Computer-assisted cognitive training (three studies)

All three studies were probably underpowered so although results were not promising there was insufficient evidence to draw conclusions about its efficacy. Only Barnes et al ^{Reference Barnes, Yaffe, Belfor, Jagust, DeCarli and Reed18} specified primary outcomes (validity score: 4). They evaluated a programme that involved distinguishing between similar sounding words and matching sentences with pictures, for 100 min daily, 5 days a week. The control group listened to audio books, read an online newspaper and played a computer game. There was no significant difference between groups on the primary outcome, the Repeatable Battery for Assessment of Cognitive Status (RBANS) after 6 weeks (Fig. 3). The only significant difference, favouring the intervention, was on the delayed memory RBANS subscale (SMD = 0.53, 95% CI 0.05-1.10).

Two studies tested computer-assisted training, but did not specify primary outcomes. Finn & McDonald ^{Reference Finn and McDonald55} evaluated a 2-month programme in a higher-quality study (validity score: 4), and Rozzini et al ^{Reference Rozzini, Costardi, Chilovi, Franzoni, Trabucchi and Padovani47} a 9-month programme (validity score: 3). In both studies, most results were not significant; only results for the visual attention CANTAB (Cambridge Automated Neuropsychiatric Test Assessment Battery) subscale ^{Reference Finn and McDonald55} and short story recall ^{Reference Rozzini, Costardi, Chilovi, Franzoni, Trabucchi and Padovani47} favoured the interventions (Table DS2).

Summary. Global cognition did not improve with cognitive training in two trials, ^{Reference Barnes, Yaffe, Belfor, Jagust, DeCarli and Reed18,Reference Rozzini, Costardi, Chilovi, Franzoni, Trabucchi and Padovani47} in one of which it was a primary outcome, and there were no consistently significant findings on other secondary outcomes. Studies were all underpowered.

Longer-term group psychological interventions (two studies)

Two lower-quality studies tested 6-month group interventions. Results were conflicting. Buschert et al ^{Reference Buschert, Friese, Teipel, Schneider, Merensky and Rujescu19} (validity score: 3 and with primary outcomes specified) tested a manualised memory training and cognitive stimulation programme, consisting of 20 2 h weekly group sessions comparing 10 people in the intervention group with 12 in the control group. The memory training used mnemonics, calendars, notes and prompts; face-name association and errorless learning. In errorless learning, information was repeated frequently to avoid recall mistakes, with repetitions becoming further apart with successful recalls (spaced retrieval). The programme also included reminiscence, psychomotor and recreational tasks (for example playing with balloons), multisensory stimulation and social interaction. Participants did homework, which carers were encouraged to support. The control group met monthly and did paper-and-pencil exercises. Only participants who attended at least half of sessions were included in analyses. Global cognition, the primary outcome, improved in the intervention group in our univariate (Table DS1) and the authors' analyses that controlled for baseline score, age and educational status on both primary outcome measures. Montgomery-Åsberg Depression Rating Scale scores were also lower in the intervention compared with the control group adjusting for these factors (mean 0.7 (s.d. = 1.3) for treatment group and 3.8 (s.d. = 6.1) for controls, F(1,18) = 8.8, P<0.01).

Troyer et al, ^{Reference Troyer, Murphy, Anderson, Moscovitch and Craik24} in a small study (validity score: 1), evaluated 10 2 h sessions, including psychoeducation, recreation, memory training and strategies, relaxation and directing to community resources. The authors found no significant differences between groups post-intervention on several measures of recall (Table DS4).

Summary.

1. (a) Twenty sessions of memory training, reminiscence, cognitive stimulation, psychomotor recreation and social interaction improved global cognition on a primary outcome in a single, very small, 6-month placebo-controlled trial that did not carry out an intention-to-treat analysis. ^{Reference Buschert, Friese, Teipel, Schneider, Merensky and Rujescu19}

2. (b) Ten sessions of memory training, psychoeducation and relaxation did not improve recall on secondary outcomes in one small 6-month trial. ^{Reference Troyer, Murphy, Anderson, Moscovitch and Craik24}

Short-term (6-week) psychological group interventions (two studies)

