J Clin Med Res

Journal of Clinical Medicine Research, ISSN 1918-3003 print, 1918-3011 online, Open Access

Article copyright, the authors; Journal compilation copyright, J Clin Med Res and Elmer Press Inc

Journal website http://www.jocmr.org

Review

Volume 9, Number 1, January 2017, pages 1-9

Effects of n-3 Polyunsaturated Fatty Acids on Dementia

**Table 1.** The Observational Studies Which Assessed the Association Between n-3 PUFA and Dementia
Authors	Study design	Subjects	Results/conclusions
AA: arachidonic acid; AD: Alzheimer’s disease; ALA: α-linolenic acid; CI: confidence interval; CIND: cognitive impairment no dementia; DHA: docosahexaenoic acid; EPA: eicosapentaenoic acid; FA: fatty acids; HR: hazard ratio; HV: healthy volunteers; OD: other dementias; OR: odds ratio; PC: phosphatidylcholine; PE: phosphatidylethanolamine; PUFA: polyunsaturated fatty acids; RBC: red blood cell; RR: relative risk.
Yamagishi et al [2]	Community-based nested case-control study	315 cases of incident disabling dementia	Serum ALA was inversely associated with risk of disabling dementia: the multivariate odds ratios (95% CI) were 0.57 (0.39 - 0.85), 0.51 (0.34 - 0.76), and 0.61 (0.41 - 0.90) for persons with the second, third, and highest quartiles of ALA, respectively, as compared with the lowest quartile (P for trend = 0.01).
Kim et al [3]	Cross-sectional study	57 elderly (age ≥ 65 years) patients	Multivariate-adjusted regression analysis showed that a higher level of ALA significantly decreased the risk of mild dementia after adjusting for age, sex, and height.
Cherubini et al [4]	Cross-sectional study	935 community-dwelling older persons	After adjustment for age, gender, education, body mass index, weight loss, smoking status, cholesterol and triglycerides levels, daily intake of alcohol, FA and total energy, cardiovascular disease, depression and other FA levels, participants with dementia had significantly lower n-3 PUFA levels (2.9% vs. 3.2%; P < 0.05), particularly ALA levels (0.34% vs. 0.39%; P < 0.05), than did participants with normal cognitive function.
Roberts et al [5]	Cross-sectional study	1,233 non-demented subjects aged ≥ 70 years	Compared to the lowest tertile, the OR (95% CI) for the upper tertiles were 0.62 (0.42 - 0.91; P for trend = 0.012) for n-3 PUFA after adjustment for age, sex, number of years of education, and caloric intake.
Schaefer et al [6]	Prospective follow-up study	899 men and women who were free of dementia at baseline, had a median age of 76.0 years, and were followed up for a mean of 9.1 years	The top quartile of plasma phosphatidylcholine DHA level was associated with a significant 47% reduction in the risk of developing all-cause dementia.
Huang et al [7]	Cross-sectional study	Subjects who participated in the Cardiovascular Health Cognition Study (CHCS)	Although consumption of lean fried fish had no protective effect, consumption of fatty fish more than twice per week was associated with a reduction in risk of dementia by 28% (95% CI: 0.51 - 1.02), and AD by 41% (95% CI: 0.36 - 0.95) in comparison to those who ate fish less than once per month. Stratification by APOE epsilon4 showed this effect to be selective to those without the epsilon4 allele.
Morris et al [8]	Prospective study conducted from 1993 through 2000, of a stratified random sample from a geographically defined community	815 residents, aged 65 - 94 years, who were initially unaffected by AD	Participants who consumed fish once per week or more had 60% less risk of AD compared with those who rarely or never ate fish (RR: 0.4; 95% CI: 0.2 - 0.9) in a model adjusted for age and other risk factors. Total intake of n-3 PUFA was associated with reduced risk of AD, as was intake of DHA. EPA was not associated with AD.
Morris et al [9]	Cross-sectional analyses of deceased participants in the Memory and Aging Project clinical neuropathological cohort study, 2004 - 2013	554 deceased participants (51.6%). The mean (SD) age at death was 89.9 (6.1) years, 67% (193) were women, and the mean (SD) educational attainment was 14.6 (2.7) years.	In models adjusted for age, sex, education, and total energy intake, seafood consumption (≥ 1 meal(s)/week) was significantly correlated with less AD pathology including lower density of neuritic plaques (β = -0.69 score units (95% CI: -1.34 to -0.04)), less severe and widespread neurofibrillary tangles (β = -0.77 score units (95% CI: -1.52 to -0.02))
van de Rest et al [10]	Longitudinal, community-based epidemiologic study of aging and dementia (the Rush Memory and Aging Project)	915 participants (age 81.4 ± 7.2 years, 25% men) who had completed at least one follow-up cognitive assessment and dietary data	Consumption of seafood was associated with slower decline in semantic memory (β = 0.024; P = 0.03) and perceptual speed (β = 0.020; P = 0.05) in separate models adjusted for age, sex, education, participation in cognitive activities, physical activity, alcohol consumption, smoking, and total energy intake. In secondary analyses, APOEε4 carriers demonstrated slower rates of decline in global cognition and in multiple cognitive domains with weekly seafood consumption and with moderate to high n-3 PUFA intake from food.
