognitive aging, childhood intelligence, and the use of food supplements: Possible involvement of n-3 fatty acids. Am J Clin Nutr 2004;80:1650-1657.

BACKGROUND:
Food supplement use is widely promoted, but little is known about the cognitive effects of food supplements.

OBJECTIVE:
We examined the effects of food supplement use on cognitive aging.

DESIGN:
This was an observational study of subjects born in 1936 whose mental ability was tested in 1947 and who were followed up in 2000-2001, at which time cognition, diet, food supplement use, and risk factors for vascular disease were assessed.
In a nested case-control study, fish-oil users were matched with nonusers, and cognitive function was related to erythrocyte n-3 fatty acid composition.

RESULTS:
Childhood intelligence quotient (IQ) did not differ significantly by category of food supplement use (ie, none, fish oil, vitamins, and other).

At the age of 64 y, cognitive function was higher in food supplement users than in nonusers before adjustment for childhood IQ. After adjustment for childhood IQ, digit symbol (mental speed) test scores were higher in food supplement users.

Fish-oil supplement users consumed more vitamin C and vegetable and cereal fiber than did non-supplement-users. In a nested case-control study, erythrocyte membrane n-3 content was higher in fish-oil supplement users than in nonusers, but cognitive function did not differ significantly between groups.

Total erythrocyte n-3 fatty acids and the ratio of docosahexaenoic acid to arachidonic acid was associated with better cognitive function in late life before and after adjustment for childhood IQ.

CONCLUSIONS:
Food supplement use and erythrocyte n-3 content are associated with better cognitive aging.If associations with n-3 content are causal, optimization of n-3 and n-6 fatty acid intakes could improve retention of cognitive function in old age.

PMID: 15585782

Heude B, Ducimetiere P, Berr C. Cognitive decline and fatty acid composition of erythrocyte membranes: The EVA Study. Am J Clin Nutr 2003;77:803-808.

BACKGROUND: Dietary factors might modify cognitive decline that results from aging. Fatty acids, which are limiting factors in brain development, are prime candidates.

OBJECTIVE: We studied the relation between erythrocyte membrane fatty acid composition and cognitive decline in free-living volunteers.

DESIGN: In 1995, erythrocyte membrane fatty acid composition was measured in 246 men and women (aged 63-74 y) from the Etude du Vieillissement Arteriel (EVA) cohort.
During a 4-y follow-up, cognitive abilities were assessed longitudinally with the Mini-Mental State Examination. Moderate cognitive decline was defined as a > or = 2-point decrease over the 4 y. The predictive value of fatty acid proportions on cognitive decline was assessed with a multivariate logistic model that included age, sex, education level, and initial Mini-Mental State Examination score as covariates.

RESULTS: Higher proportions of both stearic acid (saturated, 18:0) and total n-6 polyunsaturated fatty acids were associated with greater risk of cognitive decline; the odds ratios were 1.91 (95% CI: 1.16, 3.15) and 1.59 (95% CI: 1.04, 2.44), respectively, for 1-SD differences in fatty acid proportions.

Conversely, a higher proportion of total n-3 fatty acids was associated with a lower risk of cognitive decline; the odds ratio was 0.59 (95% CI: 0.38, 0.93).

CONCLUSIONS: The inverse association between cognitive decline and the ratio of n-3 to n-6 fatty acids in erythrocyte membranes agrees with results obtained in some studies that assessed fatty acid intake by using dietary questionnaires. These results require confirmation but provide new rationale for studying how these modifiable risk factors might be implicated in the cognitive aging process.

PMID: 12663275

Kalmijn S, Launer LJ, Ott A, et al. Dietary fat intake and the risk of incident dementia in the Rotterdam Study. Ann Neurol 1997;42(5):776-782.

A high intake of saturated fat and cholesterol and a low intake of polyunsaturated fatty acids have been related to an increased risk of cardiovascular disease.

Cardiovascular disease has been associated with dementia. We investigated the association between fat intake and incident dementia among participants, age 55 years or older, from the population-based prospective Rotterdam Study.

Food intake of 5,386 nondemented participants was assessed at baseline with a semiquantitative food-frequency questionnaire.
At baseline and after an average of 2.1 years of follow-up, we screened for dementia with a three-step protocol that included a clinical examination.
The risk of dementia at follow-up (RR [95% CI]) was assessed with logistic regression.

