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Risk Factor:
  (folate, folic acid, holotranscobalamin, vitamin B12, vitamin B6, vitamin B9)
Risk Factor Type: Nutrition and supplements
Current Understanding:
The reviewed studies do not provide consistent evidence for an association of B vitamin intake with risk of Alzheimer’s disease (AD). Some studies suggested an inverse association between folate levels and AD risk, but methodological limitations may have contributed to inconsistent findings across studies. Support for any association of vitamins B6 or B12 with AD was less apparent. Reviewed studies measured B vitamin status using either measures of dietary intake, usually recorded from food frequency questionnaires, or biomarker concentrations of the B vitamin itself or of a related marker as a measure of its bioavailability. Moreover, few studies addressed possible interactions between different B vitamins, or the possibility that B vitamins might have a role in preventing AD only among individuals with existing B-deficiencies. The majority of studies involved populations in the United States, where federal law mandates the fortification of flour with B vitamins and thus B vitamin deficiencies are uncommon. Additional prospective studies addressing these limitations will help clarify the issue. For a review of the putative mechanisms by which B vitamins may influence AD risk and detailed commentary on interpreting the findings below in a broader context, please view the Discussion.
Literature Extraction: Search strategy  * New *
Last Search Completed: 03 November 2015

Table 1:  Folate supplement use (categorical)
Table 2:  Vitamin B6 supplement use (categorical)
Table 3:  Vitamin B-complex supplement use (yes vs. no)
Table 4:  Dietary folate intake (categorical)
Table 5:  Dietary vitamin B6 intake (categorical)
Table 6:  Dietary vitamin B12 intake (categorical)
Table 7:  Total folate intake (categorical)
Table 8:  Total vitamin B6 intake (categorical)
Table 9:  Total vitamin B12 intake (categorical)
Table 10:  Serum folate (categorical)
Table 11:  Serum folate (continuous, per decreasing ordinal category)
Table 12:  Serum folate (continuous, per 1 nmol/L increase)
Table 13:  Serum vitamin B12 (categorical)
Table 14:  Serum vitamin B12 (continuous, per decreasing ordinal category)
Table 15:  Plasma holotranscobalamin (categorical)
Table 16:  Plasma or serum holotranscobalamin (continuous, per 5 pmol/L increase)

Table 1:   Folate supplement use (categorical)
Notes These reports examine any use of supplements that contain folate in relation to AD risk. Information on supplement intake was collected using food frequency questionnaires.  
  Alzheimer Disease Total Dementia  
Paper Cohort Study Type # Subjects
(% Female)
Average Follow-up Time Exposure Distribution
# of Cases Effect Size 95% CI P-value # of Cases Effect Size 95% CI P-value Ethnicity Age at Start of Follow-up:
Mean (SD)
(Range)
Diagnostic Assessment Covariates & Analysis Comment Paper
Luchsinger, 2007 WHICAP Incidence study reporting hazard ratios (HRs) 965
(70%)
6.1 y
No:         
Yes:         
(detail)
-
-
Total: 192
1.00
1.00
Ref.
0.70-1.40
Ref.
0.99
*
 
 
      Caucasian, Hispanic, African-American (Black)
(detail)
76 (6)
(65 - )
AD Diagnosis: DSM IV, NINCDS ADRDA
(detail)
A, E, G, APOE4, CHD, DM, HTN, SM, SH, VTB, VTB6‡
(detail)
Luchsinger, 2007
Luchsinger, 2007 WHICAP Incidence study reporting hazard ratios (HRs) 965
(70%)
6.1 y
<400μg/day:         
≥400μg/day:         
(detail)
-
-
Total: 192
1.00
0.70
Ref.
0.50-1.20
Ref.
0.11
*
 
 
      Caucasian, Hispanic, African-American (Black)
(detail)
76 (6)
(65 - )
AD Diagnosis: DSM IV, NINCDS ADRDA
(detail)
A, E, G, APOE4, CHD, DM, HTN, SM, SH, VTB, VTB6‡
(detail)
Luchsinger, 2007
Nelson, 2009 Cache County Study Incidence study reporting hazard ratios (HRs) 3634
(57%)
9.0 y
<400μg/day:         
≥400μg/day:         
(detail)
-
-
Total: 212
1.00
1.13
Ref.
0.69-1.87
Ref.
0.63
*
-
-
Total: 353
1.00
1.14
Ref.
0.75-1.74
Ref.
0.54
*
Caucasian
(detail)
75 (-)
(65 - )
Screening: 3MSE