Lopez et al [11]	Case-cohort study	266 community dwelling men and women aged 67 - 100 years (mean = 80.2)	Plasma DHA in the highest tertile was associated with a 65% reduced odds of all-cause dementia (95% CI: 0.17 - 0.92) and a 60% reduced odds of AD (95% CI: 0.15 - 1.10). Dietary DHA in the highest tertile was associated with a 73% reduced odds of all-cause dementia (95% CI: 0.09 - 0.79) and a 72% reduced odds of AD (95% CI: 0.09 - 0.93).
Tully et al [12]	Case-control study	The subjects (119 females and 29 males) aged 76.5 (SD 6.6) years had an MMSE score of 19.5 (SD 4.8). The control subjects (36 females and 9 males) aged 70 (SD 6.0) years were not cognitively impaired (MMSE score > 24)	Serum cholesteryl ester-EPA and DHA levels were significantly lower (P < 0.05 and P < 0.001, respectively) in all MMSE score quartiles of patients with AD compared with control values. Serum cholesteryl ester-DHA levels were progressively reduced with severity of clinical dementia. Step-wise multiple regression analysis showed that cholesteryl ester-DHA was the important determinants of MMSE score.
Conquer et al [13]	Cross-sectional study	Patients 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 DHA, total n-3 PUFA, and the n-3/n-6 ratio were lower in the AD, OD, and CIND groups. In the plasma PE fraction, levels of DHA and the total n-3 PUFA levels were significantly lower in the AD, OD, and CIND groups.
Whalley et al [14]	Observational follow-up study	120 volunteers, born in 1936, at approximate ages of 64, 66, and 68 years	Total n-3 PUFA and DHA concentrations were associated with benefits for cognition at approximately 64 years old and from approximately 64 to approximately 68 years old. After adjustment for sex, APOE epsilon4 status, and intelligence quotient at 11 years old, the effects associated with total n-3 PUFA remained significant.
Nishihira et al [15]	Cross-sectional study	185 participants (mean age 84.1 ± 3.4 years) assessed in 2011 who were free from frank dementia	Serum DHA levels decreased with increasing age (P = 0.04). Higher global cognitive function was associated with higher levels of serum EPA (P = 0.03) and DHA + EPA (P = 0.03) after controlling for confounders.
Ammann et al [16]	Retrospective cohort study	2,157 women with normal cognition enrolled in a clinical trial of postmenopausal hormone therapy	No association between RBC DHA + EPA levels and age-associated cognitive decline was found, in a cohort of older, dementia-free women.
Phillips et al [17]	Cross-sectional study	135 individuals aged between 55 and 91 years (19 AD, 55 CIND, and 61 HV)	Across the whole sample, and after controlling for age, years of education, level of socio-economic deprivation, and gender, n-3 PUFA intake, plasma PC DHA, and plasma PC EPA were all significant positive predictors of memory functioning.
Feart et al [18]	Cross-sectional analysis of the association between plasma FA and a Mediterranean diet (MeDi) adherence was performed by multi-linear regression	The study population (mean age 75.9 years) consisted of 1,050 subjects from Bordeaux (France) included in the Three-City cohort	The protective effect of the MeDi on cognitive functions might be mediated by higher plasma DHA and lower n-6/n-3 PUFA ratios.
Kroger et al [19]	Cohort study of a representative sample of persons aged ≥ 65 years	663 non-demented subjects, 149 incident cases of dementia, including 105 with AD.	In adjusted Cox regression models with age as the time scale, there were no associations between total n-3 PUFA, DHA, or EPA and dementia or AD.
Devore et al [20]	Age- and sex-adjusted Cox proportional hazard and multivariate-adjusted models to evaluate the relative risk of dementia and AD across categories of typical fish intake and fish type consumed	5,395 participants aged ≥ 55 years in the Rotterdam Study who were free of dementia and reported dietary information at baseline	During an average follow-up of 9.6 years, dementia developed in 465 participants (365 with AD). In multivariate-adjusted models, total fish intake was unrelated to dementia risk (P for trend = 0.7). Compared with participants who typically ate no fish, those with a high fish intake had a similar dementia risk (HR: 0.95; 95% CI: 0.76 - 1.19), as did those who typically ate fatty fish (HR: 0.98; 95% CI: 0.77 - 1.24). Dietary intakes of n-3 PUFA were also not associated with dementia risk.
Samieri et al [21]	Of non-demented participants who were followed up for 4 years, 65 developed dementia. The association between the proportion of plasma FA at baseline and the risk of incident dementia was assessed by multivariate proportional hazard models, taking into account depressive status	1,214 non-demented participants in the Three-City Study from Bordeaux (France)	A higher plasma EPA concentration was associated with a lower incidence of dementia (HR: 0.69; 95% CI: 0.48 - 0.98), independently of depressive status. The relations between DHA, total n-3 PUFA, and incident dementia did not remain significant in multivariate models. Higher ratios of AA to DHA and of n-6 to n-3 FA were related to an increased risk of dementia, particularly in depressive subjects (n = 90): ratio of AA to DHA (HR: 2.65; 95% CI: 1.07 - 6.56) and ratio of n-6 to n-3 (HR: 1.61; 95% CI: 1.04 - 2.47).