After adjustment for age, sex, education, and energy intake, high intakes of the following nutrients were associated with an increased risk of dementia: total fat (RR = 2.4 [1.1-5.2]), saturated fat (RR = 1.9 [0.9-4.0]), and cholesterol (RR = 1.7 [0.9-3.2]).

Dementia with a vascular component was most strongly related to total fat and saturated fat.

Fish consumption, an important source of n-3 polyunsaturated fatty acids, was inversely related to incident dementia (RR = 0.4 [0.2-0.91), and in particular to Alzheimer's disease (RR = 0.3 [0.1-0.9]).

This study suggests that a high saturated fat and cholesterol intake increases the risk of dementia, whereas fish consumption may decrease this risk.

PMID: 9392577

Morris, MC,Evans, DA, et al. Consumption of fish and n-3 fatty acids and risk of incident alzheimer disease. Arch Neurol 2003; 60:940-946

Background: Dietary n-3 polyunsaturated fatty acids improve brain functioning in animal studies, but there is limited study of whether this type of fat protects against Alzheimer disease.

Objective: To examine whether fish consumption and intake of different types of n-3 fatty acids protect against Alzheimer disease.

Design: Prospective study conducted from 1993 through 2000, of a stratified random sample from a geographically defined community. Participants were followed up for an average of 3.9 years for the development of Alzheimer disease.

Patients: A total of 815 residents, aged 65 to 94 years, who were initially unaffected by Alzheimer disease and completed a dietary questionnaire on average 2.3 years before clinical evaluation of incident disease.

Main Outcome Measure: Incident Alzheimer disease diagnosed in a structured neurologic examination by means of standardized criteria.

Results: A total of 131 sample participants developed Alzheimer disease. Participants who consumed fish once per week or more had 60% less risk of Alzheimer disease compared with those who rarely or never ate fish (relative risk, 0.4; 95% confidence interval, 0.2-0.9) in a model adjusted for age and other risk factors. Total intake of n-3 polyunsaturated fatty acids was associated with reduced risk of Alzheimer disease, as was intake of docosahexaenoic acid (22:6n-3). Eicosapentaenoic acid (20:5n-3) was not associated with Alzheimer disease. The associations remained unchanged with additional adjustment for intakes of other dietary fats and of vitamin E and for cardiovascular conditions.

Conclusion: Dietary intake of n-3 fatty acids and weekly consumption of fish may reduce the risk of incident Alzheimer disease.

PMID: 12873849

Freund-Levi Y, Eriksdotter-Jönhagen M, Cederholm T, et al. Omega-3 Fatty Acid Treatment in 174 Patients With Mild to Moderate Alzheimer Disease: OmegAD Study. Arch Neurol,2006;63(10):1402-1408.

Background: Epidemiologic and animal studies have suggested that dietary fish or fish oil rich in omega-3 fatty acids, for example, docosahexaenoic acid and eicosapentaenoic acid, may prevent Alzheimer disease (AD).

Objective: To determine effects of dietary omega-3 fatty acid supplementation on cognitive functions in patients with mild to moderate AD.

Design: Randomized, double-blind, placebo-controlled clinical trial.

Participants: Two hundred four patients with AD (age range [mean ± SD], 74 ± 9 years) whose conditions were stable while receiving acetylcholine esterase inhibitor treatment and who had a Mini-Mental State Examination (MMSE) score of 15 points or more were randomized to daily intake of 1.7 g of docosahexaenoic acid and 0.6 g of eicosapentaenoic acid (omega-3 fatty acid-treated group) or placebo for 6 months, after which all received omega-3 fatty acid supplementation for 6 months more.

Main Outcome Measures: The primary outcome was cognition measured with the MMSE and the cognitive portion of the Alzheimer Disease Assessment Scale. The secondary outcome was global function as assessed with the Clinical Dementia Rating Scale; safety and tolerability of omega-3 fatty acid supplementation; and blood pressure determinations.

