RCTs performed with adults report mixed results for DHA and-3 PUFA supplementation on cognition. Supplementation of healthy adults from 18 to 70 years of age with 850 mg DHA and 630 mg EPA daily for 12 weeks had no appreciable effect on cognition [ 168 ]. Likewise, supplementation of young adults (18 to 35 year-olds) with 1000 mg DHA and 200 mg EPA for 12 weeks had no significant cognitive effects [ 169 ]. Furthermore, daily supplementation with 250 mg DHA and 1740 mg EPA in a college-age cohort for four weeks had no effect on attention, memory, or inhibitory responses [ 170 ]. In contrast, another study performed with college-age students and a higher daily DHA dose (480 mg DHA and 720 mg EPA) for four weeks found improvements in verbal learning and memory in the supplemented group despite the very short treatment interval [ 171 ]. Similarly, Stonehouse(2013) reported improvement of episodic and working memory in 18 to 35 year-olds provided a high-DHA supplement containing 1160 mg DHA and 170 mg EPA daily for six months compared to placebo controls [ 172 ]. Interestingly, the effect on episodic memory was driven primarily by the women in the study, whereas the men were largely responsible for the effect on working memory. This is not completely surprising given the existence of sex differences in particular cognitive domains, including spatial working memory [ 173 174 ]. Recently, it was also shown that deficits in episodic memory observed in lonely individuals was prevented by-3 PUFA supplementation for four months [ 175 ]. These data suggest that detecting cognitive effects in adults likely requires substantial levels of DHA provided for extended treatment periods in an experimental cohort with a relatively narrow age range.

Observational studies suggest a correlation between blood levels of DHA and cognition in healthy adults. For example, higher serum DHA levels were associated with better non-verbal reasoning, mental flexibility, working memory and vocabulary in 35 to 54 year-olds with no neuropsychiatric disorders and no supplemental fish oil use [ 164 ]. In an extension of this study, Leckie 165 ] found that a higher ratio of DHA to ARA in serum counteracted the negative effect of low physical activity on both working memory and the trail marking task. This is important since physical activity can increase gray matter volumes and reduce the overall risk for Alzheimer’s disease [ 166 167 ].

Cognitive function reaches its peak during middle adulthood. Thus, the detection of measurable effects of DHA consumption requires lengthy observational or treatment periods, and measurable effects are most effectively observed in cases of DHA-insufficiency or cognitive impairment. Indeed, a recent meta-analysis by Abubakari 161 ] of 12 RCTs in adults found no effect of-3 PUFAs on cognitive measures. However, the authors selected trials with subjects exhibiting a multitude of baseline cognitive conditions and/or subjects diagnosed with psychiatric conditions such as depression and schizophrenia, in addition to cognitive test parameters that likely clouded any measurable effect of-3 PUFAs. Another recent meta-analysis of 34 RCTs found no effect of-3 PUFA supplementation on cognitive performance, but the investigators combined trials performed with children, adults and elderly without performing any subgroup analyses that considered age or dose [ 162 ]. This limited their conclusions greatly since assessment of cognitive function is highly dependent on developmental timeline and age. Conversely, a well-designed meta-analysis by Yurko-Mauro and colleagues revealed that DHA + EPA supplementation improves episodic memory outcomes in adults with mild memory complaints, an effect primarily attributable to daily DHA doses above 580 mg [ 163 ].

Recent RCTs have also associated the cognitive benefits of DHA with neurophysiology or anatomical changes in the brain. Witteprovided-3 PUFA supplementation (880 mg DHA and 1320 mg EPA) for 26 weeks in healthy subjects (age 50 to 75) and found improvements in executive function, white matter integrity, gray matter volume, and parameters of neurovascular function compared to individuals provided a placebo. Tokuda 217 ] provided 55 to 64 year old Japanese men who already consumed an average of 543 mg DHA per day and had substantial plasma DHA levels (7.0% of fatty acids) a supplement containing 300 mg DHA, 100 mg EPA, and 120 mg of ARA daily for four weeks. They report that treatment prevented a decline in auditory event-related potential (ERP) latencies (a measure of cognitive processing speed) that was observed in the placebo group. Deficits in auditory ERPs are typically observed in Alzheimer’s disease [ 218 ]. Finally, a very recent study reported by Strike 219 ] suggests that a combined supplemental approach may be beneficial. They gave a group of postmenopausal women between the ages of 60 and 84 years-old a daily supplement containing 1000 mg DHA, 160 mg EPA, 240 mg ginkgo biloba, 60 mg phosphatidylserine, 20 mg tocopherol, 1 mg folic acid, and 20 g vitamin B12 for six months and found a shorter mean psychomotor response latency (a measure of information processing speed) and verbal recognition memory in the treatment group relative to the placebo group. They did not detect any changes in executive function or paired associate learning. In totality, data from studies reporting the effect of dietary DHA consumption, blood DHA concentrations, and supplementation with DHA on parameters of cognition in normal aging individuals provide a substantial argument for obtaining sufficient amounts of DHA via dietary or supplemental means during aging.