Both studies were lower quality (validity score: 2) and were underpowered so although neither improved memory there was insufficient evidence to reject this intervention type. Unverzagt et al ^{Reference Unverzagt, Kasten, Johnson, Rebok, Marsiske and Koepke14} specified primary outcomes and compared three interventions, all of ten sessions teaching specific cognitive strategies, with a no-treatment control. The interventions were: memory training strategies; reasoning training; and processing speed training. Booster training was provided to 60% of participants, approximately 11 months later. Memory training participants did not improve post-intervention, or 1 or 2 years later on the composite memory measure v. those receiving no treatment (SMD = −0.01, 95% CI −0.18 to −0.10, P>0.05). Participants receiving the processing speed intervention improved on processing speed (SMD = −1.4, 95% CI −1.1 to −0.8, P<0.001) and the reasoning group participants improved on reasoning post-intervention (SMD = 0.57, P<0.001) and 2 years (SMD = 0.28, P<0.05), but not 1 year later (SMD = 021, P>0.05), compared with those receiving no treatment.

Rapp et al ^{Reference Rapp, Brenes and Marsh46} did not specify primary outcomes. They evaluated six weekly 2 h sessions, of psychoeducation, relaxation, memory strategies (cueing, categorisation, chunking, method of loci) and homework. Participants received a manual, which was also sent to the control group who otherwise had no treatment. There were no significant differences between groups on several memory measures, post-intervention or 6 months later.

Summary.

1. (a) Memory did not improve over 6 weeks in two short-term, underpowered group intervention trials teaching memory strategies, which were not placebo-controlled. ^{Reference Unverzagt, Kasten, Johnson, Rebok, Marsiske and Koepke14,Reference Rapp, Brenes and Marsh46}

2. (b) Specific interventions to improve reasoning and processing speed respectively significantly improved these primary outcomes, in an underpowered single, non-placebo-controlled trial. ^{Reference Unverzagt, Kasten, Johnson, Rebok, Marsiske and Koepke14}

Family psychological interventions (one study)

This lower-quality study indicated that a family psychological intervention might improve prospective memory. Kinsella et al ^{Reference Kinsella, Mullaly, Rand, Ong, Burton and Price20} (validity score: 2) compared a course of five weekly 1.5 h family intervention sessions to a waiting list control. Sessions involved problem-solving everyday memory difficulties and practising possible strategies. Written session material was provided. Results on the primary outcome, an unvalidated (to our knowledge) prospective memory test favoured the intervention 2 weeks and 4 months post-intervention, controlling for baseline scores and age; the SMD for this comparison was not significant in our univariate analysis (Fig. 2).

Summary. Prospective memory improved up to 4 months later in this underpowered trial that was not placebo-controlled, on a non-validated measure, but only when baseline memory scores were taken into account. ^{Reference Kinsella, Mullaly, Rand, Ong, Burton and Price20}

Individual psychological interventions (one study)

This lower-quality study (validity score: 3) found that an individual psychological intervention did not improve memory. Jean et al ^{Reference Jean, Simard, Wiederkehr, Bergeron, Turgeon and Hudon53} evaluated six individual 45 min sessions over 3 weeks, focusing on errorless learning of picture-name associations with spaced retrieval (see earlier). In the control condition, the pictures were presented without spaced retrieval. Participants were given written information about memory. The unvalidated primary outcomes evaluated the number of unknown faces (episodic memory) and famous names (semantic memory) matched correctly. There was no significant treatment effect on these measures in mixed-linear models (F(2,35) = 49.390, F(2,35) = 11569), or on Mini-Mental State Examination (MMSE).

Summary. Six individual sessions of errorless learning and spaced retrieval did not improve prospective memory in one placebo-controlled, underpowered study where this was a primary outcome. ^{Reference Jean, Simard, Wiederkehr, Bergeron, Turgeon and Hudon53}

Exercise

Exercise has been associated with favourable effects on neuronal survivability and function, neuroinflammation, vascularisation, neuroendocrine response to stress and brain amyloid burden. It also improves cardiovascular health, which is associated with cognitive health. ^{Reference Baker, Frank, Foster-Schubert, Green, Wilkinson and McTiernan17}

Group exercise programmes (two studies). Results from two studies comparing year-long, twice-weekly, group-based exercise programmes to active control conditions were mixed. In a very high-quality study (validity score: 5), van Uffelen et al ^{Reference van Uffelen, Chinapaw, van and Hopman-Rock38,Reference van Uffelen, Chin, Hopman-Rock and van Mechelen54} compared a moderate-intensity walking programme to low-intensity relaxation, balance and flexibility exercises, and found no significant effect in any cognitive domain, including the primary outcome of immediate word recall (Fig. 2) or in quality of life. In a lower-quality study (validity score: 3; no primary outcomes specified), Suzuki et al ^{Reference Suzuki, Shimada, Makizako, Doi, Yoshida and Tsutsumimoto42} compared groups involving circuit training and some outdoor walking with a control group who attended three health promotion classes. The intervention group improved in terms of MMSE score, immediate memory and verbal fluency (Table DS2).