Results: One hundred seventy-four patients fulfilled the trial. At baseline, mean values for the Clinical Dementia Rating Scale, MMSE, and cognitive portion of the Alzheimer Disease Assessment Scale in the 2 randomized groups were similar. At 6 months, the decline in cognitive functions as assessed by the latter 2 scales did not differ between the groups. However, in a subgroup (n = 32) with very mild cognitive dysfunction (MMSE >27 points), a significant (P<.05) reduction in MMSE decline rate was observed in the omega-3 fatty acid-treated group compared with the placebo group. A similar arrest in decline rate was observed between 6 and 12 months in this placebo subgroup when receiving omega-3 fatty acid supplementation. The omega-3 fatty acid treatment was safe and well tolerated.

Conclusions: Administration of omega-3 fatty acid in patients with mild to moderate AD did not delay the rate of cognitive decline according to the MMSE or the cognitive portion of the Alzheimer Disease Assessment Scale. However, positive effects were observed in a small group of patients with very mild AD (MMSE >27 points).

Barberger-Gateau P, Luc Letenneur L, et al. Fish, meat, and risk of dementia: cohort study. BMJ 2002; 325: 932-933.

Elderly people who eat fish or seafood at least once a week are at lower risk of developing dementia, including Alzheimer's disease, finds a study in this week?s British Medical Journal. The study confirms the positive role played by nutrition, in particular fish fatty acids, on mental health.

Using data from a large aging study, a team of French researchers set out to test whether there was a relation between consumption of fish (rich in polyunsaturated fatty acids) or meat (rich in saturated fatty acids) and risk of dementia.

The study involved 1,674 people aged 68 and over without dementia and living at home in southwestern France. Their frequency of consumption of meat and fish or seafood was recorded as daily, at least once a week (but not every day), from time to time (but not every week), or never. Participants were followed up two, five, and seven years afterwards.

Participants who ate fish or seafood at least once a week had a significantly lower risk of being diagnosed as having dementia in the seven subsequent years. When education was taken into account, the strength of the association was slightly reduced, suggesting that this "protective" effect was partly explained by higher education of regular consumers, said the authors.

They found no significant association between meat consumption and risk of dementia.

As well as providing vascular protection, the fatty acids contained in fish oils could reduce inflammation in the brain and may have a specific role in brain development and regeneration of nerve cells, suggested the authors.

They noted that healthy dietary habits acquired in infancy could be associated with achievement of higher education. But also, highly educated people might also adhere more closely to dietary recommendations on fish consumption.

Lim G, Calon F, et al. A Diet Enriched with the Omega-3 Fatty Acid Docosahexaenoic Acid Reduces Amyloid Burden in an Aged Alzheimer Mouse Model. The Journal of Neuroscience 2005;25(12):3032-3040.

Epidemiological studies suggest that increased intake of the omega-3 (n-3) polyunsaturated fatty acid (PUFA) docosahexaenoic acid (DHA) is associated with reduced risk of Alzheimer's disease (AD). DHA levels are lower in serum and brains of AD patients, which could result from low dietary intake and/or PUFA oxidation. Because effects of DHA on Alzheimer pathogenesis, particularly on amyloidosis, are unknown, we used the APPsw (Tg2576) transgenic mouse model to evaluate the impact of dietary DHA on amyloid precursor protein (APP) processing and amyloid burden. Aged animals (17-19 months old) were placed in one of three groups until 22.5 months of age: control (0.09% DHA), low-DHA (0%), or high-DHA (0.6%) chow. -Amyloid (A) ELISA of the detergent-insoluble extract of cortical homogenates showed that DHA-enriched diets significantly reduced total A by >70% when compared with low-DHA or control chow diets. Dietary DHA also decreased A42 levels below those seen with control chow. Image analysis of brain sections with an antibody against A (amino acids 1-13) revealed that overall plaque burden was significantly reduced by 40.3%, with the largest reductions (40-50%) in the hippocampus and parietal cortex. DHA modulated APP processing by decreasing both - and -APP C-terminal fragment products and full-length APP. BACE1 (-secretase activity of the -site APP-cleaving enzyme), ApoE (apolipoprotein E), and transthyretin gene expression were unchanged with the high-DHA diet. Together, these results suggest that dietary DHA could be protective against -amyloid production, accumulation, and potential downstream toxicity.

Yehuda S, Rabinovitz S, Mostofsky DI. Essential fatty acids are mediators of brain biochemistry and cognitive functions. J Neurosci Res 1999;56:565-570.