More recent RCTs have yielded more compelling results than the earlier work. The Memory Improvement With Docosahexaenoic Acid Study (MIDAS) study, performed by Yurko-Mauro and colleagues [ 213 ], provided 900 mg of DHA or a placebo daily for 24 weeks in 485 healthy elderly individuals (mean age of 70 years-old) who had a self-reported mild memory complaint and a MMSE score over 26 (cognitively normal). Those supplemented with DHA exhibited improved episodic and visual recognition memory, but not in executive or working memory, and plasma DHA levels were directly correlated to scores in episodic memory. Furthermore, Vakhapova 215 ] reported benefits in an elderly population with memory complaints (non-dementia) of improved immediate recall memory and sustained attention when provided a daily 300 mg DHA-phosphatidylserine supplement for 15 weeks. In a cross-over RCT, Nilsson 216 ] reported a benefit of 3 g daily-3 PUFA supplementation (1050 mg DHA) for five weeks in measures of working memory and selective attention in a group of middle age to elderly subjects. It is intriguing to think that the metric used by Yurko-Mauroand Vakhapovaof a mild subjective memory complaint might be an early correlate of age-related cognitive decline, and their findings could indicate the potential power of DHA supplementation during the long, early and undetectable phases of cognitive impairment and dementia.

Data from RCTs in healthy aging adults has been historically sparse, but recently more trials have been reported, with some mixed but generally positive effects of DHA and-3 PUFA supplementation on cognition. Initial reports indicated no differences in overall cognition in a group of elderly individuals over 65 years of age receiving daily high or low dose fish oil for 26 weeks, however subgroup analysis did reveal improvements in attention in those with the ApoE4 genotype [ 210 ]. Similarly, Dangour 209 ] found no effect of daily-3 PUFA supplementation for two years on cognitive measures in a group of 70 to 79 year old healthy individuals. However, controls in this study did not have a decline in cognitive performance over the two-year span, possibly masking any potential effect of DHA. Additionally, Stough 211 ] reported no effect of daily DHA (252 mg) for 90 days on cognition as measured by Cognitive Drug Research (CDR) scores, however this cohort included a wide range of ages (45 to 80) and a small sample size, making interpretations difficult. In contrast, a combined supplementation of 800 mg DHA and 12 mg lutein for four months in healthy 60 to 80 year-old women, improvements in verbal fluency, memory scores, and rate of learning were seen [ 212 ].