Individual exercise programmes (three studies). None of these lower-quality studies specified primary outcomes. Busse et al ^{Reference Busse, Filho, Magaldi, Coelho, Melo and Betoni26} (validity score: 3) evaluated 9 months of resistance exercises, for 1 h twice a week. Scores on a test of everyday memory (Rivermead Behaviour Memory Test) improved in the intervention group relative to the no-treatment controls, but CAMCog (Cambridge Cognition Examination) scores and digit span did not.

The remaining two studies had validity scores of 2. Baker et al ^{Reference Baker, Frank, Foster-Schubert, Green, Wilkinson and McTiernan17} compared cognition in adults exercising less than 90 min weekly participating in a 6-month high-intensity aerobic exercise intervention or a stretching and balance exercise control. Each intervention was for 1 h 4 days a week. The first eight sessions, and thereafter one session a week, were supervised. Adherence was monitored. Significant between-group effects, favouring the intervention, were reported on the Digit Symbol Substitution Test (DSST) (attention and processing speed), trail making test B and verbal fluency (Table DS2). For verbal fluency, effects were more apparent for category than letter fluency (letter, P = 0.20, category, P = 0.03). Scherder et al ^{Reference Scherder, Van, Deijen, Van Der Knokke, Orlebeke and Burgers41} compared: assisted walking for 30 min, 3 days a week for 6 weeks; hand and face exercises for the same duration; and a control group, half of whom received additional social visits. The only significant between-group differences, all in favour of the interventions, were on the category fluency and trail making tests (Table DS2).

Summary.

1. (a) A very high-quality study found that memory, the primary outcome, did not improve with a year-long aerobic exercise group compared with a relaxation, balance and flexibility exercise active control group. ^{Reference van Uffelen, Chinapaw, van and Hopman-Rock38,Reference van Uffelen, Chin, Hopman-Rock and van Mechelen54} A lower-quality study found that participants in a similar intervention improved on fluency, memory and global cognition relative to a health promotion control. ^{Reference Suzuki, Shimada, Makizako, Doi, Yoshida and Tsutsumimoto42}

2. (b) The studies of individual exercise studies were low quality and their results were inconsistent. ^{Reference Baker, Frank, Foster-Schubert, Green, Wilkinson and McTiernan17,Reference Busse, Filho, Magaldi, Coelho, Melo and Betoni26,Reference Scherder, Van, Deijen, Van Der Knokke, Orlebeke and Burgers41} Category fluency and trail-making test scores improved with individual aerobic exercise on secondary outcomes in two studies, of 6 weeks and 6 months duration, but no other cognitive outcomes improved in more than one study.

Cholinesterase inhibitors (nine studies)

Three large studies compared donepezil 10 mg daily to placebo, and results were inconsistent. The highest-quality one (validity score: 5) by Doody et al ^{Reference Doody, Ferris, Salloway, Sun, Goldman and Watkins15} was a 48-week study that included two primary outcome measures: ADAS-Cog, on which results favoured donepezil, and the Clinical Dementia Rating (CDR) on which there was no significant between-group difference (Fig. 2). On secondary outcomes, only patient global assessment differed significantly between groups, in favour of donepezil. The two other large studies were higher-quality studies (validity score: 4). Salloway et al ^{Reference Salloway, Ferris, Kluger, Goldman, Griesing and Kumar48} carried out a 24-week, adequately powered study and there were no significant differences between donepezil and placebo on the primary outcomes, the New York University Paragraph Delayed Recall test or the Clinician Global Impression of Change (CGIC), or on any secondary outcomes except for the ADAS-Cog. Petersen et al ^{Reference Petersen, Thomas, Grundman, Bennett, Doody and Ferris45} found no significant difference between groups on conversion to Alzheimer's disease, the primary outcome (Fig. 3) or any other measures over 3 years. One small, lower-quality study (validity score: 1) that did not identify primary outcomes found that donepezil and antidepressant treatment improved immediate memory but not other cognitive outcomes, compared with antidepressants alone. ^{Reference Pelton, Harper, Tabert, Sackeim, Scarmeas and Roose27}

