Summary of findings 2. Antioxidants compared to placebo for maintaining cognitive function in cognitively healthy people in mid and late life.

Antioxidants compared to placebo for maintaining cognitive function in cognitively healthy people in mid and late life
Patient or population: cognitively healthy people in mid and late life Setting: community Intervention: antioxidant vitamins (vitamins C, E, and beta‐carotene, alone or in combination) Comparison: placebo
Outcomes	Anticipated absolute effects* (95% CI)		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with placebo	Risk with Antioxidants
Vitamin E supplementation Overall cognitive functioning assessed with: MMSE Scale from: 0 to 30 follow‐up: 3 months	The mean MMSE score was 26.6	MD 1.4 higher (1.18 higher to 1.62 higher)	‐	74 (1 RCT)	⊕⊝⊝⊝ VERY LOW 1 2 3	Higher score indicates better cognitive function.
Vitamin E supplementation Overall cognitive functioning assessed with: TICS Scale from: 0 to 41 follow‐up: range 6 years to 10 years	Two studies found no evidence of an effect of vitamin E		‐	(2 RCTs)	⊕⊕⊝⊝ LOW 4 5	Range of follow‐up durations was approximate. Mean in one study was 9.6 years and in the other study was 8.9 years. There were 5226 participants in one study. The number in the other study was not reported for this time point (approximately 800).
Beta‐carotene supplementation Overall cognitive functioning assessed with: TICS Scale from: 0 to 41 follow‐up: mean 12 months	The mean TICS score was 34.29	MD 0.14 lower (0.37 lower to 0.09 higher)	‐	1904 (1 RCT)	⊕⊕⊕⊝ MODERATE 6	Higher score indicates better cognitive function.
Beta‐carotene supplementation Overall cognitive functioning assessed with: TICS follow‐up: mean 8.9 years	Not reported	MD 0.13 lower (0.46 lower to 0.19 higher)	‐	(1 RCT)	⊕⊕⊝⊝ LOW 4 7	Mean difference with 95% CI reported in paper. Absolute values in each treatment group not reported. Number in each treatment group at final follow‐up not reported.
Beta‐carotene supplementation Overall cognitive functioning assessed with: TICS Scale from: 0 to 41 follow‐up: mean 18 years	The mean TICS score was 34.23	MD 0.18 higher (0.01 higher to 0.35 higher)	‐	4052 (1 RCT)	⊕⊕⊕⊝ MODERATE 6
Vitamin C supplementation Overall cognitive functioning assessed with: TICS follow‐up: mean 8.9 years	Not reported	MD 0.46 higher (0.14 higher to 0.78 higher)	‐	(1 RCT)	⊕⊕⊝⊝ LOW 4 7	Mean difference with 95% CI reported in paper. Absolute values in each group not reported. Number in each treatment group at final follow‐up not reported.
Supplementation with beta‐carotene + vit C + vit E Overall cognitive functioning assessed with: TICSm Scale from: 0 to 39 follow‐up: mean 5 years	The mean TICSm score was 24.02	MD 0.09 higher (0.05 lower to 0.23 higher)	‐	20536 (1 RCT)	⊕⊕⊕⊝ MODERATE 8
Supplementation with beta‐carotene + vit C + vit E Overall cognitive functioning assessed with: 3MS (modified MMSE) Scale from: 0 to 100 follow‐up: median 6.9 years	The mean 3MS score was 92.1	MD 0.6 higher (0.2 lower to 1.4 higher)	‐	1100 (1 RCT)	⊕⊕⊕⊝ MODERATE 4	Higher score indicates better cognitive function.
Incidence of all‐cause dementia follow‐up: mean approximately 5 years	Two studies, one using a combination of beta‐carotene, vit C and vit E and one using vit E ± selenium, found no significant difference in the incidence of dementia.		‐	25 993 (2 RCTs)	⊕⊕⊝⊝ LOW 8 9
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio; OR: Odds ratio;
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

¹ Downgraded for risk of bias due to lack of blinding (open‐label study)

² Downgraded for indirectness (diabetic participants only)

³ Downgraded for imprecision due to small sample size

⁴ Downgraded for risk of bias due to incomplete outcome data

⁵ Downgraded for indirectness (both studies included only women and in one study all participants also had cardiovascular disease or 3 or more coronary risk factors)

⁶ Downgraded for indirectness (included men only)

⁷ Downgraded for indirectness (included only women with cardiovascular disease or ≥ 3 coronary risk factors)

⁸ Downgraded for indirectness (all participants had high risk of coronary heart disease death over the next 5 years)

⁹ Downgraded for imprecision due to wide confidence interval

^{MMSE: Mini Mental State Examination
 TICS: Telephone Interview for Cognitive Status
 TICSm: Modified Telephone Interview for Cognitive Status
 3MS: The Modified Mini‐Mental State Examination}