Major advances have been made in understanding the biochemistry of essential fatty acids (FA) and their interactions with metabolic pathways leading to the production of longer and more complex fatty acids and lipids.

Less understood are the roles played by FA which are known to affect neurotransmitters, peptides, releasing factors, hormones, and a variety of physiological and cognitive processes.

Based on empirical findings we propose that (a) FA exert a controlling function in the modulation of neuronal membrane fluidity, and (b) the critical factor in FA action and efficacy is not absolute level but rather the ratio between various groups of FA.

This approach unifies the biochemical and cognitive results obtained from many different and unrelated fields of research.

Conquer JA, Tierney MC, Zecevic J, et al. Fatty acid analysis of blood plasma of patients with Alzheimer?s disease, other types of dementia, and cognitive impairment. Lipids 2000;35(12):1305-1312.

Fatty acid differences, including docosahexaenoic acid (DHA; 22:6n-3) have been shown in the brains of Alzheimer's patients (AD) as compared with normal age-matched individuals.

Furthermore, low serum DHA is a significant risk factor for the development of AD.

The relative concentration of DHA and other fatty acids, however, in the plasma of AD patients compared with patients with other kinds of dementias (other dementias; OD), patients who are cognitively impaired but nondemented (CIND), or normal patients is not known.

In this study we analyzed the total phospholipid, phosphatidylcholine (PC), phosphatidylethanolamine (PE), and lysophosphatidylcholine (lysoPC) fractions of plasma from patients diagnosed with AD, OD, or CIND and compared them with a group of elderly control subjects with normal cognitive functioning.

Plasma phospholipid and PC levels of 20:5n-3, DHA, total n-3 fatty acids, and the n-3/n-6 ratio were lower in the AD, OD, and CIND groups.
Plasma phospholipid 24:0 was lower in the AD, OD, and CIND groups as compared with the group of control patients, and total n-6 fatty acid levels were higher in the AD and CIND groups only.

In the plasma PE fraction, levels of 20:5n-3, DHA, and the total n-3 fatty acid levels were significantly lower in the AD, OD, and CIND groups.
DHA levels were lower in the lysoPC fraction of CIND individuals only. There were no other differences in the fatty acid compositions of the different phospholipid fractions.
Therefore, in AD, OD, and CIND individuals, low levels of n-3 fatty acids in the plasma may be a risk factor for cognitive impairment and/or dementia.

Interestingly, a decreased level of plasma DHA was not limited to the AD patients but appears to be common in cognitive impairment with aging.

McCarty MF. Vascular nitric oxide, sex hormone replacement, and fish oil may help to prevent Alzheimer's disease by suppressing synthesis of acute-phase cytokines. Med Hypotheses 1999;53(5):369-374.

The neurodegenerative plaques of Alzheimer's disease (AD) are characterized by a self-sustaining acute-phase reaction in which both interleukin-1 (IL-1) and interleukin-6 (IL-6) are up-regulated.

The fact that IL-6 is detectable in early stage diffuse plaques encourages the speculation that the acute-phase process is crucial to the pathogenesis of AD.

The epidemiological association of AD with estrogen deficiency, as well as with various disorders characterized by vascular endotheliopathy, suggest a protective role for vascular nitric oxide (NO).

NO has an autocrine anti-inflammatory impact on endothelium, owing in part to antagonism of NF-kappaB activity; since induction of IL-6 is dependent on NF-kappaB, this may explain recent evidence that NO inhibits macrophage IL-6 production.

It is reasonable to postulate that, analogously, cerebrovascular NO decreases IL-6 production in the brain.
Vascular NO may also have direct neuroprotective activity. Estrogen, in addition to promoting vascular NO synthesis, can block IL-6 production by a more direct mechanism in cells expressing estrogen receptors; since such receptors have been reported in brain glia and astrocytes, estrogen has the potential to limit brain IL-1 activity.
Testosterone likewise can inhibit IL-6 induction in androgen-responsive cells, which may include brain glia and astrocytes.

Since fish oil and gamma linolenic acid (GLA) suppress IL-1 production by stimulated monocytes, they conceivably could exert this effect in the brain as well; the comparatively low prevalence of AD in elderly Japanese is intriguing in this regard.