Galantamine was investigated in three trials, and results on primary outcomes in the highest-quality trials were not significant. Winblad et al ^{Reference Winblad, Gauthier, Scinto, Feldman, Wilcock and Truyen51} evaluated galantamine, titrated to 12 mg twice daily in two large, high-quality, 24-month, placebo-controlled RCTs (validity scores 5). Neither reported a significant effect on the primary outcome, incident dementia (developing dementia in intervention 22.9% v. control group 22.6%, P = 0.15, 25.4% v. 31.2%, P = 0.62). On secondary measures, statistical comparisons favoured galantamine in one of the two studies for global functioning (measured on the CDR) and attention (DSST). In a small, lower-quality trial, Koontz & Baskys ^{Reference Koontz and Baskys22} only reported significant between-group differences on two subscales of the CANTAB, both measuring executive functioning (Table DS2).

One high-quality study (validity score: 5), by Feldman et al ^{Reference Feldman, Ferris, Winblad, Sfikas, Mancione and He31} compared 3-12 mg daily of rivastigmine and placebo. There were no significant differences between participants on any measures over 2 years, including the primary outcome, progression to Alzheimer's disease (Fig. 3).

Finally, Rozzini et al ^{Reference Rozzini, Costardi, Chilovi, Franzoni, Trabucchi and Padovani47} compared people receiving any cholinesterase inhibitor to those taking placebo after 1 year in a lower-quality study (validity score: 2). There were no significant between-group differences on any measures (Table DS4).

Summary.

1. (a) Incident Alzheimer's disease was not reduced in four, higher-quality trials where this was the primary outcome - two evaluated galantamine, one donepezil, and one rivastigmine. ^{Reference Feldman, Ferris, Winblad, Sfikas, Mancione and He31,Reference Petersen, Thomas, Grundman, Bennett, Doody and Ferris45,Reference Winblad, Gauthier, Scinto, Feldman, Wilcock and Truyen51}

2. (b) Donepezil improved global cognition in one high-quality trial where it was a primary outcome measure, ^{Reference Doody, Ferris, Salloway, Sun, Goldman and Watkins15} and a second where it was a secondary outcome, ^{Reference Salloway, Ferris, Kluger, Goldman, Griesing and Kumar48} but global cognition did not improve in the five other large, high-quality trials of cholinesterase inhibitors. ^{Reference Feldman, Ferris, Winblad, Sfikas, Mancione and He31,Reference Petersen, Thomas, Grundman, Bennett, Doody and Ferris45,Reference Rozzini, Costardi, Chilovi, Franzoni, Trabucchi and Padovani47,Reference Winblad, Gauthier, Scinto, Feldman, Wilcock and Truyen51}

3. (c) Donepezil did not improve global functioning in one trial where this was a primary outcome. ^{Reference Doody, Ferris, Salloway, Sun, Goldman and Watkins15} Galantamine improved global functioning in one trial on a secondary outcome measure. ^{Reference Winblad, Gauthier, Scinto, Feldman, Wilcock and Truyen51}

4. (d) Galantamine improved executive functioning and attention on secondary outcome measures in a single trial. ^{Reference Winblad, Gauthier, Scinto, Feldman, Wilcock and Truyen51}

5. (e) Donepezil as an adjunct to antidepressants improved immediate memory, also on a secondary outcome. ^{Reference Pelton, Harper, Tabert, Sackeim, Scarmeas and Roose27}

Piribedil (one study)

Piribedil is a dopamine receptor agonist. Animal models have suggested acetylcholine release in hippocampi and the frontal cortex as a putative mechanism of action. Nagaraja & Jayashree ^{Reference Nagaraja and Jayashree23} evaluated this over 3 months in a higher-quality trial (validity score: 4) with 30 in each group, all with a MMSE of 21-25; the primary outcome, response on the MMSE (predefined as a score of 26+), favoured piribedil (Fig. 5). Mean MMSE change from baseline also favoured the intervention group (t = 283, P<0.01). It was well tolerated.