Table 1. The Observational Studies Which Assessed the Association Between n-3 PUFA and Dementia

Authors

Study design

Subjects

Results/conclusions

AA: arachidonic acid; AD: Alzheimer’s disease; ALA: α-linolenic acid; CI: confidence interval; CIND: cognitive impairment no dementia; DHA: docosahexaenoic acid; EPA: eicosapentaenoic acid; FA: fatty acids; HR: hazard ratio; HV: healthy volunteers; OD: other dementias; OR: odds ratio; PC: phosphatidylcholine; PE: phosphatidylethanolamine; PUFA: polyunsaturated fatty acids; RBC: red blood cell; RR: relative risk.

Yamagishi et al [2]

Community-based nested case-control study

315 cases of incident disabling dementia

Serum ALA was inversely associated with risk of disabling dementia: the multivariate odds ratios (95% CI) were 0.57 (0.39 - 0.85), 0.51 (0.34 - 0.76), and 0.61 (0.41 - 0.90) for persons with the second, third, and highest quartiles of ALA, respectively, as compared with the lowest quartile (P for trend = 0.01).

Kim et al [3]

Cross-sectional study

57 elderly (age ≥ 65 years) patients

Multivariate-adjusted regression analysis showed that a higher level of ALA significantly decreased the risk of mild dementia after adjusting for age, sex, and height.

Cherubini et al [4]

Cross-sectional study

935 community-dwelling older persons

After adjustment for age, gender, education, body mass index, weight loss, smoking status, cholesterol and triglycerides levels, daily intake of alcohol, FA and total energy, cardiovascular disease, depression and other FA levels, participants with dementia had significantly lower n-3 PUFA levels (2.9% vs. 3.2%; P < 0.05), particularly ALA levels (0.34% vs. 0.39%; P < 0.05), than did participants with normal cognitive function.

Roberts et al [5]

Cross-sectional study

1,233 non-demented subjects aged ≥ 70 years

Compared to the lowest tertile, the OR (95% CI) for the upper tertiles were 0.62 (0.42 - 0.91; P for trend = 0.012) for n-3 PUFA after adjustment for age, sex, number of years of education, and caloric intake.

Schaefer et al [6]

Prospective follow-up study

899 men and women who were free of dementia at baseline, had a median age of 76.0 years, and were followed up for a mean of 9.1 years

The top quartile of plasma phosphatidylcholine DHA level was associated with a significant 47% reduction in the risk of developing all-cause dementia.

Huang et al [7]

Cross-sectional study

Subjects who participated in the Cardiovascular Health Cognition Study (CHCS)

Although consumption of lean fried fish had no protective effect, consumption of fatty fish more than twice per week was associated with a reduction in risk of dementia by 28% (95% CI: 0.51 - 1.02), and AD by 41% (95% CI: 0.36 - 0.95) in comparison to those who ate fish less than once per month. Stratification by APOE epsilon4 showed this effect to be selective to those without the epsilon4 allele.

Morris et al [8]

Prospective study conducted from 1993 through 2000, of a stratified random sample from a geographically defined community

815 residents, aged 65 - 94 years, who were initially unaffected by AD

Participants who consumed fish once per week or more had 60% less risk of AD compared with those who rarely or never ate fish (RR: 0.4; 95% CI: 0.2 - 0.9) in a model adjusted for age and other risk factors. Total intake of n-3 PUFA was associated with reduced risk of AD, as was intake of DHA. EPA was not associated with AD.