These considerations suggest that a healthy cerebrovascular endothelium, sex hormone activity, and dietary fish oil/GLA may slow or prevent AD onset by dampening acute-phase mechanisms in the brain.

PMID: 10616034

Newman, PE. Could diet be one of the causal factors of Alzheimer's disease? Med Hypotheses 1992; 39(2):123-126.

Recent developments show that the brains of persons who have died from Alzheimer's Disease (AD) have a deficiency of Essential Fatty acids in one of the principal classes of phospholipids. It is hypothesized that faulty brain cell membranes resulting from this deficiency may allow passage of an enzyme into the bilayer membrane space which cuts beta amyloid precursor proteins attached to such cells at a critical intramembrane position releasing a complete sequence of beta amyloid protein into the extracellular space. Beta amyloid protein appears to be the principal active constituent of senile plaques thought to be a probable cause of brain damage resulting in AD.
Treatment of persons suffering from AD with desferrioxamine, a trivalent ion chelator to remove aluminum has shown results in slowing the progression of this disease, implicating aluminum and/or other chelated substances in its etiology. Both EFA deficiency and aluminum buildup may be prevented by dietary precautions.

Kalmijn S, van Boxtel MPJ, Ocke M, et al. Dietary intake of fatty acids and fish in relation to cognitive performance at middle age. Neurol 2004;62:275-280.

OBJECTIVE:
To examine the associations of fatty acid and fish intake with cognitive function.

METHODS:
Data are from a cross-sectional population-based study among 1,613 subjects ranging from 45 to 70 years old.
From 1995 until 2000, an extensive cognitive battery was administered and compound scores were constructed for memory, psychomotor speed, cognitive flexibility (i.e., higher order information processing), and overall cognition.
A self-administered food-frequency questionnaire was used to assess habitual food consumption.The risk of impaired cognitive function (lowest 10% of the compound score) according to the energy adjusted intake of fatty acids was assessed with logistic regression, adjusting for age, sex, education, smoking, alcohol consumption, and energy intake.

RESULTS:
Marine omega-3 polyunsaturated fatty acids (PUFA) (eicosapentaenoic acid and docosahexaenoic acid) were inversely related to the risk of impaired overall cognitive function and speed (per SD increase: OR = 0.81, 95% CI 0.66 to 1.00 and OR = 0.72, 95% CI 0.57 to 0.90).
Results for fatty fish consumption were similarly inverse.

Higher dietary cholesterol intake was significantly associated with an increased risk of impaired memory and flexibility (per SD increase: OR = 1.27, 95% CI 1.02 to 1.57 and OR = 1.26, 95% CI 1.01 to 1.57).
Per SD increase in saturated fat intake, the risk of impaired memory, speed, and flexibility was also increased, although not significantly.

CONCLUSIONS:
Fatty fish and marine omega-3 PUFA consumption was associated with a reduced risk and intake of cholesterol and saturated fat with an increased risk of impaired cognitive function in this middle-aged population.

PMID: 14745067

de Lau LML, Bornebroek M, et al. Dietary fatty acids and the risk of Parkinson disease Neurology 2005;64:2040-2045

Background: Unsaturated fatty acids are important constituents of neuronal cell membranes and have neuroprotective, antioxidant, and anti-inflammatory properties.

Objective: To determine if a high intake of unsaturated fatty acids might be associated with a lower risk of Parkinson disease (PD).

Methods: In the Rotterdam Study, a prospective population-based cohort study of people ages 55, the association between intake of unsaturated fatty acids and the risk of incident PD was evaluated among 5,289 subjects who were free of dementia and parkinsonism and underwent complete dietary assessment at baseline.
PD was assessed through repeated in-person examination, and the cohort was continuously monitored by computer linkage to medical records. The data were analyzed using Cox proportional hazards regression models.

Results: After a mean follow-up of 6.0 years, 51 participants with incident PD were identified.
Intakes of total fat, monounsaturated fatty acids (MUFAs), and polyunsaturated fatty acids (PUFAs) were significantly associated with a lower risk of PD, with an adjusted hazard ratio per SD increase of energy-adjusted intake of 0.69 (95% CI 0.52 to 0.91) for total fat, of 0.68 (95% CI 0.50 to 0.94) for MUFAs, and 0.66 (95% CI 0.46 to 0.96) for PUFAs.
No associations were found for dietary saturated fat, cholesterol, or trans-fat.