Summary. Pirbidel improved cognition over 3 months on a primary outcome in one small placebo-controlled study. ^{Reference Nagaraja and Jayashree23}

Nicotine (one study)

Brain nicotinic receptors are important for cognitive function. ^{Reference Newhouse, Kellar, Aisen, White, Wesnes and Coderre21} Newhouse et al ^{Reference Newhouse, Kellar, Aisen, White, Wesnes and Coderre21} compared transdermal nicotine (titrated to a 15 mg patch/day) to placebo in a very high-quality study (validity score: 5, with primary outcomes specified). Attention, measured on the Connors Cognitive Performance Test improved (F = 4.89, P = 0.031, effect size 078) but global functioning on the CGIC did not, on mixed-models repeated-measures analyses of variance. On secondary outcome measures, the treatment group showed less forgetting in between immediate and delayed recall than placebo (F = 4.42, P = 0.04), better delayed word recall (F = 5.92, P = 0.018) and less anxiety on the older Adult Self Report worries and anxiety subscales (F = 3.48, P = 0.04; F = 3.14, P = 0.05).

Summary. Nicotine patches improved attention, but not global functioning, over 6 months on primary outcomes in one, high-quality study. ^{Reference Newhouse, Kellar, Aisen, White, Wesnes and Coderre21} Delayed recall and self-reported anxiety improved on secondary outcomes.

Huannao Yicong (one study)

Li et al ^{Reference Li, Yao, Zhao, Guan, Cai and Cui28} evaluated this Chinese medicinal compound, which includes ginseng, in a study that identified primary outcomes but was low quality (validity score: 0). Increases or changes in hippocampal mitochondria have been proposed as mechanisms of action. Over 2 months, comparisons favoured the intervention on the primary outcome, response (improvement of 6+ points) on the Cognitive Effect Index (CEI), which comprised the MMSE, Cognitive Capacity Screening Examination (CCSE) and a social functioning scale (Short-Form (SF)-36, Chinese version). We found that the mean difference in CEI scores between groups post-treatment was not significant (Table DS1). The analyses excluded people who did not take their medication.

Summary. Results in one low-quality trial were equivocal: more participants taking Huannao Yicong than placebo responded on a cognition and social functioning measure, but the mean difference between groups on this measure was not significant. ^{Reference Li, Yao, Zhao, Guan, Cai and Cui28}

Gingko biloba (two studies)

Results from these studies were inconsistent, but the highest-quality trials suggested it is ineffective. Proposed mechanisms of action of Gingko biloba include increasing brain blood supply, reducing blood viscosity, modifying neurotransmitter systems, and reducing oxygen free radical density. ^{Reference Birks and Evans56} A very high-quality study (validity score: 5, published in two papers: deKosky et al ^{Reference DeKosky, Williamson, Fitzpatrick, Kronmal, Ives and Saxton35} and Snitz et al ^{Reference Snitz, O'Meara, Carlson, Arnold, Ives and Rapp57} ) found that 240 mg daily, taken for a median of 6.1 years, did not reduce incident dementia or Alzheimer's disease. In a lower-quality (validity score: 3), 6-month study that was not placebo controlled, Zhao et al ^{Reference Zhao, Dong, Yu, Xiao and Li25} reported that participants prescribed 56.7 mg daily Gingko biloba performed better than those receiving no treatment on nonsense picture recognition and logical memory tests (Fig. 3).

Summary. On primary outcomes, 240 mg daily Gingko biloba did not reduce incident dementia in a very high-quality trial over 6 years; ^{Reference DeKosky, Williamson, Fitzpatrick, Kronmal, Ives and Saxton35,Reference Snitz, O'Meara, Carlson, Arnold, Ives and Rapp57} whereas 56.7 mg daily improved cognition in a second trial compared with usual treatment. ^{Reference Zhao, Dong, Yu, Xiao and Li25}

NSAIDs (two studies)

Non-steroidal anti-inflammatory drugs reduce brain neurotoxic inflammatory responses, so could improve cognition. ^{Reference Weggen, Eriksen, Das, Sagi, Wang and Pietrzik58} Thal et al, ^{Reference Thal, Ferris, Kirby, Block, Lines and Yuen49} in a very high-quality large study (validity score: 5), found significantly more incident cases of Alzheimer's disease over 4 years in participants randomised to 25 mg daily of rofecoxib (a COX-2 inhibitor) than those taking placebo (Fig. 4). There was no significant difference between groups on secondary outcomes. In 2003, rofecoxib was withdrawn due to cerebrovascular and cardiovascular side-effects.

Gomez-Isla et al ^{Reference Gomez-Isla, Blesa, Boada, Clarimon, Del and Domenech44} evaluated 900 mg a day of triflusal, a COX-1 and COX-2 inhibitor in a lower-quality study (validity score: 3), which was terminated early. It found no significant difference between groups on the primary cognitive outcome, ADAS-Cog (Fig. 2). The only significant finding on secondary outcomes was a lower rate of conversion to Alzheimer's disease in the intervention group (HR = 210, 95% CI 1.10-4.01, P = 0.024).