Morris et al [9]

Cross-sectional analyses of deceased participants in the Memory and Aging Project clinical neuropathological cohort study, 2004 - 2013

554 deceased participants (51.6%). The mean (SD) age at death was 89.9 (6.1) years, 67% (193) were women, and the mean (SD) educational attainment was 14.6 (2.7) years.

In models adjusted for age, sex, education, and total energy intake, seafood consumption (≥ 1 meal(s)/week) was significantly correlated with less AD pathology including lower density of neuritic plaques (β = -0.69 score units (95% CI: -1.34 to -0.04)), less severe and widespread neurofibrillary tangles (β = -0.77 score units (95% CI: -1.52 to -0.02))

van de Rest et al [10]

Longitudinal, community-based epidemiologic study of aging and dementia (the Rush Memory and Aging Project)

915 participants (age 81.4 ± 7.2 years, 25% men) who had completed at least one follow-up cognitive assessment and dietary data

Consumption of seafood was associated with slower decline in semantic memory (β = 0.024; P = 0.03) and perceptual speed (β = 0.020; P = 0.05) in separate models adjusted for age, sex, education, participation in cognitive activities, physical activity, alcohol consumption, smoking, and total energy intake. In secondary analyses, APOEε4 carriers demonstrated slower rates of decline in global cognition and in multiple cognitive domains with weekly seafood consumption and with moderate to high n-3 PUFA intake from food.

Lopez et al [11]

Case-cohort study

266 community dwelling men and women aged 67 - 100 years (mean = 80.2)

Plasma DHA in the highest tertile was associated with a 65% reduced odds of all-cause dementia (95% CI: 0.17 - 0.92) and a 60% reduced odds of AD (95% CI: 0.15 - 1.10). Dietary DHA in the highest tertile was associated with a 73% reduced odds of all-cause dementia (95% CI: 0.09 - 0.79) and a 72% reduced odds of AD (95% CI: 0.09 - 0.93).

Tully et al [12]

Case-control study

The subjects (119 females and 29 males) aged 76.5 (SD 6.6) years had an MMSE score of 19.5 (SD 4.8). The control subjects (36 females and 9 males) aged 70 (SD 6.0) years were not cognitively impaired (MMSE score > 24)

Serum cholesteryl ester-EPA and DHA levels were significantly lower (P < 0.05 and P < 0.001, respectively) in all MMSE score quartiles of patients with AD compared with control values. Serum cholesteryl ester-DHA levels were progressively reduced with severity of clinical dementia. Step-wise multiple regression analysis showed that cholesteryl ester-DHA was the important determinants of MMSE score.

Conquer et al [13]

Cross-sectional study

Patients 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 DHA, total n-3 PUFA, and the n-3/n-6 ratio were lower in the AD, OD, and CIND groups. In the plasma PE fraction, levels of DHA and the total n-3 PUFA levels were significantly lower in the AD, OD, and CIND groups.

Whalley et al [14]

Observational follow-up study

120 volunteers, born in 1936, at approximate ages of 64, 66, and 68 years

Total n-3 PUFA and DHA concentrations were associated with benefits for cognition at approximately 64 years old and from approximately 64 to approximately 68 years old. After adjustment for sex, APOE epsilon4 status, and intelligence quotient at 11 years old, the effects associated with total n-3 PUFA remained significant.

Nishihira et al [15]

Cross-sectional study

185 participants (mean age 84.1 ± 3.4 years) assessed in 2011 who were free from frank dementia

Serum DHA levels decreased with increasing age (P = 0.04). Higher global cognitive function was associated with higher levels of serum EPA (P = 0.03) and DHA + EPA (P = 0.03) after controlling for confounders.

Ammann et al [16]

Retrospective cohort study

2,157 women with normal cognition enrolled in a clinical trial of postmenopausal hormone therapy

No association between RBC DHA + EPA levels and age-associated cognitive decline was found, in a cohort of older, dementia-free women.

Phillips et al [17]

Cross-sectional study

135 individuals aged between 55 and 91 years (19 AD, 55 CIND, and 61 HV)

Across the whole sample, and after controlling for age, years of education, level of socio-economic deprivation, and gender, n-3 PUFA intake, plasma PC DHA, and plasma PC EPA were all significant positive predictors of memory functioning.