AD Diagnosis: NINCDS ADRDA
(detail)
A, E, G, ALC, APOE4, BMI, Kcal, DM, MI, PA, SM, SH, VTB, VTB6‡
(detail)
Nelson, 2009
* Derived value.
‡ Covariates: "A" (age), "E" (education), "G" (gender), "ALC" (alcohol intake), "APOE4" (APOE e4 genotype), "BMI" (body mass index), "Kcal" (caloric intake), "CHD" (coronary heart disease), "DM" (diabetes mellitus), "HTN" (hypertension), "MI" (mycardial infarction history), "PA" (physical activity), "SM" (smoking status), "SH" (stroke history), "VTB" (vitamin B12), "VTB6" (vitamin B6)
 
Table 2:   Vitamin B6 supplement use (categorical)
Notes These reports examine any use of supplements that contain vitamin B6 in relation to AD risk. Information on supplement intake was collected using food frequency questionnaires.  
  Alzheimer Disease Total Dementia  
Paper Cohort Study Type # Subjects
(% Female)
Average Follow-up Time Exposure Distribution
# of Cases Effect Size 95% CI P-value # of Cases Effect Size 95% CI P-value Ethnicity Age at Start of Follow-up:
Mean (SD)
(Range)
Diagnostic Assessment Covariates & Analysis Comment Paper
Nelson, 2009 Cache County Study Incidence study reporting hazard ratios (HRs) 3634
(57%)
9.0 y
<2 mg/day:         
≥2 mg/day:         
(detail)
-
-
Total: 212
1.00
0.84
Ref.
0.53-1.35
Ref.
0.46
*
-
-
Total: 353
1.00
0.95
Ref.
0.62-1.46
Ref.
0.81
*
Caucasian
(detail)
75 (-)
(65 - )
Screening: 3MSE

AD Diagnosis: NINCDS ADRDA
(detail)
A, E, G, ALC, APOE4, BMI, Kcal, DM, MI, PA, SM, SH, FOLTOTL, VTB‡§
(detail)
Nelson, 2009
* Derived value.
‡ Covariates: "A" (age), "E" (education), "G" (gender), "ALC" (alcohol intake), "APOE4" (APOE e4 genotype), "BMI" (body mass index), "Kcal" (caloric intake), "DM" (diabetes mellitus), "MI" (mycardial infarction history), "PA" (physical activity), "SM" (smoking status), "SH" (stroke history), "FOLTOTL" (total folate), "VTB" (vitamin B12)
§ Covariates for total dementia are different.
 
Table 3:   Vitamin B-complex supplement use (yes vs. no)
Notes These reports examine any use of supplements that contain vitamin B6 in relation to AD risk. Information on supplement intake was collected via participant interview through a medication inventory.  
  Alzheimer Disease Total Dementia  
Paper Cohort Study Type # Subjects
(% Female)
Average Follow-up Time Exposure Distribution
# of Cases Effect Size 95% CI P-value # of Cases Effect Size 95% CI P-value Ethnicity Age at Start of Follow-up:
Mean (SD)
(Range)
Diagnostic Assessment Covariates & Analysis Comment Paper
Zandi, 2004 Cache County Study Incidence study reporting hazard ratios (HRs) 3227
(56%)
3.1 y
*
No vitamins: 95%
Yes (includes multivitamins): 5%
(detail)
95
4
Total: 99
1.00
0.94†
Ref.
0.28-2.29
Ref.
0.91
*
 
 
      Caucasian
(detail)
72 (-)
(65 - )
(detail)
Screening: DQ, 3MSE

AD Diagnosis: NINCDS ADRDA
(detail)
A, E, G, APOE4, HS‡
(detail)
Zandi, 2004
* Derived value.
† Five or fewer cases exist.
‡ Covariates: "A" (age), "E" (education), "G" (gender), "APOE4" (APOE e4 genotype), "HS" (health status)
 
Table 4:   Dietary folate intake (categorical)
Notes These studies evaluated folate intake from diet in relation to AD risk. The studies measured dietary intake of folate using food frequency questionnaires.  
  Alzheimer Disease Total Dementia  
Paper Cohort Study Type # Subjects
(% Female)
Average Follow-up Time Exposure Distribution
# of Cases Effect Size 95% CI P-value # of Cases Effect Size 95% CI P-value Ethnicity Age at Start of Follow-up:
Mean (SD)
(Range)
Diagnostic Assessment Covariates & Analysis Comment Paper
Luchsinger, 2007 WHICAP Incidence study reporting hazard ratios (HRs) 965
(70%)
6.1 y
Lowest quartile: 25%
Highest quartile: 25%
(detail)
-
-
Total: 192
1.00
0.80
Ref.
0.50-1.20
Ref.
0.32
*
 
