Clarke R et al [23] 2003, England | Dementia | -Aspirin/ placebo = 74/75 -FA + vitamin B12/ placebo = 74/75 -vitamin E + C/ placebo = 75/74 (Median age = 75) | DSM-5 | -Intervention groups: (1) aspirin (81 mg) (2) FA (2 mg) + vitamin B12 (1 mg) (3) vitamins E (500 mg) + C (200 mg) -Control group: Placebo tablets -Study duration: 12 weeks | -Cognition: MMSE, ADAS-Cog -Biomarkers: serum Hcy, vitamin B12 and plasma folate. | - No effect of treatment on cognitive function was detected. - B-vitamins were associated with reduction in plasma Hcy level. - B-vitamin was effective in reducing biochemical factors associated with cognitive impairment. |
Eussen SJ et al [24] 2006, Netherlands | Mild vitamin B12 deficiency | -Vitamin B12 = 54 (82 ± 5) - Vitamin B12 + FA = 51 (83 ± 6) - Control group = 57 (82 ± 5) | serum vitamin B12 between 100 and 200 pmol/L | -Intervention groups: (1) Vitamin B12 (1000 µg) (2) Vitamin B12 (1000 µg) + FA (400 µg) -Control group: Placebo tablets -Study duration: 24 weeks | -Cognition: MMSE, CDR, GDS, cognitive test battery. -Biomarkers: tHcy, red blood cell folate, vitamin B12 | - Vitamin B12 supplementation corrected mild vitamin B12 deficiency. Vitamin B12 + FA supplementation increased red blood cell folate concentrations and decreased tHcy concentrations by 36%. - Neither supplementation with vitamin B12 alone nor that in combination with FA was accompanied by any improvement in cognitive domains. |
Jiang B et al [25] 2020, China | MCI with HHcy | -Intervention group = 46 (65.23 ± 5.75) -Control group = 46 (63.73 ± 6.12) | Petersen criteria | -Intervention group: FA(0.8mg) + vitamin B12(1.5mg) -Control group: convention treatments -Study duration: 24 weeks | -Cognition: MoCA, ADL, CDR, HAM-A, HAM-D, and HIS. -Biomarkers: tHcy, folate, vitamin B12 | - The concentrations of folate and B12 increased and tHcy decreased in the intervention group. - The MoCA score was higher when compared with that before treatment and in the control group. - Folate and VitB12 can effectively reduce levels of tHcy in patients with MCI and improve cognitive function. |
Smith AD et al [26] 2010, England | MCI | -Intervention group = 85 (77.0 ± 5.2) -Control group = 83 (76.2 ± 4.5) | Petersen criteria | -Intervention group: FA (0.8mg) + vitamin B12 (0.5mg) + vitamin B6 (20mg) -Control group: Placebo tablets -Study duration: 2 years | - Brain MRI - Biomarkers: tHcy | -B vitamins supplement can decrease Hcy levels. - B vitamins supplement can reduce the rate of atrophy of the brain in elderly people with MCI. |
Li M et al [27] 2021, China | MCI | -FA + DHA = 60 (70.33 ± 7.70) -FA = 60 (70.20 ± 6.13) -DHA = 60 (71.55 ± 6.62) - Control group = 60 (70.38 ± 6.73) | DSM-5 | -Intervention groups: (1) FA (0.8mg) + DHA (0.8mg) (2) FA (0.8mg) (3) DHA (0.8mg) -Control group: Placebo tablets -Study duration: 6 months | -Cognition: FSIQ, WAIS-RC, MMSE -Biomarkers: Hcy, plasma DHA and inflammatory cytokines (MCP-1, TNF-α, IL-6, IL-10 and IL-1β) | -FA combined with DHA significantly improved cognitive function. -FA combined with DHA intervention significantly reduced plasma inflammatory cytokine levels. |