Feart et al [18]

Cross-sectional analysis of the association between plasma FA and a Mediterranean diet (MeDi) adherence was performed by multi-linear regression

The study population (mean age 75.9 years) consisted of 1,050 subjects from Bordeaux (France) included in the Three-City cohort

The protective effect of the MeDi on cognitive functions might be mediated by higher plasma DHA and lower n-6/n-3 PUFA ratios.

Kroger et al [19]

Cohort study of a representative sample of persons aged ≥ 65 years

663 non-demented subjects, 149 incident cases of dementia, including 105 with AD.

In adjusted Cox regression models with age as the time scale, there were no associations between total n-3 PUFA, DHA, or EPA and dementia or AD.

Devore et al [20]

Age- and sex-adjusted Cox proportional hazard and multivariate-adjusted models to evaluate the relative risk of dementia and AD across categories of typical fish intake and fish type consumed

5,395 participants aged ≥ 55 years in the Rotterdam Study who were free of dementia and reported dietary information at baseline

During an average follow-up of 9.6 years, dementia developed in 465 participants (365 with AD). In multivariate-adjusted models, total fish intake was unrelated to dementia risk (P for trend = 0.7). Compared with participants who typically ate no fish, those with a high fish intake had a similar dementia risk (HR: 0.95; 95% CI: 0.76 - 1.19), as did those who typically ate fatty fish (HR: 0.98; 95% CI: 0.77 - 1.24). Dietary intakes of n-3 PUFA were also not associated with dementia risk.

Samieri et al [21]

Of non-demented participants who were followed up for 4 years, 65 developed dementia. The association between the proportion of plasma FA at baseline and the risk of incident dementia was assessed by multivariate proportional hazard models, taking into account depressive status

1,214 non-demented participants in the Three-City Study from Bordeaux (France)

A higher plasma EPA concentration was associated with a lower incidence of dementia (HR: 0.69; 95% CI: 0.48 - 0.98), independently of depressive status. The relations between DHA, total n-3 PUFA, and incident dementia did not remain significant in multivariate models. Higher ratios of AA to DHA and of n-6 to n-3 FA were related to an increased risk of dementia, particularly in depressive subjects (n = 90): ratio of AA to DHA (HR: 2.65; 95% CI: 1.07 - 6.56) and ratio of n-6 to n-3 (HR: 1.61; 95% CI: 1.04 - 2.47).