 
      Caucasian, Hispanic, African-American (Black)
(detail)
76 (6)
(65 - )
AD Diagnosis: DSM IV, NINCDS ADRDA
(detail)
A, E, G, APOE4, CHD, DM, HTN, SM, SH, VTB, VTB6‡
(detail)
Luchsinger, 2007
Morris, 2006 CHAP Cohort study reporting odds ratios (ORs) 1041
(62%)
3.9 y
Lowest quintile (median: 184.0 µg/day): 20%
Second quintile (median: 240.2 µg/day): 20%
Third quintile (median: 279.6 µg/day): 20%
Fourth quintile (median: 330.3 µg/day): 20%
Highest quintile (median: 405.2 µg/day): 20%
(detail)
-
-
-
-
-
Total: 161
1.00
1.70
0.90
1.50
1.80
Ref.
0.70-4.10
0.40-2.40
0.60-3.50
0.80-4.10
Ref.
0.24
0.82
0.37
0.16
*
 
 
 
 
 
      Caucasian, African-American (Black)
(detail)
73 (-)
(65 - )
Screening: CERAD

AD Diagnosis: NINCDS ADRDA
(detail)
A, E, G, APOE4, VITED, FUT, CA-Past, RE, NCNTOTL‡
(detail)
Morris, 2006
Nelson, 2009 Cache County Study Incidence study reporting hazard ratios (HRs) 3634
(57%)
9.0 y
Lowest quintile: 20%
Second quintile: 20%
Third quintile: 20%
Fourth quintile: 20%
Highest quintile: 20%
(detail)
-
-
-
-
-
Total: 212
1.00
0.76
1.10
1.16
1.02
Ref.
0.46-1.27
0.69-1.75
0.72-1.86
0.62-1.67
Ref.
0.29
0.69
0.54
0.94
*
-
-
-
-
-
Total: 353
1.00
0.63
0.97
0.99
0.86
Ref.
0.40-1.01
0.64-1.47
0.64-1.51
0.55-1.35
Ref.
0.05
0.89
0.96
0.51
*
Caucasian
(detail)
75 (-)
(65 - )
Screening: 3MSE

AD Diagnosis: NINCDS ADRDA
(detail)
A, E, G, ALC, APOE4, BMI, Kcal, DM, MI, PA, SM, SH, VTB, VTB6‡
(detail)
Nelson, 2009
* Derived value.
‡ Covariates: "A" (age), "E" (education), "G" (gender), "ALC" (alcohol intake), "APOE4" (APOE e4 genotype), "BMI" (body mass index), "Kcal" (caloric intake), "CHD" (coronary heart disease), "DM" (diabetes mellitus), "VITED" (dietary vitamin E), "FUT" (follow up time), "HTN" (hypertension), "MI" (mycardial infarction history), "CA-Past" (Past Cognitive Activity ), "PA" (physical activity), "RE" (race/ethnicity), "SM" (smoking status), "SH" (stroke history), "NCNTOTL" (total niacin), "VTB" (vitamin B12), "VTB6" (vitamin B6)
 
Table 5:   Dietary vitamin B6 intake (categorical)
Notes These studies evaluated vitamin B6 intake from diet in relation to AD risk. The studies measured dietary intake of vitamin B6 using food frequency questionnaires.  
  Alzheimer Disease Total Dementia  
Paper Cohort Study Type # Subjects
(% Female)
Average Follow-up Time Exposure Distribution
# of Cases Effect Size 95% CI P-value # of Cases Effect Size 95% CI P-value Ethnicity Age at Start of Follow-up:
Mean (SD)
(Range)
Diagnostic Assessment Covariates & Analysis Comment Paper
Morris, 2006 CHAP Cohort study reporting odds ratios (ORs) 1041
(62%)
3.9 y
Lowest quintile (median: 1.2 mg/day): 20%
Second quintile (median: 1.4 mg/day): 20%
Third quintile (median: 1.6 mg/day): 20%
Fourth quintile (median: 1.9 mg/day): 20%
Highest quintile (median: 2.2 mg/day): 20%
(detail)
-
-
-
-
-
Total: 161
1.00
0.70
1.60
1.00
0.70
Ref.
0.30-1.70
0.80-3.40
0.40-2.30
0.30-1.40
Ref.
0.42
0.2
0.99
0.36
*
 
 
 
 
 
