Omega-3 Fatty Acids and Cognitive Function

Introduction

Dementia is a major increasing global health challenge. An estimated 50 million people worldwide are currently living with dementia and this number is expected to increase to 131.5 million by 2050 [(1,2]. Worldwide annual dementia costs are $1 trillion; therefore, modalities to prevent cognitive decline are particularly important. Approximately 15–20% of those age 65 years and older have mild cognitive impairment (MCI), an intermediate stage in the continuum from normal aging to dementia [3]. Alzheimer’s disease (AD) is a progressive, neurodegenerative condition, with senile plaques, neurofibrillary tangles, neuronal dysfunction and neural failure. No cure or drug is available to change the progression of AD; therefore, dietary modalities to prevent cognitive impairment become important on a population basis. The very long chain omega-3 (n-3) polyunsaturated fatty acids (PUFA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are required in the diet for metabolic structure and function. DHA is a major fatty acid in membrane phospholipids in the grey matter of the brain and makes up approximately 25% of total fatty acids in the human cerebral cortex and 50% of all PUFA in the central nervous system [4–6]. DHA is transported into the brain in the form of lysophosphatidylcholine by the major facilitator superfamily domain-containing protein 2a (Mfsd2a) [7]. Mfsd2a knockout mice had 50% lower levels of DHA in brains with consequent cognitive deficits and neuronal cell loss in hippocampus and cerebellum, providing strong support for the role of DHA in cognitive function [7]. This review provides an update on articles published in 2021 and 2022 on the role of n-3 PUFA and DHA in neural development and prevention of cognitive decline and dementia.

DHA and Neural Development

An increased risk of poor neural development in infants has been observed with low levels of maternal DHA in epidemiological studies [reviewed in 8*,9]. A deficiency of dietary n-3 PUFA during fetal development in utero and postnatal has been associated with a loss of discriminative learning ability [10]. Infants born to mothers whose diet was supplemented with DHA had higher mental processing scores and higher degrees of stereopsis and stereoacuity at 4 years of age [11,12]. Breast-fed infants of mothers who were supplemented with DHA during lactation had significantly better psychomotor development, hand-eye coordination and visual acuity at 2.5 years compared to breast-fed infants of mothers who received a placebo [13]. At least 300 mg of DHA daily is recommended for pregnant and nursing women to meet the needs of the fetus and breast-feeding infant [14].

Prospective Cohort Studies in the Adult

In 2022, 3 new meta-analyses reported on the association between fish and n-3 PUFA intake and cognitive decline. Wood et al [15**] provide results between fish intake and AD in 5 prospective cohort studies in those > age 55. The Rotterdam study of 5,386 subjects showed that > 18.5 g/d of fish consumption at baseline was associated with a 70% reduced risk of AD at 1.2 year follow-up (95% CI: 0.1–0.9) [16] although 9.6 year follow-up showed no association, highlighting a limitation of baseline dietary intake as the only assessment of diet in long-term prospective studies [17]. At 5.4 year follow-up in the Cardiovascular Health Cognition Study of 2,233 individuals age ≥ 65 years, consumption of more than 2 fatty fish meals per week showed a 41% decreased risk of AD in those without the apolipoprotein (apo) E4 allele (95% CI: 0.36–0.95) compared to those eating less than once/month [18]. At 3.9 year follow-up In the Chicago Memory and Aging Project of 815 subjects ages 65–94 years, one or more fish meals per week was associated with a 60% reduction in risk of AD (95% CI: 0.2–0.9; p=0.07) with those in the top 3 quintiles having a multivariate-adjusted relative risk (RR) as low as 0.2 (95% CI: 0.1–0.8) [19]. In 9.1 year follow-up of 899 subjects in the Framingham Heart Study, those in the upper quartile of DHA in plasma phosphatidylcholine (mean DHA intake of 0.18 g/d of fish intake equating to 3 servings/week) had a significant 47% reduction in risk of developing all-cause dementia (RR=0.53, 95% CI 0.29–0.97; p=0.04) and a 39% reduction in risk of Alzheimer’s disease (RR=0.61, 95% CI 0.31–1.18; p=0.14 [20]. In the Rush Memory and Aging Project of 915 subjects with a mean age of 81.4 years living in retirement communities and without AD, at 4.9 year follow-up, cognitive ability using a 19-test battery showed that consumption of one seafood meal per week was associated with slower rates of decline in semantic memory (β=0.024; p=0.03) and perceptual speed (β=0.020, p=0.05) after adjustment [21]. Both apoE3 and apoE4 carriers had slower rates of decline in global cognition and multiple cognitive domains with weekly seafood consumption and moderate to high intake of n-3 PUFA from food although the effect was more pronounced in apoE4 carriers. The group of 161 fish oil supplement consumers had slower rates of decline in the global cognitive measure (β=0.024, p = 0.02) and in episodic memory (β=0.027, p=0.03) compared with the nonconsumers [21].

