Eussen 2006.

Methods	3‐arm, parallel group, randomised, placebo‐controlled trial, 24 week's duration.
Participants	Location: The Netherlands. Setting of recruitment and treatment: Free‐living older persons and older persons living in care‐facility homes, recruited via mailed health questionnaires. Sample size Number randomised: 195, of whom 119 had CDR 0 at baseline and were included in this review: 38 in vitamin B12 group, 38 in vitamin B12 + folic acid group, 43 in placebo group. "Randomization was stratified according to MMA concentration at the screening visit (< and > 0.45 µmol/L), age (< and > 80), sex and MMSE score (< and > 24 points)." Participant baseline characteristics: Age in years (mean ± SD) : vit B12 80.42 ± 5.52, vit B12 + FA 80.82 ± 4.18, placebo 79.86 ± 4.74. Female sex : vit B12 29/38 (76%), vit B12 + FA 29/38 (76%), placebo 34/43 (79%). Cognitive function ‐ MMSE score (mean ± SD): vit B12 28.18 ± 1.43, vit B12 + FA 28.34 ± 1.40, placebo 27.93 ± 1.80. Inclusion criteria: Aged ≥ 70 years. Mild vitamin B12 deficiency defined as (1) a serum vitamin B12 concentration between 100 and 200 pmol/L, or (2) a serum vitamin B12 concentration between 200 and 300 pmol/L. Plasma MMA concentration ≥ 0.32 μmol/L. Serum creatinine concentration ≤ 120 μmol/L. Ingested 90% or more of capsules during a 2‐week placebo run‐in period prior to randomisation. Exclusion criteria: History of cobalamin deficiency. Use of cobalamin (> 50 µg/day) or folic acid (> 200 µg/day). Surgery or diseases of the stomach or small intestine, anaemia, dementia, life‐threatening diseases, or severe hearing or visual problems
Interventions	Intervention: 1) Vitamin B12: 1000 µg vitamin B12 (cyanocobalamin) per day orally for 24 weeks. 2) Vitamin B12 and folic acid: 1000 µg vitamin B12 (cyanocobalamin) plus 400 µg folic acid per day orally for 24 weeks. Comparator: Placebo capsule. The placebo capsules contained AVICEL PH102 (Medipulp GmbH, Aschaffenburg, Germany) as a filler. Use of additional interventions (common to both treatment arm): not reported.
Outcomes	Cognitive function Cognitive function was assessed before and after 24 wk of treatment with the use of an extensive neuropsychologic test battery that included the domains of attention, construction, sensorimotor speed, memory, and executive function. Cognitive function was assessed by 6 trained and registered neuropsychologists during the run‐in period (baseline) and at week 24 of the intervention during a 1.5 to 2 hour session. Neuropsychological test battery included: finger tapping, computerised; motor planning 2 and 3, computerised; Figure of Rey copy, immediate recall and delayed recall; 15 word learning immediate recall, delayed recall and recognition; Trail‐making test, part A and part B; Digit span forward and backward; Raven Progressive Matrices; Stroop test; Similarities, WAIS; Word fluency, letter; Word fluency, animals. Depression measured with Geriatric Depression Scale Biochemical measures: vitamin B12, methylmalonic acid, holotranscobalamin, homocysteine, red blood cell folate.
Source of Funding	Study supported by grants from ZON‐MW, The Hague, Netherlands; Kellogg's Benelux, Zaventem, Belgium; Foundation to Promote Research into Functional Vitamin B12 Deficiency and the European Union BIOMED Demonstration Project; Nutricia Health Foundation, Wageningen, Netherlands.
Declaration of Interest
Notes	Compliance was checked by counting the number of unused capsules remaining in capsule dispensers and by verifying pill counts in the participants’ diaries. Mean compliance was 99%. Professor Simone Eussen and Professor Lisette de Groot kindly provided data separately on participants with CDR 0.5 at baseline for inclusion in this review.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"Randomized", no further information.
Allocation concealment (selection bias)	Unclear risk	No information.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quotes: "The capsules given to the separate treatment groups were identical in appearance, smell and taste." "The study had a double‐blind design." Comment: participants and personnel blind to allocation.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "The study had a double‐blind design." No specific mention of outcome assessors. Comment: outcome assessors probably blind to allocation.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Incomplete outcome data varied between cognitive tests. For included outcomes, data available for minimum of 82% of participants. In study as a whole, "16% ... were unable to complete the trial, mostly because of illness, and the dropout rate was slightly higher in the vitamin B12 + folic acid group than in the other groups." Dropout in whole study: 10/64 B12, 15/66 B12 + folic acid, 8/65 placebo. Comment: major effect of differential dropout unlikely.
Selective reporting (reporting bias)	Low risk	All outcomes mentioned in methods fully reported.
Other bias	Low risk	No other biases identified.