While dietary DHA intake is a convenient measure, there are inherent flaws in the reliability and accuracy of data acquired from food frequency questionnaires [ 201 ]. Therefore, studies that measure tissue levels of DHA could provide a more appropriate measure of current and past DHA status in relation to cognitive performance. Indeed, some but not all observational studies have linked DHA concentrations in blood with overall cognition and select cognitive domains. For example, a recent study measured the cognitive function of 2157 postmenopausal women at baseline and annually for six years and found no correlation between erythrocyte DHA + EPA and cognitive performance in seven cognitive domains at baseline or over time [ 202 ]. On the other hand, the Etude du Vieillissement Arteriel (EVA) cohort of French 63 to 74 year-olds exhibited a reduced risk of overall cognitive decline over four years in those with higher erythrocyte-3 PUFA content [ 203 ]. Dullemeijer 204 ] performed a cross-sectional longitudinal study in a Dutch cohort (50–70 years old) and found that higher plasma concentrations of total-3 PUFAs at baseline was associated with less decline in sensorimotor and complex speed-related cognitive domains three years later. However, they did not observe associations with changes in memory, information-processing speed, or word fluency. Whalley 205 ] performed a battery of cognitive tests in a Scottish cohort at ages 64, 66, and 68 years old and found a positive correlation between overall cognitive performance over time and erythrocyte DHA content at baseline (64 years old). Interestingly, this effect was only apparent in the absence of the ApoE4 allele, indicating a genetic influence on the link between peripheral DHA levels and cognition. The Framingham Offspring Study performed in a large group of elderly women (mean age 67 years old) reported that the women with erythrocyte DHA levels (but not EPA) in the lowest quartile had lower brain volume and poorer scores for visual memory, executive function, and abstract thinking than those in the top three quartiles [ 206 ]. Lower serum DHA (but not EPA) was also found in a small selected case study group of elderly with reduced performance in the MMSE compared to a cognitively healthy control group [ 207 ]. In this study, DHA serum concentrations were correlated with performance on a majority of the tests (memory, attention, and mental flexibility). Recently, Otsuka 208 ] reported results of a cross-sectional longitudinal study in Japanese elderly adults that revealed a link between low serum DHA levels and a greater risk for cognitive decline over a decade as measured by the MMSE. This is especially profound given that elderly Japanese have twice the circulating levels of DHA as compared to similar cohorts in England [ 208 209 ]. Overall, these reports provide a suggestive link between the tissue levels of DHA and cognition during aging.

Many observational studies have linked dietary consumption of-3 PUFAs, and DHA in particular, with improvements in cognitive function and/or reductions in cognitive decline in healthy, aging populations. For example, DHA intake was correlated with performance and speed in a verbal learning test performed in a cohort of 45 to 70 year-old healthy individuals [ 192 ]. Van Gelder 193 ] performed a prospective study using longitudinal data that calculated EPA + DHA consumption at baseline and at five years later in 70 to 89 year-olds and found that the decline in baseline mini-mental state exam (MMSE) scores was negatively associated with dietary EPA + DHA levels. In a group of 65 to 80 year-old healthy individuals, consumption of greater than 2.1 g of-3 PUFAs per day was associated with better memory and executive function [ 194 ]. Velho 195 ] reported that, in a cohort of healthy elderly (over 65 years-old), those that improved their MMSE scores at 8.5 months from baseline had higher consumption of-3 PUFAs than those who did not show improvements. Cross-sectional analysis of elderly Spanish residents (= 304), with an average age of 75 years-old, found a positive correlation between dietary DHA consumption and MMSE scores and that lower DHA intake was a predictor of cognitive impairment [ 196 ]. In a large cohort of Chinese adults (average age of 65; part of the Singapore Longitudinal Aging Studies) the daily consumption of fish oil supplements was associated with higher baseline MMSE scores and a lower risk of decline in cognition over a 1.5-year span [ 197 ]. Titiova 198 ] more recently reported a prospective observational study in a healthy elderly population where baseline dietary DHA intake levels at age 70 were positively correlated with larger gray matter volume and declarative memory test performance (seven minute screen) at age 75. In a larger prospective study using data from the China Health and Nutrition Survey, Qin 199 ] examined the decline in global cognitive scores over an average of 5.3 years in a group of Chinese adults (= 1566, mean age 63 years old). This study detected a positive correlation between at least one serving of fish per week and slower declines in global cognitive function, composite and verbal memory scores. Finally, most recently del Brutto 200 ] reported on a cohort from a rural middle-to-low income area of Ecuador that cognitive function as measured by Montreal Cognitive Assessment (MoCA) scores was positively related to the number of fish servings per week, and the data suggested an intake of at least four fish servings per week was best.

Support of the clinical findings above can be found in preclinical animal experimentation, in which age-related neuronal loss was shown to begin at the end of adolescence in rat brains [ 189 ]. Total synaptic loss is the best correlate of cognitive decline during aging, as overall synaptic density affects cognitive ability [ 190 ]. Increases in oxidative stress and inflammation in both nervous and immune systems also occur with aging [ 191 ], leading to DNA damage and telomere shortening. DHA has proven synaptic effects that improve synapse strength and numbers, and DHA can help prevent or mitigate oxidative stress and neuroinflammation. These actions will be discussed in more detail in the section on potential DHA mechanisms during aging.