Summary.

1. (a) Rofecoxib increased incident cases of Alzheimer's disease in one very high-quality study on a primary outcome. ^{Reference Thal, Ferris, Kirby, Block, Lines and Yuen49}

2. (b) One trial of triflusal reported no significant effect on cognition on a primary outcome measure, although it was associated with a reduced risk of conversion to Alzheimer's disease on a secondary outcome. ^{Reference Gomez-Isla, Blesa, Boada, Clarimon, Del and Domenech44}

B vitamins (two studies)

Higher homocysteine plasma concentrations are associated with cognitive impairment; levels are decreased by B vitamins. Two placebo-controlled trials investigated the effectiveness of B vitamins (folic acid, B₁₂ and B₆). In a very high-quality study (validity score: 5 and primary outcome specified), van Uffelen et al ^{Reference van Uffelen, Chinapaw, van and Hopman-Rock38} found no significant difference on the primary outcome of immediate memory over 6 months. On secondary outcomes, the group taking vitamins performed better than the placebo group on the DSST (attention and processing speed; longitudinal regression, coefficient not given, P = 0.02). De Jager et al ^{Reference de Jager, Oulhaj, Jacoby, Refsum and Smith30} found in a lower-quality (validity score: 3), 2-year study that executive functioning improved relative to placebo (Table DS2).

Summary. Immediate memory did not improve in a high-quality study in which this was primary outcome. ^{Reference van Uffelen, Chinapaw, van and Hopman-Rock38} Out of numerous secondary measures, attention improved in one trial and executive functioning in another, ^{Reference de Jager, Oulhaj, Jacoby, Refsum and Smith30} so results were inconsistent.

Vitamin E (two studies)

One large, higher-quality trial (validity score: 4) reported by Petersen et al ^{Reference Petersen, Thomas, Grundman, Bennett, Doody and Ferris45} found no significant treatment effect of vitamin E (2000 IU) on the primary outcome measure, progression to Alzheimer's disease or on a range of secondary outcomes over 3 years. Zhou et al ^{Reference Zhou, Lin and Yuan50} reported in a lower-quality study (validity score: 1) that participants receiving vitamin E 500 mg daily improved v. placebo on picture recognition (Table DS2).

Summary.

1. (a) Vitamin E did not reduce incident dementia in one high-quality study on a primary outcome. ^{Reference Petersen, Thomas, Grundman, Bennett, Doody and Ferris45}

2. (b) In a lower-quality study 500 mg daily was associated with improvement in picture recognition, a secondary outcome. ^{Reference Zhou, Lin and Yuan50}

Omega-3 polyunsaturated fatty acids (two studies)

Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are dietary polyunsaturated fatty acids (PUFA), which have structural and functional roles in the brain. Both these studies had validity scores of 3. Chiu et al ^{Reference Chiu, Su, Cheng, Liu, Chang and Dewey29} found that, as primary outcomes, ADAS-Cog improved over 6 months in people taking 1080 mg EPA and 720 mg DHA v. placebo after adjusting for age, gender and education, but no differences were reported on the Clinician's Interview-Based Impression of Change (CIBIC-plus, global functioning). When we calculated SMD for ADAS-Cog at follow-up between groups, there were no significant differences (Table DS1).

Sinn et al ^{Reference Sinn, Milte, Street, Buckley, Coates and Petkov34} in a small study compared groups receiving EPA-rich fish oil (1670 mg EPA and 160 mg DHA) and DHA-rich fish oil (1550 mg DHA and 400 mg EPA) with a placebo group. Using a linear-mixed model analysis, letter fluency scores significantly improved over 6 months in the DHA group v. placebo, and depressive symptoms, measured using the Geriatric Depression Score, were reduced in both groups (Table DS2).

Summary.

1. (a) Cognition improved on a primary outcome in one study, but only after adjusting for age, gender and education. ^{Reference Chiu, Su, Cheng, Liu, Chang and Dewey29}

2. (b) Verbal fluency improved with DHA-rich fish oil and depressive symptoms were reduced by DHA- and EPA-rich oil after 6 months in a single small study on secondary outcome measures. ^{Reference Sinn, Milte, Street, Buckley, Coates and Petkov34}