Durga 2007.

Methods	2‐arm, placebo‐controlled, randomised clinical trial, with 3‐year duration of treatment
Participants	Location: Gelderland region in the Netherlands, single centre Recruitment: Division of Human Nutrition, Wageningen University, Wageningen, Netherlands Number randomised: 406 in intervention, 413 in comparison Participant baseline characteristics: Age at baseline (years), mean (SD): placebo: 60 (6) folic acid: 60 (5) Male, n (%): placebo: 292 (70%) folic acid: 294(72%) MMSE (points): placebo: 29 (28‐30) folic acid: 29(28‐30) Inclusion criteria: Participants were men and post‐menopausal women aged 50–70 years. More than 80% self‐reported compliance during a 6‐week placebo run‐in period was required. Exclusion criteria: homocysteine concentration less than 13 micromol/L and greater than 26 micromol/L self‐reported medical diagnosis of renal or thyroid disease self‐reported use of medications that influence folate metabolism participants reportedly used B vitamin supplements or drugs that could affect atherosclerotic progression
Interventions	Intervention (n = 405): 800 μg per day folic acid. Comparator group (n = 413): placebo
Outcomes	Cognitive outcomes: 5 cognitive tests were used: word learning test, concept shifting test, Stroop colour‐word test, verbal fluency test, letter digit substitution test These 5 tests were used to construct 5 a priori defined cognitive domains using z‐scores: memory, sensorimotor speed, complex speed, information processing speed, and word fluency Outcomes used in this review were: Global cognitive function (average of 5 domains); Episodic memory: Memory (Z15‐Word Learning test ‘total immediate recall’+Z15‐Word Learning Test ‘maximum immediate recall’+Z15‐Word Learning Test ‘delayed recall’)/3) Executive function: Word fluency (ZVerbal Fluency test) Speed of processing: Information processing speed (ZLetter Digit Substitution test )
Notes	Funding sources: The research was funded by a grant from the Netherlands Organisation for Health Research and Development (ZonMw, grant number 20010002), Wageningen University, and Wageningen Centre for Food Sciences. Wageningen Centre for Food Sciences is an alliance of major Dutch food industries, research institutes and the Dutch government. Wageningen Centre for Food Sciences does long‐term strategic research for the development of new and innovated food with attention to health aspects. Declarations of interest: Jane Durga currently works at Nestle Research Center in Lausanne, Switzerland and Petra Verhoef currently works at the Unilever Food and Health Research Institute in Vlaardingen, the Netherlands. The work at both food companies entails examining the health benefits of a variety of food ingredients, including folic acid. However, the study reported in the current manuscript was completed and submitted to The Lancet before the authors joined the companies, when they were still employed by Wageningen University and Wageningen Centre for Food Sciences. All authors declare that they have no conflict of interest.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "Patients were allocated treatment or placebo with permuted blocks of sizes four and six, which varied randomly. Specialised staff who were not involved in the study allocated and labelled the capsule boxes with participants’ unique sequence number. Participants in the same household received the same treatment." Comment: Method of sequence generation was not reported.
Allocation concealment (selection bias)	Low risk	Quote: "Specialized staff who were not involved in the study allocated and labelled the capsule boxes with participants’ unique sequence number". Comment: appropriate allocation concealment
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "The folic acid and placebo capsules ... were indistinguishable in appearance". 70% of participants in the folic acid group and 71% in the placebo group thought they had been allocated to folic acid. Comment: well blinded
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Comment: All staff, including all authors, were unaware of group assignment until completion of the trial and after data analyses. Quote: outcome assessment well blinded
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: 17 participants lost to follow‐up were assigned the median test score of the total population at the end of the study. Comment: Although there were imputations, the small proportion of loss to follow‐up unlikely to affect results.
Selective reporting (reporting bias)	Unclear risk	Quote: From clinicaltrials.gov: "Cognitive performance at year 3 (cognitive domains: simple speed, cognitive flexibility, and memory; and information processing speed and semantic memory)". Comment: unclear if the domains reported were prespecified (authors were contacted for further information)
Other bias	Low risk	No other risks detected