Total gray matter volume declines with age [ 177 ], matching a parallel decrease in DHA composition [ 178 ]. This drop in DHA may be partially due to changes in activities for the enzymes responsible for DHA accretion into phospholipids [ 179 180 ] or to shifts in plasma pharmacokinetics [ 181 ]. Importantly,-3 PUFA intake is positively correlated with gray matter volume in adults [ 182 ] and in brain regions responsible for cognition in normal, elderly adults [ 183 ]. During normal aging there is a gradual 10%–15% loss of total neuronal synapses resulting in a cognitive decline that is typically noticed around age 65 [ 184 ], and an increasing risk of dementia that is largely negligible before age 60 [ 185 ]. However, processes leading to neuronal loss and the impairment of brain functions may be active at much younger ages [ 186 ]. For example, in susceptible young adults, an age-related reduction of neurons in the brain is reported [ 187 ]. Of note, declines in episodic memory can begin as early as 20 years of age [ 188 ].

The age demographics of the global population is shifting as lifespans increase over time due in part to advancements in medicine and positive economic development. The segment of people 65 and older is projected to triple to 1.5 billion globally by 2050 (WHO, [ 176 ]). Unfortunately, cognitive ability declines naturally with age even in the healthiest of individuals. This decline is typically subtle, but it is nonetheless undesirable and ultimately affects the quality of life. Environmental factors such as diet, exercise, and DHA consumption can positively affect the normal aging process and overall mental health and performance.

RCTs have provided evidence indicating largely positive effects of-3 PUFA supplementation on cognitive measures in subjects with MCI or dementia. Early evidence from Terano 236 ] indicated improved dementia scores in patients with moderately severe dementia caused by thrombotic cerebrovascular disorder who received 720 mg of DHA daily for 12 months. Combined supplementation with DHA (240 mg) and ARA (240 mg) daily for 90 days was shown to improve attention and immediate memory in patients with mild cognitive dysfunction [ 237 ]. Furthermore, supplementation with 720 mg DHA and 1080 mg EPA daily for 24 weeks in MCI patients improved their scores in the Clinician’s Global Impression of Change (CIBC)-plus and Alzheimer’s Disease Assessment Scale (ADAS)-cog [ 238 ]. Sinn 239 ] administered several doses of-3 PUFAs, including high EPA (1670 mg), high DHA (1550 mg), or high LA (2200 mg) daily for six months in MCI patients and detected improvements only in the high DHA group particularly for Initial Letter Fluency, a measure of fluid thinking ability. The other cognitive measures did not show any differences, but the baseline erythrocyte DHA levels in this study were higher than those of Chiu(5%4.2%). In a small, preliminary trial of 25 MCI patients, administration of a high-DHA (1440 mg) supplement also containing small amounts of EPA, tryptophan, phospholipids, and melatonin daily for three months improved MMSE scores, semantic verbal fluency and olfactory sensitivity [ 240 ]. The benefits of DHA on cognition in MCI may be dose-dependent since a recent report found no effect of daily supplementation with 180 mg DHA plus 120 mg EPA for 180 days in mild to moderate MCI patients on scores in the MMSE and Abbreviated Mental Test (AMT) [ 241 ]. Overall, optimal tissue levels of DHA are important in reducing the likelihood of developing, and improving the symptoms of, MCI and dementia.

Combinations with other nutrients are likely also important. Interesting results from the homocysteine and B vitamins in cognitive impairment (VITACOG) trial were very recently published in which 168 patients with MCI (≥70 years of age) were given placebo or high dose Hcy-lowering B vitamins (folic acid, B6, B12) and assessed for brain atrophy via MRI at baseline and at a two-year follow-up [ 134 ]. B vitamin treatment reduced the brain atrophy rates by 40%, an effect only observed in the subgroup with the highest tertile of baseline plasma-3 PUFA levels. Baseline plasma DHA, but not EPA, was a significant predictor of reduced yearly brain atrophy rate in those who took B vitamins, but not in placebo controls. Thus, the DHA status of the MCI patient affected the correlation between vitamin B supplementation and brain atrophy, and possibly cognitive decline by extension. It would be interesting to determine whether the Hcy and DHA status of the MCI subject affects or predicts the rate of conversion from MCI to dementia (about 5%–10% per year). If so, perhaps supplementation with B vitamins in combination with DHA in MCI patients would be an effective prophylactic treatment aimed at reducing the risk of further cognitive decline and the development of dementia.

