Shinto 2014.

Methods	3‐arm (omega‐3; placebo, parallel group, alpha lipoic acid) placebo‐controlled, double‐blind, randomised controlled trial The arm with alpha lipoic acid was not included in this review; trial duration from April 2004 to December 2009.
Participants	Country: USA Diagnosis: probable AD (NINCDS‐ADRDA criteria) Follow‐up: 12 months Inclusion criteria: probable AD; aged ≥ 55 years, MMSE score 15‐26, Clinical Dementia Rating Scale 0.5‐1.0, not depressed (Center for Epidemiological Studies of Depression Score < 4.0) Exclusion criteria: non‐AD dementia; residence at long‐term care facility at screening visit; history of clinically significant stroke; health conditions such as cancer (prostate cancer Gleason grade < 3 and non‐metastatic cancers were acceptable), liver disease, history of ventricular fibrillation or ventricular tachycardia, major psychiatric disorder, major central nervous system diseases (e.g. brain tumour, seizure disorder); taking lipid‐lowering medication; hyperlipidaemia (triglycerides > 500 mg/dL, low‐density lipoprotein > 160 mg/dL, total cholesterol > 240 mg/dL); fish oil or cod liver oil supplementation within 30 days of enrolment; > 1 x 6 ounce (150 g) serving per week of fish or seafood within 30 days of enrolment; lipoic acid supplementation within 30 days of enrolment; taking systemic corticosteroids, neuroleptics, antiparkinsonian agents or narcotic analgesics Acetylcholinesterase inhibitors, memantine, vitamin E and ginkgo biloba were allowed if stable for 4 months prior to study enrolment Total number of participants: 39 (13 in omega‐3 PUFA group, 13 in alpha lipoic acid group, 13 in placebo group) Per‐protocol population: 34 (11 in omega‐3 PUFA group, 12 in alpha lipoic acid group, 11 in placebo group) Baseline characteristics: age (SD) years: omega‐3 PUFA 75.9 (8.1); placebo 75.2 (10.8) female sex: omega‐3 PUFA 62%; placebo 54% (based on data provided by Dr. Shinto) college or greater: omega‐3 PUFA 39%; placebo 54% MMSE, mean (SD): omega‐3 PUFA 20.7 (2.7); placebo 22.2 (3.1) DHA in % of total in red blood cell membranes (SD): omega‐3 PUFA 5.1 (1.3); placebo 4.4 (1.0) EPA in % of total in red blood cell membranes (SD): omega‐PUFA 0.6 (0.2); placebo 0.6 (0.1) body mass index, kg/m2 (SD): omega‐3 PUFA 26.2 (4.5); placebo 23.8 (3.1) use of cholinesterase inhibitors or memantine: omega‐3 PUFA 92%; placebo 77% use of memantine, number (%): omega‐3 PUFA 139 (58.4%); placebo 104 (63.4%)
Interventions	Intervention 1: 1 placebo tablet (replacing alpha lipoic acid) in the morning, 2 placebo capsules (replacing omega‐3 PUFA) in the morning and 1 in the afternoon with food. Placebo for omega‐3 contained soybean oil with 5% fish oil and lemon flavour Intervention 2: omega‐3 PUFA capsules (fish oil concentrate in the triglyceride form at 3 g/day, daily dose of DHA 675 mg and EPA 975 mg, flavoured with lemon), 2 capsules in the morning with food, 1 capsule in the evening with food. 1 placebo tablet (replacing alpha lipoic acid) was additionally given in the morning Intervention 3: alpha lipoic acid 600 mg/day in 1 tablet and 2 omega‐3 capsules in the morning with food, 1 omega‐3 capsule in the afternoon with food (daily dose of DHA 675 mg and EPA 975 mg) Treatment duration: 12 months Only data of intervention 2 (omega‐3 PUFA) and intervention 1 (placebo) was included in this review
Outcomes	Primary: lipid oxidation measured as change in urine peripheral F2‐isoprostane levels (adjusted for creatinine) from baseline to 12 months Secondary: cognitive function measured with ADAS‐Cog, change from baseline to 12 months cognitive function measured with MMSE, change from baseline to 12 months OARS‐ADL/OARS‐IADL Questionnaire, change from baseline to 12 months (according to personal information from Dr. Shinto; in Shinto 2014 an other scale is cited) The primary outcome of the study was not included in this review (surrogate outcome). Adverse effects reported, but not assessed as outcome
Notes	Study registration number on ClincalTrials.gov, NCT00090402 The research was supported by the National Institutes of Health/National Institute of Aging (NIH/NIA) R21AG023805, NIH/NIA AG08017 and NIH General Clinical Research Grant M01RR00334. Nordic Natural, Watsonville, CA, USA, supplied the fish oil and placebo oil. There was no visible influence by industry in the planning phase, conducting phase or analysing process Statistical analysis by linear mixed‐effects model adjusted for age and education
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Participants were randomised by a computer generated scheme that was stratified by smoking status (current smoker versus nonsmoker) [...]" p. 3
Allocation concealment (selection bias)	Low risk	"Participants were randomized by a computer generated scheme that was stratified by smoking status (current smoker versus nonsmoker) as this would have the greatest impact on the primary outcome" p. 3
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"The study assessed the maintenance of blinding over 12 months by asking the participant's study partner, the participant, and all research staff involved in administering outcome measures about knowledge of group assignment at 12 months" p. 4 "When asked about treatment assignment at the end of the study, the majority reported no knowledge of treatment assignment: research staff (100%), AD participant (84%), participant study partner (81%)" p. 5
Blinding of outcome assessment (detection bias) All outcomes	Low risk	The study assessed the maintenance of blinding over 12 months by "asking […] all research staff involved in administering outcome measures about knowledge of group assignment at 12 months" p. 4 "When asked about treatment assignment at the end of the study, the majority reported no knowledge of treatment assignment: research staff (100%), AD participant (84%), participant study partner (81%)" p. 5
Incomplete outcome data (attrition bias) All outcomes	Low risk	Drop‐outs equally distributed in omega‐3 (1 death, 1 moved) and placebo group (1 death, 1 discarded). Missing data considered by mixed‐effects models
Selective reporting (reporting bias)	Low risk	Outcomes were congruent with trials protocol
Other bias	Low risk	Small baseline imbalance but we did not judge it relevant for this review Second author was named in Quinn 2010 as co‐inventor on a patent for DHA for the treatment of AD but waived rights to royalties related to this patent

AD: Alzheimer's disease; ADAS‐Cog: Alzheimer's Disease Assessment Scale ‐ Cognitive subscale; ADCS‐ADL: Alzheimer's Disease Cooperative Study ‐ Activities of Daily Living; ADL: activities of daily living; ADRDA: Alzheimer's Disease and Related Disorders Association; CDR‐SOB: Clinical Dementia Rating ‐ Sum of Boxes; DAD: Disability Assessment for Dementia; DHA: docosahexaenoic acid; EPA: eicosapentaenoic acid; IADL: instrumental activities of daily living; ITT: intention to treat; LOCF: last observation carried forward; MADRS: Montgomery‐Åsberg Depression rating scale; MMSE: Mini‐Mental State Examination; NINCDS: National Institute of Neurological and Communicative Disorders and Stroke; NPI: Neuropsychiatric Inventory; OARS‐ADL: Older Americans Resources and Services ‐ Activities of Daily Living; OARS‐IADL: Older Americans Resources and Services ‐ Instrumental Activities of Daily Living; SD: standard deviation.