In 2022, Kosti et al [22**] reported a dose-response meta-analysis of 11 prospective, cohort studies of 46,488 individuals some of whom had mild cognitive impairment but were without dementia or AD at baseline. Fish intake of up to 2 portions (250 g) per week (assessed by food frequency questionnaire) was associated with a 10% reduction (95% CI: 0.79, 1.02, N=5) in all-cause dementia and a 30% reduction (95% CI: 0.54,0.89, N=3) in risk of AD.

In 2021, Zhu et al [23*] reported a prospective cohort meta-analysis of 14 studies of 54,177 participants of whom 1696 patients had AD, 1118 patients had dementia, and 2889 had MCI at baseline. High levels of n-3 PUFA intake were associated with a 14% reduction in risk of MCI (RR, 0.86; 95% CI, 0.75, 0.98).

In 2022, Chu et al [24*] presented results of a prospective, cohort study with 2-year follow-up of 129 pts with AD (mean age 76.5±6.6 years). Those with low baseline DHA levels, but not EPA, had a higher risk of cognitive decline (OR=1.131, 95% CI: 1.020, 1.254; p=0.020).

In summary, these new reports support an inverse association between intake of fish and cognitive decline and risk of AD, that apoE genotype modified the effect and that DHA may be responsible for the benefit. The results extend the findings of an earlier dose-response meta-analysis of 21 studies of 181,580 subjects in which fish consumption (a 1-serving/wk increment) significantly reduced risks of dementia (RR: 0.95; 95% CI: 0.90, 0.99) and AD (RR: 0.93; 95% CI: 0.90, 0.95) [25]. DHA intake was also inversely associated with risks of dementia (RR: 0.86; 95% CI: 0.76, 0.96) and AD (RR: 0.63; 95% CI: 0.51, 0.76). The effect of apoE genotype supports results of an earlier report in which delayed progression of cognitive decline was observed at an early stage in apoE4 carriers in 1 RCT of AD and in apoE4 carriers in 3 RCTs of cognitively healthy subjects [26]. Three major protein isoforms exist in the apoE gene, apoE2, 3 and 4. The apoE3/4 and apoE4/4 genotypes have a 2–3 and 12–15 fold increased risk of AD, respectively, compared to the apoE3/E3 genotype [27,28]. Moreover, the average age onset of AD falls from 84 years in apoE4 non-carriers to 76 years in apoE3/E4 and 68 years in apoE4/E4 [28,29]. Postulated reasons for the increased risk in apoE4 carriers include defective amyloid-β (Aβ) clearance which leads to increased deposition of Aβ in senile plaques [30], a loss of neuronal synaptic plasticity and dendrite outgrowth, neuroinflammation, blood-brain-barrier dysfunction and lower brain uptake of DHA [31,32**]. Moreover, supplementation with DHA for 18 months resulted in lower plasma levels of DHA in those heterozygous or homozygous for apoE4, possibly accounting for lower brain levels [33].

Randomized Clinical Trials of Omega-3 Fatty Acids in Adults with Cognitive Impairment

In a 2022 review by Wood et al [15**] of 13 randomized controlled trials (RCTs) of adults ≥50 years with mild cognitive impairment, supplemental n-3 PUFA had a protective effect against cognitive decline in 9 studies but no effect in 4 studies with higher amounts showing most benefit. Importantly, significant improvement occurred prior to cognitive impairment or with early and mild cognitive impairment whereas those with AD had no benefit. These results extend those of an earlier systematic review of 7 RCTs in patients with AD in which benefit from n-3 PUFA supplementation was observed in those with mild (early) AD, suggesting that for the best outcome, n-3 PUFA should be started with mild cognitive decline [34].

In 9 RCTs of which 5 included MCI or AD reviewed by Kosti et al [22**] in 2022, a dose-response relationship was found between the omega-3 index achieved and improvement in executive function but not in general cognition. Of these 9, age range was > 50 in 7 trials but > 18 in 2 trials which may have minimized benefit. A wide range in EPA and/or DHA supplementation (from 2 to 36 months) and doses (112.5 mg to 1680 mg EPA and 297 mg to 1680 mg of DHA) may also have affected outcome.

In an RCT of 60 adults between the ages of 60 and 90 from New Zealand with MCI, supplementation with 1491 mg DHA + 351 mg EPA daily had no effect on cognition compared to a placebo (1857 mg linoleic acid) at 12 months [35*].

To summarize this section, the effects of n-3 PUFA supplementation in mild AD corroborate epidemiological observational studies showing that n-3 PUFA may be beneficial early in disease onset when there is slight impairment of brain function; however, there is not enough evidence to support n-3 PUFA in the treatment of AD. Yassine et al [31] recommended that high-dose DHA supplementation be considered in apoE4 carriers before the onset of AD dementia or in the early stages.