Observational studies have linked the consumption of-3 PUFAs with a lower prevalence of dementia [ 229 ] and lower overall risk of developing dementia [ 230 ]. Albanesefound a significant dose-dependent decrease in dementia relative to fish intake in a large group of subjects (14,960) residing in middle-to-low income areas [ 229 ]. The Three-City cohort study of 8085 French residents over the age of 65 found an inverse relationship between fish consumption and overall risk of dementia over a four-year timeframe in ApoE4 non-carriers (80% of subjects) [ 230 ]. Blood levels of DHA have also been tied inversely to mild cognitive impairment (MCI) and dementia. For instance, in the Framingham study, plasma phosphatidylcholine fatty acid content was measured in 899 subjects with an average age of 76 and no dementia at baseline. When re-assessed for cognitive ability nine years later, individuals in the top quartile for baseline plasma PC-DHA levels had a 47% lower risk of all-dementia (grouped with AD)the other three quartiles combined. No other fatty acid was significantly correlated (including EPA), and food intake surveys revealed that this quartile had an average DHA intake of 180 mg per day [ 231 232 ]. Cherubini 233 ] also reported higher levels of plasma DHA in cognitively normal subjects as compared to those with dementia in an aging Italian cohort. With regards to MCI, Milte 234 ] detected higher levels of the-6 PUFA docosapentaenoic acid (DPA-6; 22:5(-6)) in the erythrocytes of MCI patients relative to healthy controls. More recently, Yin 235 ] reported lower blood levels of DHA in amnestic and multi-domain MCI patients as compared to normal control subjects. These are intriguing findings since the DPA-6 replaces DHA in the brain during DHA deficiency in an inefficient attempt to retain function.

There is a normal degradation in cognitive ability and brain atrophy with age [ 221 222 ]. However, the rate of atrophy is markedly higher in mild cognitive impairment (MCI) and dementia. The atrophy rate is especially high in the subgroup of MCI subjects that eventually develop clinically diagnosed AD [ 223 ], the most prevalent neurodegenerative disease. Approximately half of all individuals with MCI progress into AD within five years. Furthermore, brain glucose metabolism decreases 10%–15% during normal aging, and the extent of cognitive decline in MCI and AD is associated with the degree of glucose metabolism loss (nearly 35% in some brain regions; [ 224 226 ]). Preclinical animal studies have convincingly shown that DHA provided over a substantial amount of time can reduce neuronal loss and improve learning and memory as the animals age (For meta-analysis, see [ 227 ]). However, studying the effects of DHA on the risk of dementia is very challenging given the low incidence rates in cognitively healthy individuals. Some estimates have called for nearly 50,000 participants at baseline for proper statistical power [ 228 ], whereas the rate of cognitive decline during dementia is a more accessible measure. In addition, changes in cognitive domains are dependent upon the specific type of dementia. For example, early changes in AD are seen in episodic memory, whereas in vascular dementia early deficits in executive function are seen. Later stages of dementia and AD involve a multitude of cognitive domains.

During aging, an increasing share of the resources available for normal cellular maintenance are spent on repair mechanisms needed by the cell to cope with the cumulative effects of oxidative, inflammatory, and other environmental insults. With this shift in demand, any diminished availability of energy, as a result of poor mitochondrial function, may result in neurodegenerative processes that can lead to neuronal loss and eventually to cognitive impairment, dementia, or other neuropsychiatric maladies. Unfortunately, neurodegenerative processes and neuronal cell death occur well before clinical signs of cognitive deficits are confirmed [ 186 ]. Dementia is not a disease itself, but rather a group of chronic symptoms that are common to several neuropsychiatric disorders (Alzheimer’s disease (AD), Lewy body dementia, Parkinson’s disease,). Dementia symptoms, such as deficits in memory, language and executive function, lead to poor cognitive function in these individuals [ 186 ]. Dementia often results in poor self-care that can lead to inadequate nutrition, which could potentially exacerbate the cognitive deficits. In the most severe cases of dementia there is a loss of functional independence that results in institutionalization. Worst-case scenarios occur in low- and middle-income, developing countries where access to nutrient-dense foods and the ability to afford medical and functional care are leading to exponential growth in dementia prevalence rates [ 220 ].