Bai D, et al [28] 2021, China | MCI | -FA + DHA = 60 (70.33 ± 7.70) -FA = 60 (70.20 ± 6.13) -DHA = 60 (71.55 ± 6.62) - Control group = 60 (70.38 ± 6.73) | DSM-5 | -Intervention groups: (1) FA (0.8mg) + DHA (0.8mg) (2) FA (0.8mg) (3) DHA (0.8mg) -Control group: Placebo tablets -Study duration: 6 months | Cognition: FSIQ, WAIS-RC, MMSE -Biomarkers: serum folate, Hcy, plasma DHA and Aβ-related biomarkers (SAM, SAH, APP-mRNA and so on) | -Folic acid and DHA improve cognitive function and reduce blood Aβ production in MCI patients. |
Ma F et al [29] 2019, China | MCI | -FA = 60 (68.42 ± 3.62) -vitamin B12 = 60 (69.47 ± 2.88) -FA + vitamin B12 = 60 (69.16 ± 2.46) - Control group = 60 (68.54 ± 3.90) | Petersen criteria | -Intervention groups: (1) FA (0.8mg) (2) vitamin B12 (25µg) (3) FA (0.8mg) + vitamin B12 (25µg) -Control group: Placebo tablets -Study duration: 6 months | -Cognition: WAIS-RC -Biomarkers: IL-6, TNF-α | - Improvement of the cognitive performance FSIQ, verbal IQ, Information and Digit Span scores of the WAIS-RC in patients treated with the combination of FA and vitamin B. - Reduction of proinflammatory cytokines levels (including IL-6, TNF-α and MCP-1) compared with vitamins alone or control. |
Kwok T et al [30] 2011, Hong Kong, China | AD, vascular dementia | -Intervention group = 70 (79.1 ± 6.7) -Control group = 70 (77.2 ± 7.9) | NINCDS–ADRDA criteria, NINDS–AIREN criteria | -Intervention group: FA (5 mg) + methylcobalamin (Endogenous VitB12 ,1mg) -Control group: Placebo tablets -Study duration: 24 months | -Cognition: MMSE, MDRS -Biomarker: plasma tHcy, vitamin B12 and folate. | -Decrease in Hcy levels vs. placebo. -FA and vitamin B12 supplement did not improve the global cognitive decline. |
Kwok T et al [16] 2020, Hong Kong, China | MCI | -Intervention group = 138 (78.0 ± 5.3) -Control group = 141 (76.9 ± 5.4) | Petersen and Morris criteria | -Intervention group: FA (400µg) + methylcobalamin (500µg) -Control group: Placebo tablets -Study duration: 24 months | -Cognition: MMSE, CDR, NTB -Biomarkers: serum folate, active VitB12, creatinine | - Decrease in Hcy levels vs. placebo. - FA and vitamin B12 supplement did not significantly attenuate cognitive decline in older people with MCI. |
Sun Y et al [31] 2007, Taiwan, China | Dementia | -Intervention group = 45 (74.9 ± 7.1) -Control group = 44 (74.6 ± 7.5) | DSM-4 | -Intervention group: mecobalamin (0.5 mg) + multivitamin supplement (include B6 5 mg, FA 1 mg, other vitamins and iron) -Control group: Placebo tablets -Study duration: 26 weeks | -Cognition: ADAS-cog, ADL, MMSE, Cognitive Abilities Screening Instrument and Instrumental ADL Scale. -Biomarker: serum Hcy. | - No significant differences in cognition or ADL scores between the 2 groups. - Decrease in Hcy levels. |
Aisen PS et al [12] 2008, America | AD | -Intervention group = 240 (75.7 ± 8.0) -Control group = 169 (77.3 ± 7.9) | MMSE score between 14 and 26 | -Intervention group: FA(5mg) + vitamin B6 (25mg) + B12(1 mg) -Control group: Placebo tablets -Study duration: 18 months | -Cognition: ADAS-cog, CDR-SOB, ADCS-ADL, Neuropsychiatric Inventory, QOL-AD and the time of attainment of significant endpoints. -Biomarkers: Plasma tHcy, vitamin B6. | - No significant improvements detected in cognitive function. - Decrease in Hcy levels in the intervention group compared to control. |