Randomized Clinical Trials of Omega-3 Fatty Acids in Cognitively Healthy Adults

Our group reported that 250 patients with stable clinical coronary artery disease (CAD) on statin treatment randomized to 1.8 g EPA and 1.5 g DHA daily over 30 months had significantly better scores than control (no supplementation) for verbal fluency, language and memory (mean: 1.08, 95% CI:0.25, 1.91, p=0.011) and two tests of visual-motor coordination (mean: −2.95, 95%% CI: −5.33, −0.57, p=0.015 and mean: −9.44, 95% CI: −18.60, −0.30, p=0.043, respectively) [36*]. Post-hoc analyses indicated no difference by age, sex or diabetes status. EPA+DHA delayed cognitive aging by 2.5 years (Figure). Therefore, cognitively healthy, older adults with stable CAD should be counseled on the potential benefit of EPA and DHA supplementation to potentially slow cognitive decline over 30 months. This amount of EPA and DHA can only be obtained from supplements rather than from diet alone.

Prior RCTs which have examined the effect of EPA and DHA on cognitive function in cognitively healthy subjects over age 50 are summarized in Table 1 [36–50]. Trial duration ranged from 3 months to 5 years and total dose of EPA and DHA ranged from 285 mg to 3.36 g daily. Five studies have reported over the past 18 months. Ichinose et al [47*] reported that 137 mg of EPA and 297 mg of DHA in 200 ml of a milk beverage vs placebo of 200 ml milk daily resulted in a higher mean change in MMSE in DHA compared to placebo at 12 months (p<0.05). In a trial of 4,218 cognitively healthy adults (mean age 70.9±5.8 years) randomized to 840 mg EPA+DHA daily or none over 2–3 years, no difference in annual rate of cognitive change using a global score for 8 neuropsychological tests was observed [48*]. Of 57 women mean age 72±7 years in a retirement center in urban South Africa, those randomized to 2.2 g n-3 PUFA daily (canned pilchards and fish spread) had a significantly higher cognitive abilities screening instrument score at 12 weeks compared to canned meat balls and texturized soya [49**]. Of note, in a RCT of 390 subjects (mean age 73) randomized to 1720 mg of DHA and 600 mg of EPA over 18 mo, apoE4 carriers improved significantly on reasoning (p=0.02) compared to placebo of 990 mg oleic acid. [50] See Malik et al [36*] for descriptions of the other trials. In summary, of the 15 RCTs in cognitively healthy older adults, 7 reported benefit on cognitive function measured by neuropsychological testing whereas 8 reported no benefit.

Differences in outcomes in the trials could be due to differences in dose of DHA and EPA, duration of trial, the type of placebo, number of subjects, the stage of cognitive decline and rate of decline, the types of cognitive function tests employed and apoE genotype. The length of the intervention is important as evidenced from the LipiDiDiet study in which there was no difference at 24 months but there was benefit at 36 months [51,52*]. Differences by sex were also shown to be important in a 2022 cross-sectional report of 386 healthy adults (mean age 77.4±3.8 years) [53*]. Higher n-3 PUFA concentrations were associated with better non-verbal memory and processing speed in fully adjusted models (β’s of 0.21 and 0.19, respectively). Men with higher n-3 PUFA levels had better executive functioning and processing speed whereas women had better verbal and non-verbal episodic memory [53*]. The difference by sex suggests that failure to account for sex could account for variability in studies and needs to be considered in future studies.

Mechanisms for Benefit

The beneficial effect of DHA on cognition and controlling neuroinflammation may result from its downstream products which include the specialized pro-resolving lipid mediators: D-series resolvins, maresins and protectins, all of which lead to resolution of inflammation. Table 3 in Mallick’s paper shows the DHA-derived resolvins and their receptors with functions [10]. Neuroprotectin D1 (NPD1) has been reported to prevent neuronal death and improve brain cell survival and repair in aging and neurodegenerative diseases [54]. NPD-1, resolvin D1 and aspirin-triggered resolvin D1 improve brain function and impair neuronal death through downregulation of NF-kB, TLR4, CD200 and IL6R [55,56]. NDP1 can repress inflammation, oxidative stress and cell apoptosis induced by Aβ42, thereby promoting neuronal survival. NDP1 may prevent AD progression through upregulating PPAR-γ and amyloid precursor protein-α, and downregulating β-amyloid precursor protein, leading to decreased Aβ42 release and reducing the Aβ peptide in neuronal tissue [57,58]. Deficiency of NPD1 and the enzyme involved in its formation, 15-LOX-1, has been observed in AD brain. DHA, the precursor of NPD1, elicits an Aβ42-lowering effect both in vitro and in mouse models [59–61].

Conclusion

DHA is critical throughout all life stages from the need for fetal development to the maintenance of cognitive function in adults and the elderly. Pregnant and lactating women should be recommended to take DHA supplements. Patients with memory complaints or a family history of AD and those with clinical CAD should be counseled on the potential benefits of fish intake and supplementation with n-3 PUFA. Accumulating evidence suggests that APOE4 carriers have a lower brain uptake and DHA levels and would particularly benefit from DHA intervention prior to any significant neuropathology, which affects brain DHA uptake. A future RCT should be considered in ‘at-risk’ cognitively healthy participants with incident dementia or AD as the primary outcome for at least 5 years including those with the apoE4 genotype and including a standard battery of cognitive tests.