4.4. DHA and Cognition in Alzheimer’s Disease

AD is a uniquely human, progressive neurological disease resulting in hallmark neuropathology consisting of senile plaques, neurofibrillary tangles, neuronal atrophy, and abnormal brain glucose metabolism. AD accounts for more than 70% of dementia cases and has an estimated worldwide prevalence of about 4.4% of the population over 65 years old [ 242 ]. This prevalence is expected to grow from 5.2 million Americans in 2014 to 13.8 million Americans and to 115 million people globally by 2050 (Alzheimer’s Association 2014 report [ 243 ], WHO 2012 Dementia Report [ 244 ]). Deaths from AD rose by 66% in a recent eight-year span, highlighting the lack of efficacious therapeutic options currently available, aging societal demographics, and shifting environmental impacts such as nutrition and physical activity [ 186 ]. A recent study in Medicare fee-for-service beneficiaries in the US found that the average total cost for a patient with dementia during the final five years of life was nearly $300,000. The out-of-pocket expenses during the final five years of life were approximately 80 times more for dementia patients when compared to those with heart disease or cancer [ 245 ]. Caretaking costs associated with dementia and Alzheimer’s in the US is not generally reimbursed by Medicare, and these costs often completely deplete the household wealth of the patient and/or family member caretakers. Unfortunately, no therapeutic cure is currently available, and few investigational new drugs are currently being tested as pharmaceutical companies have traditionally experienced frequent failures in attempts to find efficacy [ 186 246 ].

Late onset sporadic AD (LOAD) is the most prevalent form of AD and has the lowest identifiable link to genetics. Therefore, LOAD may be most sensitive to environmental factors, such as diet and DHA intake. This is especially true given that neuropathological changes occur decades before clinically identifiable cognitive deficits, providing a long window of time for the cumulative effects of environmental factors to affect the manifestation of the disease. Traditionally, clinical studies have focused on later stages of the disease, when the disease neuropathology appears to be intractable and resistant to therapeutic approaches. AD affects 32% of people over 85 years old [ 247 ], and age is the single greatest risk factor, suggesting that even AD can be considered normal physiological aging.

n -3) to DHA [ vs . preformed via diet). Recent data also suggests that AD patients have problems processing DHA [ Brain DHA composition likely plays a role in AD. The brains of non-DHA supplemented Alzheimer’s patients have 65–95 nmol/g of unesterified DHA, much less than normal controls (110 nmol/g; [ 248 249 ]). Furthermore, deficient liver biosynthesis of DHA has been observed in AD patients, where it appears that DHA biosynthesis halts at the last β-oxidation step from tetracosahexaenoic acid (24:6-3) to DHA [ 248 ]. However, this is likely a minimal source of DHA (. preformed via diet). Recent data also suggests that AD patients have problems processing DHA [ 61 ], therefore the magnitude of DHA’s effects may be less in later stages of the disease [ 250 ]. Phospholipids PC and PE from various brain regions (particularly hippocampus) in the AD brain have reduced DHA content compared to control brains, further implicating DHA in the etiology of the disease [ 251 252 ].

n -3 PUFAs and DHA with regards to risk and incidence of AD. Morris et al. [ n -3 PUFAs as compared to healthy individuals [ et al. [ et al. [ et al. [ et al. [ Observational studies are generally supportive of a preventative role of dietary-3 PUFAs and DHA with regards to risk and incidence of AD. Morris 253 ] found that one or more servings of fish per week (or about 200 mg of DHA) was associated with a 60% lower risk of developing AD and that total intake of DHA (but not EPA) was also a determinant of lower AD risk. Furthermore, patients with early stage AD reportedly have lower dietary intakes of-3 PUFAs as compared to healthy individuals [ 254 ]. Very recently, the AD Neuroimaging Initiative trial reported results in 229 normal, 397 MCI, and 193 AD patients assessed frequently over a two-year period. They found significant correlations between fish oil supplement use and lower brain atrophy in the hippocampus and cortical gray matter areas across all subjects [ 255 ]. There is some inconsistency in the reports of blood DHA levels in AD patients likely due to altered DHA pharmacology and bioavailability and the particular tissue or lipid fraction analyzed. One of the earlier reports indicated that total PL, PC and PE isolated from the plasma of subjects with AD, dementia, or cognitive impairment no dementia (CIND) contained less DHA than found in healthy elderly controls [ 256 ]. Furthermore, Tully 257 ] reported that community-living elderly with AD had approximately half the serum concentrations of cholesteryl ester-DHA in comparison to non-dementia controls. These data also indicated that DHA and total saturated fatty acid levels were determinants of the clinical dementia rating. Wang 258 ] found that lower scores on the MMSE in mild and moderate AD patients were associated with lower erythrocyte DHA content. More recently, Lopez 259 ] evaluated an elderly cohort with an average age of 80 years-old for dementia and blood DHA levels. They reported that plasma DHA levels in the highest tertile had 65% reduced odds of all-cause dementia and a 60% reduced chance of AD, an effect that was recapitulated with dietary intake questionnaire data (highest tertile of DHA intake had 72% reduced odds of developing AD). Phillips 260 ] also found positive correlations between composite memory scores (verbal reasoning, contextual, visual, and verbal memory) and overall cognitive status with plasma PC-DHA content across a cohort of normal elderly, cognitive impairment no dementia, and AD subjects.