**Table 2.** The Intervention Studies Which Assessed the Association Between n-3 PUFA and Dementia
Authors	Duration and dose of n-3 PUFA	Subjects	Severity of dementia	Results/conclusions
AD: Alzheimer’s disease; ALA: α-linolenic acid; AVLT: auditory verbal learning test; CIND: cognitive impairment no dementia; DHA: docosahexaenoic acid; EPA: eicosapentaenoic acid; GDS; geriatric depression scale; LA: linoleic acid; MCI: mild cognitive impairment; MMSE: mini-mental state examination (scores < 24 are indicative for impaired cognitive functioning, and the maximum possible score on the MMSE test is 30); PAL: paired associate learning; PUFA: polyunsaturated fatty acids; RBC: red blood cell.
Boespflug et al [22]	Fish oil (EPA + DHA: 2.4 g/day, n = 11) or placebo (corn oil, n = 10) for 24 weeks	Healthy older adults (62 - 80 years) with subjective memory impairment	Subjective memory impairment, but not meeting criteria for MCI or dementia	In the fish oil group, blood oxygen level-dependent (BOLD) increases at 24 weeks were observed in the right posterior cingulate and left superior frontal regions during memory loading. A region-of-interest analysis indicated that the baseline to endpoint change in posterior cingulate cortex BOLD activity signal was significantly greater in the fish oil group compared with the placebo group.
Phillips et al [23]	n-3 PUFA (600 mg EPA and 625 mg DHA per day) or placebo (olive oil) over a 4-month period	57 participants with CIND and 19 with AD	CIND and AD	There was no benefit of n-3 PUFA supplementation for subjects with cognitive impairment and dementia.
Eriksdotter et al [24]	Daily intake of 2.3 g n-3 PUFA or placebo for 6 months; subsequently all received the n-3 PUFA for the next 6 months	174 AD patients (74 ± 9 years)	AD	Preservation of cognitive functioning was significantly associated to increasing plasma n-3 PUFA levels over time.
Geleijnse et al [25]	400 mg/day of EPA-DHA, 2 g/day of ALA, both EPA-DHA and ALA, or placebo for 40 months	2,911 coronary patients (78% men) aged 60 - 80 years	MMSE score, 28.2 - 28.4	Changes in MMSE score during intervention did not differ significantly between EPA-DHA and placebo (-0.65 vs. -0.69 points, P = 0.44). The risk of cognitive decline was 1.03 (95% CI: 0.84 - 1.26, P = 0.80) for EPA-DHA (vs. placebo).
Sinn et al [26]	EPA (1.67 g EPA + 0.16 g DHA/day; n = 17), DHA (1.55 g DHA + 0.40 g EPA/day; n = 18) or the n-6 PUFA, LA (LA; 2.2 g/day; n = 15) for 6 months	50 people aged > 65 years with MCI	MCI	Compared with LA group, GDS scores improved in the EPA (P = 0.04) and DHA (P = 0.01) groups and verbal fluency in DHA group (P = 0.04). Improved GDS scores were correlated with increased DHA + EPA (r = 0.39, P = 0.02). Improved self-reported physical health was associated with increased DHA.
Irving et al [27]	1.7 g of DHA and 0.6 g of EPA (n = 89) or placebo 0.6 g of LA per day (n = 85) for 6 months	204 patients (aged 73 ± 9, 52% women) with AD.	Mild to moderate AD	At 6- and 12-month follow-up, weight had increased 0.7 ± 2.5 kg (P = 0.02) and 1.4 ± 2.9 kg (P < 0.001) in the n-3/n-3 group. In the placebo group, weight was unchanged at 6 months but had increased (P = 0.01) at 12 months follow-up after n-3 PUFA supplementation was initiated. Appetite improved in the n-3/n-3 group over the treatment period (P = 0.01). In logistic regression analyses, not carrying the APOEe4 allele and high plasma DHA concentrations were independently related to weight gain in the combined group of patients at 6 months follow-up.
van de Rest et al [28]	1,800 mg/day EPA-DHA, 400 mg/day EPA-DHA, or placebo capsules for 26 weeks	302 cognitively healthy individuals aged 65 years or older	MMSE score > 21	No overall effect of 26 weeks of EPA and DHA supplementation on cognitive performance was observed.
Freund-Levi et al [29]	Daily intake of 1.7 g DHA and 0.6 g EPA or placebo for 6 months	204 AD patients (74 ± 9 years) with acetylcholine esterase inhibitor treatment and an MMSE > 15	AD with an MMSE > 15	No significant overall treatment effects on neuropsychiatric symptoms, on activities of daily living or on caregiver’s burden were found. However, significant positive treatment effects on the scores in the agitation in APOEε4 carriers (P = 0.006) and in depression scores in non-APOEε4 carriers (P = 0.005) were found.
Kulzow et al [30]	n-3 PUFA (2,200 mg/day, n = 22) or placebo (n = 22) for 26 weeks	44 (20 female) cognitively healthy individuals aged 50 - 75 years	Cognitively healthy	Recall of object locations was significantly better after n-3 PUFA supplementation compared with placebo. Performance in the AVLT was not significantly affected by n-3 PUFA.
Chiu et al [31]	n-3 PUFA 1.8 g/day or placebo (olive oil) for 24 weeks	23 participants with mild or moderate AD and 23 with MCI	AD and MCI	The treatment group showed better improvement on the Clinician's Interview-Based Impression of Change Scale than those in the placebo group over the 24-week follow-up (P = 0.008). There was no significant difference in the cognitive portion of the Alzheimer’s disease assessment scale (ADAS-cog) change during follow-up in these two groups. However, the n-3 PUFA group showed significant improvement in ADAS-cog compared to the placebo group in participants with MCI (P = 0.03), which was not observed in those with AD. Higher proportions of EPA on RBC membranes were also associated with better cognitive outcome (P = 0.003).
Hashimoto et al [32]	An additional 1,720 mg of DHA per day for 12 months	Participants in elderly care facilities and nursing homes (n = 75; 88.5 ± 0.6 years)	MMSE score, 14.5 ± 1.4 (placebo) and 13.7 ± 1.1 (active)	After 12 months, the mean change in MMSE subitem “Registration” score from baseline to month 12 showed a tendency to be greater in the active group than that in the placebo group. Mean changes in the Apathy scale from baseline to month 12 were less, and the changes in the Zung Self-Rating Depression Scale and the total Zarit Burden Interview scores showed a tendency to be lower in the active group than in the placebo group, respectively.
Yurko-Mauro et al [33]	900 mg/day of DHA and placebo for 24 weeks	485 healthy subjects, aged ≥ 55 with MMSE > 26	MMSE > 26	Intention-to-treat analysis demonstrated significantly fewer PAL six pattern errors with DHA versus placebo at 24 weeks (difference score, -1.63 ± 0.76 (95% CI: -3.1 to -0.14), P = 0.03). DHA supplementation was also associated with improved immediate and delayed verbal recognition memory scores (P < 0.02), but not working memory or executive function tests. Plasma DHA levels doubled and correlated with improved PAL scores (P < 0.02) in the DHA group.
Quinn et al [34]	Algal DHA at a dose of 2 g/day or to identical placebo. Duration of treatment was 18 months.	402 individuals were randomized and a total of 295 participants completed the trial	Mild to moderate AD (MMSE, 14 - 26)	Supplementation with DHA compared with placebo did not slow the rate of cognitive and functional decline in patients with mild to moderate AD.

