van Uffelen 2008.

Methods	The FACT study (Folate physical Activity Cognition Trial). 2 x 2 factorial, randomised controlled trial (RCT) comparing the effects of (1) a walking programme with a placebo activity programme, and (2) vitamin B supplementation with placebo supplementation over 1 year.
Participants	Location: Netherlands. Setting of recruitment and treatment: Community setting in a Dutch town. Sample size: Number randomised: 90 in intervention, 89 in comparison. Number completed: 71 in intervention, 67 in comparison. Participant baseline characteristics: Age (mean (SD)): Men vitamin B (n = 44) = 75 (2.7); Men placebo (n = 41) = 74 (2.9); women vitamin B (n = 34) = 76 (2.9); women placebo (n = 33) = 76 (2.9). MMSE (median (25th–75th percentile): Men vitamin B (n = 44) = 28 (28–29); men placebo (n = 41) = 29 (28–29); women vitamin B (n = 34) = 29 (29–30); women placebo (n = 33) = 29 (28–30). Inclusion criteria: Memory complaints (answer ‘‘yes’’ to question ‘‘do you have memory complaints’’, or at least twice answering ‘‘sometimes’’ on the Strawbridge cognition scale 26); Objective memory impairment (10 WLT delayed recall ≤5 and percentage savings ≤100)); Normal general cognitive function (TICS ≥ 19 and MMSE ≥ 24); Intact daily functioning (no report of disability in activities of daily living on GARS scale 30 except on the item ‘‘taking care of feet and toe nails’’); Absence of dementia; Being able to perform moderate intensity physical activity without making use of walking devices — for example, a rollator or a walking frame. Exclusion criteria: Using vitamin supplements/vitamin injections/drinks with folic acid, vitamins B‐12 and B‐6, comparable to the vitamin supplement given in the intervention; Suffering from epilepsy, multiple sclerosis, Parkinson’s disease, kidney disorder requiring haemodialysis, psychiatric impairment; Suffering from depression as measured by the Geriatric Depression Scale (cut off (5)); Using medication for rheumatoid arthritis or psoriasis which interfered with the vitamin supplement; Alcohol abuse (men 21 drinks a week, women 15 drinks a week); Currently living in a nursing home or on a waiting list for a nursing home.
Interventions	Active intervention: 5 mg folic acid, 0.4 mg vitamin B‐12 (cyanocobalamin) and 50 mg vitamin B‐6 (pyridoxine hydrochloride) once daily for a year. Comparator: Placebo.
Outcomes	Outcomes of interest in the review: Overall cognitive functioning: MMSE; Specific cognitive functioning subdomain: episodic memory: Auditory Verbal Learning Test (AVLT); Specific cognitive functioning subdomain: executive functioning: Stroop Colour Word Test‐Abridged (SCWT‐A), (also measured: letter fluency); Specific cognitive functioning subdomain: speed of processing: Digit Symbol Substitution Test (DSST); Quality of life: Dementia ‐ quality‐of‐life (D‐QOL), (also measured: health‐related QoL with SF‐12); Adverse events.
Source of Funding	Funded by Body@Work, Research Center Physical Activity, Work and Health, TNO‐VU University Medical Center. External financial support was obtained from the municipality of Alkmaar and the ‘‘Stichting Fonds voor het Hart’’. VIATRIS provided the FA/B12/B6 pills and placebo pills.
Declaration of Interest	"None of the external sources had input into protocol development, data collection, analyses, and interpretation or drafting this manuscript.
Notes	International Standard Randomised Controlled Trial Number Register (ISCTRN) 19227688
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: After the baseline interview, participants were randomised using the option ‘‘random sample of cases’’ in SPSS. Comment: Computer software used for randomisation leading to adequate sequence generation in the study.
Allocation concealment (selection bias)	Unclear risk	Quote: "Participants and exercise instructors were blinded to group allocation by being left unaware of which exercise programme was supposed to be effective. The pills were coded as A or B by the manufacturer. The key was decoded after data analysis". Comment: Further information required.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "Pills were coded A or B by manufacturer and then decoded only after data analysis". Comment: Participants and personnel were blinded to the intervention a participant received.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "All cognitive outcome measures were assessed by trained examiners, who were also blinded to group allocation". Comment: Low risk of detection bias as the examiners were blinded to group allocation.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: "For both interventions, data were analysed on a modified intention‐to‐treat basis, including participants with at least one post‐baseline assessment". Comment: All participants accounted for and data analysed from all participants with an intention‐to‐treat method.
Selective reporting (reporting bias)	Low risk	Quote: "The walking program and/or FA/B12/B6 supplementation were not effective in improving cognition within one year". Comment: The only outcome measure tested was cognitive function and this was included in the results.
Other bias	Low risk	No other potential biases detected.

^{AD: Alzheimer's disease
 ADAS‐cog: Alzheimer's Disease Assessment Scale ‐ cognitive
 ADCS: Alzheimer's Disease Cooperative Study
 ADL: Activities of Daily Living
 APOE ϵ4: Apolipoprotein‐E gene, ϵ4 allele
 AVLT: Auditory Verbal Learning Test
 CAMDEX: Cambridge Mental Disorders of the Elderly Examination
 CDR: Clinical Dementia Rating scale
 CIND: Cognitive Impairment ‐ no dementia
 CLOX: Clock drawing executive test
 CrPic: Chromium picolinate
 CT: Computerised tomography
 CVLT: California Verbal Learning Test
 D‐QOL: Dementia Quality of Life questionnaire
 DSM‐IV: Diagnostic and Statistical Manual of Mental Disorders, 4th Edition
 DSST: Digit Symbol Substitution Test
 EQ‐5D: Euroqol‐5D: a standardized instrument for use as a measure of health outcome
 FA: Folic acid 
 GARS: Groningen Activity Restriction Scale
 HVLT: Hopkins Verbal Learning Test
 holoTC: Holotranscobalamin
 IQCODE: Informant Questionnaire on Cognitive Decline in the Elderly
 IQR: Interquartile range
 ISRCTN: International Standard Randomised Controlled Trial Number
 MCI: Mild cognitive impairment
 MMA: Methylmalonic acid
 MMSE: Mini‐Mental State Examination
 MoCA: Montreal Cognitive Assessment
 MRI: Magnetic resonance imaging
 PAL: Paired Associate Learning
 QoL: Quality of life
 RBC: Red blood cell
 SCWT‐A: Stroop Color‐Word Test ‐ Abridged
 SDMT: Symbol Digit Modalities Test
 SF‐12: 12‐item Short Form Survey
 TIA: Transient Ischaemic Attack
 TICS28: 28‐item Telephone Interview for Cognitive Status
 TICSm: Modified Telephone Interview for Cognitive Status
 vit: vitamin
 WAIS: Wechsler Adult Intelligence Scale
 wk: week
 10 WLT: 10 Word Learning Test}