et al. had a DHA-alone group to assess any potential counteractive effects of ARA in the combination administration. Subsequently, initial results from the OmegAD study in 174 mild-to-moderate AD patients (mean age 74) provided 1720 mg DHA plus 600 mg EPA daily for six months found no changes in ADAS-cog, MMSE, or Alzheimer’s Prevention Initiative (API) tests [ N = 295), multi-center (51) study was reported by Quinn and colleagues [ versus placebo, indicating a potential genotype dependence for DHA’s effects in AD. Most recently, updated results have been described by the investigators of the OmegAD study where they have analyzed the levels of n -3 PUFAs present in the plasma acquired at baseline and after six months of the high-DHA supplement [ N = 33) from the OmegAD study [ RCTs investigating the therapeutic potential of DHA in improving the symptoms of AD are scarce and have mixed results at best. One of the first studies was performed by Kotani and colleagues [ 237 ], where they supplemented AD patients for 90 days with a daily dose of 240 mg DHA plus 240 mg ARA. This study found no significant changes in the repeatable battery for assessment of neuropsychological status test (RBANS; test five main cognitive domains). It would have been intriguing if Kotanihad a DHA-alone group to assess any potential counteractive effects of ARA in the combination administration. Subsequently, initial results from the OmegAD study in 174 mild-to-moderate AD patients (mean age 74) provided 1720 mg DHA plus 600 mg EPA daily for six months found no changes in ADAS-cog, MMSE, or Alzheimer’s Prevention Initiative (API) tests [ 261 262 ]. However, in this early report of the OmegAD study, they did discover that a small subset of AD patients with milder cognitive dysfunction had lower declines in MMSE scores after supplementation. The next reported study was a small preliminary RCT that dosed AD patients for 24 weeks with a daily supplement containing 720 mg of DHA and 1080 mg of EPA. It reported improvements in the Clinician’s Interview-Based Impression of Change Scale (CIBIC-plus), but not the ADAS-cog score [ 238 ]. Subsequently a large (= 295), multi-center (51) study was reported by Quinn and colleagues [ 250 ], where they provided approximately 1000 mg of algal DHA daily for 18 months to patients with mild to moderate AD. They did not detect any differences in ADAS-cog or clinical dementia rating, suggesting that DHA is likely more effective as a prophylactic rather than a therapeutic treatment for AD. Interestingly, DHA-treated subjects in the ApoE4 negative subgroup had less decline in ADAS-cog and MMSE over timeplacebo, indicating a potential genotype dependence for DHA’s effects in AD. Most recently, updated results have been described by the investigators of the OmegAD study where they have analyzed the levels of-3 PUFAs present in the plasma acquired at baseline and after six months of the high-DHA supplement [ 263 ]. They report that increasing plasma levels of DHA in these AD patients was tied to preservation of cognition as measured by ADAS-cog scores. Higher concentrations of plasma DHA resulted in a lower rate of cognitive decline, an effect that was similar across genders. Cerebrospinal fluid (CSF) measures were also obtained in a small group of patients (= 33) from the OmegAD study [ 264 ]. The patients in the treatment group had significant increases in the concentration of DHA in the CSF, and these concentrations were inversely correlated to CSF levels of tau (total and phosphorylated) and directly proportional to CSF levels of interleukin (IL)-1 receptor type II (anti-inflammatory effect). Tau levels are elevated during the prodromal phase (total tau) and clinical phase (phosphorylated tau) of AD, and these intriguing results suggest that DHA may be able to mitigate this increase to some extent.