Table 2. The Intervention Studies Which Assessed the Association Between n-3 PUFA and Dementia

Authors

Duration and dose of n-3 PUFA

Subjects

Severity of dementia

Results/conclusions

AD: Alzheimer’s disease; ALA: α-linolenic acid; AVLT: auditory verbal learning test; CIND: cognitive impairment no dementia; DHA: docosahexaenoic acid; EPA: eicosapentaenoic acid; GDS; geriatric depression scale; LA: linoleic acid; MCI: mild cognitive impairment; MMSE: mini-mental state examination (scores < 24 are indicative for impaired cognitive functioning, and the maximum possible score on the MMSE test is 30); PAL: paired associate learning; PUFA: polyunsaturated fatty acids; RBC: red blood cell.

Boespflug et al [22]

Fish oil (EPA + DHA: 2.4 g/day, n = 11) or placebo (corn oil, n = 10) for 24 weeks

Healthy older adults (62 - 80 years) with subjective memory impairment

Subjective memory impairment, but not meeting criteria for MCI or dementia

In the fish oil group, blood oxygen level-dependent (BOLD) increases at 24 weeks were observed in the right posterior cingulate and left superior frontal regions during memory loading. A region-of-interest analysis indicated that the baseline to endpoint change in posterior cingulate cortex BOLD activity signal was significantly greater in the fish oil group compared with the placebo group.

Phillips et al [23]

n-3 PUFA (600 mg EPA and 625 mg DHA per day) or placebo (olive oil) over a 4-month period

57 participants with CIND and 19 with AD

CIND and AD

There was no benefit of n-3 PUFA supplementation for subjects with cognitive impairment and dementia.

Eriksdotter et al [24]

Daily intake of 2.3 g n-3 PUFA or placebo for 6 months; subsequently all received the n-3 PUFA for the next 6 months

174 AD patients (74 ± 9 years)

Preservation of cognitive functioning was significantly associated to increasing plasma n-3 PUFA levels over time.

Geleijnse et al [25]

400 mg/day of EPA-DHA, 2 g/day of ALA, both EPA-DHA and ALA, or placebo for 40 months

2,911 coronary patients (78% men) aged 60 - 80 years

MMSE score, 28.2 - 28.4

Changes in MMSE score during intervention did not differ significantly between EPA-DHA and placebo (-0.65 vs. -0.69 points, P = 0.44). The risk of cognitive decline was 1.03 (95% CI: 0.84 - 1.26, P = 0.80) for EPA-DHA (vs. placebo).

Sinn et al [26]

EPA (1.67 g EPA + 0.16 g DHA/day; n = 17), DHA (1.55 g DHA + 0.40 g EPA/day; n = 18) or the n-6 PUFA, LA (LA; 2.2 g/day; n = 15) for 6 months

50 people aged > 65 years with MCI

MCI

Compared with LA group, GDS scores improved in the EPA (P = 0.04) and DHA (P = 0.01) groups and verbal fluency in DHA group (P = 0.04). Improved GDS scores were correlated with increased DHA + EPA (r = 0.39, P = 0.02). Improved self-reported physical health was associated with increased DHA.

Irving et al [27]

1.7 g of DHA and 0.6 g of EPA (n = 89) or placebo 0.6 g of LA per day (n = 85) for 6 months

204 patients (aged 73 ± 9, 52% women) with AD.

Mild to moderate AD

At 6- and 12-month follow-up, weight had increased 0.7 ± 2.5 kg (P = 0.02) and 1.4 ± 2.9 kg (P < 0.001) in the n-3/n-3 group. In the placebo group, weight was unchanged at 6 months but had increased (P = 0.01) at 12 months follow-up after n-3 PUFA supplementation was initiated. Appetite improved in the n-3/n-3 group over the treatment period (P = 0.01). In logistic regression analyses, not carrying the APOEe4 allele and high plasma DHA concentrations were independently related to weight gain in the combined group of patients at 6 months follow-up.

van de Rest et al [28]

1,800 mg/day EPA-DHA, 400 mg/day EPA-DHA, or placebo capsules for 26 weeks

302 cognitively healthy individuals aged 65 years or older

MMSE score > 21

No overall effect of 26 weeks of EPA and DHA supplementation on cognitive performance was observed.