Conclusion: These findings suggest that high intake of unsaturated fatty acids might protect against Parkinson disease.

Das UN. Beneficial effect(s) of n-3 fatty acids in cardiovascular diseases: but, why and how? Prostaglandins Leukot, Essent Fatty Acids 2000;63(6):351-362.

Low rates of coronary heart disease was found in Greenland Eskimos and Japanese who are exposed to a diet rich in fish oil.

Suggested mechanisms for this cardio-protective effect focused on the effects of n-3 fatty acids on eicosanoid metabolism, inflammation, beta oxidation, endothelial dysfunction, cytokine growth factors, and gene expression of adhesion molecules; But, none of these mechanisms could adequately explain the beneficial actions of n-3 fatty acids.

One attractive suggestion is a direct cardiac effect of n-3 fatty acids on arrhythmogenesis.

N-3 fatty acids can modify Na+ channels by directly binding to the channel proteins and thus, prevent ischemia-induced ventricular fibrillation and sudden cardiac death.

Though this is an attractive explanation, there could be other actions as well. N-3 fatty acids can inhibit the synthesis and release of pro-inflammatory cytokines such as tumor necrosis factoralpha (TNFalpha) and interleukin-1 (IL-1) and IL-2 that are released during the early course of ischemic heart disease.
These cytokines decrease myocardial contractility and induce myocardial damage, enhance the production of free radicals, which can also suppress myocardial function.

Further, n-3 fatty acids can increase parasympathetic tone leading to an increase in heart rate variability and thus, protect the myocardium against ventricular arrhythmias.
Increased parasympathetic tone and acetylcholine, the principle vagal neurotransmitter, significantly attenuate the release of TNF, IL-1beta, IL-6 and IL-18.

Exercise enhances parasympathetic tone, and the production of anti-inflammatory cytokine IL-10 which may explain the beneficial action of exercise in the prevention of cardiovascular diseases and diabetes mellitus.

TNFalpha has neurotoxic actions, where as n-3 fatty acids are potent neuroprotectors and brain is rich in these fatty acids.

Based on this, it is suggested that the principle mechanism of cardioprotective and neuroprotective action(s) of n-3 fatty acids can be due to the suppression of TNFalpha and IL synthesis and release, modulation of hypothalamic-pituitary-adrenal anti-inflammatory responses, and an increase in acetylcholine release, the vagal neurotransmitter.

Thus, there appears to be a close interaction between the central nervous system, endocrine organs, cytokines, exercise, and dietary n-3 fatty acids.

This may explain why these fatty acids could be of benefit in the management of conditions such as septicemia and septic shock, Alzheimer's disease, Parkinson's disease, inflammatory bowel diseases, diabetes mellitus, essential hypertension and atherosclerosis.

PMID: 11133172

Puskas LG, Kitajka K, Nyakas C, et al. Short-term administration of omega-3 fatty acids from fish oil results in increased transthyretin transcription in old rat hippocampus. PNAS 2003;100(4):1580-1584.

Reduced brain levels of long chain polyunsaturated fatty acids [arachidonic acid and docosahexanoic acid (DHA)] are observed in elderly subjects and patients with Alzheimer's disease.

To determine the effects of n-3 fatty acids on aged rat brain, 2-year-old rats were fed fish oil (27% DHA content) for 1 month, and gene expression analysis and fatty acid and molecular species composition of the major phospholipid species were assessed.

No significant alteration could be observed in the fatty acid composition of ethanolamine phosphoglycerides and phosphatidylserines with the exception of DHA, which was slightly higher in brains of rats receiving fish oil. However, a drastic reduction in arachidonic acid in phosphatidylinositoles was observed.

The expression of 23 genes was altered in response to fish oil feeding in the hippocampus. The transcription of transthyretin (TTR) was induced by 10-fold as evidenced by microarray analysis and confirmed by real-time quantitative RT-PCR.

Expression of IL-1 and NO synthase, which has been implicated in the prevention of neurological diseases, was unaltered.

TTR is an amyloid beta protein scavenger, so an increase in its expression could prevent amyloid aggregate formation.

We believe the beneficial effects of fish oil might be common to other agents, i.e., induce TTR expression, like nicotine and Ginkgo biloba extract.

PMID: 12566565