Freund-Levi et al [29]

Daily intake of 1.7 g DHA and 0.6 g EPA or placebo for 6 months

204 AD patients (74 ± 9 years) with acetylcholine esterase inhibitor treatment and an MMSE > 15

AD with an MMSE > 15

No significant overall treatment effects on neuropsychiatric symptoms, on activities of daily living or on caregiver’s burden were found. However, significant positive treatment effects on the scores in the agitation in APOEε4 carriers (P = 0.006) and in depression scores in non-APOEε4 carriers (P = 0.005) were found.

Kulzow et al [30]

n-3 PUFA (2,200 mg/day, n = 22) or placebo (n = 22) for 26 weeks

44 (20 female) cognitively healthy individuals aged 50 - 75 years

Cognitively healthy

Recall of object locations was significantly better after n-3 PUFA supplementation compared with placebo. Performance in the AVLT was not significantly affected by n-3 PUFA.

Chiu et al [31]

n-3 PUFA 1.8 g/day or placebo (olive oil) for 24 weeks

23 participants with mild or moderate AD and 23 with MCI

AD and MCI

The treatment group showed better improvement on the Clinician's Interview-Based Impression of Change Scale than those in the placebo group over the 24-week follow-up (P = 0.008). There was no significant difference in the cognitive portion of the Alzheimer’s disease assessment scale (ADAS-cog) change during follow-up in these two groups. However, the n-3 PUFA group showed significant improvement in ADAS-cog compared to the placebo group in participants with MCI (P = 0.03), which was not observed in those with AD. Higher proportions of EPA on RBC membranes were also associated with better cognitive outcome (P = 0.003).

Hashimoto et al [32]

An additional 1,720 mg of DHA per day for 12 months

Participants in elderly care facilities and nursing homes (n = 75; 88.5 ± 0.6 years)

MMSE score, 14.5 ± 1.4 (placebo) and 13.7 ± 1.1 (active)

After 12 months, the mean change in MMSE subitem “Registration” score from baseline to month 12 showed a tendency to be greater in the active group than that in the placebo group. Mean changes in the Apathy scale from baseline to month 12 were less, and the changes in the Zung Self-Rating Depression Scale and the total Zarit Burden Interview scores showed a tendency to be lower in the active group than in the placebo group, respectively.

Yurko-Mauro et al [33]

900 mg/day of DHA and placebo for 24 weeks

485 healthy subjects, aged ≥ 55 with MMSE > 26

MMSE > 26

Intention-to-treat analysis demonstrated significantly fewer PAL six pattern errors with DHA versus placebo at 24 weeks (difference score, -1.63 ± 0.76 (95% CI: -3.1 to -0.14), P = 0.03). DHA supplementation was also associated with improved immediate and delayed verbal recognition memory scores (P < 0.02), but not working memory or executive function tests. Plasma DHA levels doubled and correlated with improved PAL scores (P < 0.02) in the DHA group.

Quinn et al [34]

Algal DHA at a dose of 2 g/day or to identical placebo. Duration of treatment was 18 months.

402 individuals were randomized and a total of 295 participants completed the trial

Mild to moderate AD (MMSE, 14 - 26)

Supplementation with DHA compared with placebo did not slow the rate of cognitive and functional decline in patients with mild to moderate AD.

**Table 3.** Characteristics of Patients Whose Dementia Can Be Improved or Prevented by n-3 PUFA
1. Mild memory and/or cognitive impairment
a) Subjective memory impairment
b) Mild cognitive impairment (MCI)
c) Cognitive impairment no dementia (CIND)
d) Mild Alzheimer’s disease
2. Higher intake of fish
3. Additional daily n-3 PUFA intake > 2.0 g
4. Additional daily DHA intake > 900 mg
5. Duration of treatment > 6 months

Table 3. Characteristics of Patients Whose Dementia Can Be Improved or Prevented by n-3 PUFA

1. Mild memory and/or cognitive impairment

a) Subjective memory impairment

b) Mild cognitive impairment (MCI)

c) Cognitive impairment no dementia (CIND)

d) Mild Alzheimer’s disease

2. Higher intake of fish

3. Additional daily n-3 PUFA intake > 2.0 g

4. Additional daily DHA intake > 900 mg

5. Duration of treatment > 6 months