      Caucasian, African-American (Black)
(detail)
73 (-)
(65 - )
Screening: CERAD

AD Diagnosis: NINCDS ADRDA
(detail)
A, E, G, APOE4, VITED, FUT, CA-Past, RE, NCNTOTL‡
(detail)
Morris, 2006
Nelson, 2009 Cache County Study Incidence study reporting hazard ratios (HRs) 3634
(57%)
9.0 y
Lowest quintile: 20%
Second quintile: 20%
Third quintile: 20%
Fourth quintile: 20%
Highest quintile: 20%
(detail)
-
-
-
-
-
1.00
0.78
1.06
0.91
0.84
Ref.
0.47-1.28
0.67-1.68
0.57-1.45
0.53-1.35
Ref.
0.33
0.8
0.69
0.46
*
-
-
-
-
-
1.00
-
1.06
0.82
0.80
Ref.
0.50-1.24
0.70-1.61
0.53-1.28
0.51-1.23
Ref.
0.31
0.78
0.38
0.32
*
Caucasian
(detail)
75 (-)
(65 - )
Screening: 3MSE

AD Diagnosis: NINCDS ADRDA
(detail)
A, E, G, ALC, APOE4, BMI, Kcal, DM, MI, PA, SM, SH, FOLTOTL, VTB‡
(detail)
Nelson, 2009
* Derived value.
‡ Covariates: "A" (age), "E" (education), "G" (gender), "ALC" (alcohol intake), "APOE4" (APOE e4 genotype), "BMI" (body mass index), "Kcal" (caloric intake), "DM" (diabetes mellitus), "VITED" (dietary vitamin E), "FUT" (follow up time), "MI" (mycardial infarction history), "CA-Past" (Past Cognitive Activity ), "PA" (physical activity), "RE" (race/ethnicity), "SM" (smoking status), "SH" (stroke history), "FOLTOTL" (total folate), "NCNTOTL" (total niacin), "VTB" (vitamin B12)
 
Table 6:   Dietary vitamin B12 intake (categorical)
Notes These studies evaluated vitamin B12 intake from diet in relation to AD risk. The studies measured dietary intake of vitamin B12 using food frequency questionnaires.  
  Alzheimer Disease Total Dementia  
Paper Cohort Study Type # Subjects
(% Female)
Average Follow-up Time Exposure Distribution
# of Cases Effect Size 95% CI P-value # of Cases Effect Size 95% CI P-value Ethnicity Age at Start of Follow-up:
Mean (SD)
(Range)
Diagnostic Assessment Covariates & Analysis Comment Paper
Morris, 2006 CHAP Cohort study reporting odds ratios (ORs) 1041
(62%)
3.9 y
Lowest quintile (median: 2.5 μg/day): 20%
Second quintile (median: 4.2 μg/day): 20%
Third quintile (median: 5.6 μg/day): 20%
Fourth quintile (median: 7.7 μg/day): 20%
Highest quintile (median: 14.0 μg/day): 20%
(detail)
-
-
-
-
-
Total: 161
1.00
1.40
0.80
1.50
1.00
Ref.
0.70-2.70
0.30-2.30
0.60-4.00
-
Ref.
0.33
0.67
0.4
0.99
*
 
 
 
 
 
      Caucasian, African-American (Black)
(detail)
73 (-)
(65 - )
Screening: CERAD

AD Diagnosis: NINCDS ADRDA
(detail)
A, E, G, APOE4, VITED, FUT, CA-Past, RE, NCNTOTL‡
(detail)
Morris, 2006
Nelson, 2009 Cache County Study Incidence study reporting hazard ratios (HRs) 3634
(57%)
9.0 y
Lowest quintile: 20%
Second quintile: 20%
Third quintile: 20%
Fourth quintile: 20%
Highest quintile: 20%
(detail)
-
-
-
-
-
Total: 212
1.00
1.08
0.83
1.46
0.95
Ref.
0.67-1.76
0.49-1.40
0.91-2.33
0.61-1.49
Ref.
0.75
0.49
0.11
0.82
*
-
-
-
-
-
Total: 353
1.00
1.08
0.84
1.30
0.90
Ref.
0.73-1.75
0.52-1.36
0.84-2.01
0.60-1.37
Ref.
0.58
0.48
0.24
0.62
*
Caucasian
(detail)
75 (-)
(65 - )
Screening: 3MSE

AD Diagnosis: NINCDS ADRDA
(detail)
A, E, G, ALC, APOE4, BMI, Kcal, DM, MI, PA, SM, SH, FOLTOTL, VTB6‡
(detail)
Nelson, 2009
* Derived value.
‡ Covariates: "A" (age), "E" (education), "G" (gender), "ALC" (alcohol intake), "APOE4" (APOE e4 genotype), "BMI" (body mass index), "Kcal" (caloric intake), "DM" (diabetes mellitus), "VITED" (dietary vitamin E), "FUT" (follow up time), "MI" (mycardial infarction history), "CA-Past" (Past Cognitive Activity ), "PA" (physical activity), "RE" (race/ethnicity), "SM" (smoking status), "SH" (stroke history), "FOLTOTL" (total folate), "NCNTOTL" (total niacin), "VTB6" (vitamin B6)
 
Table 7:   Total folate intake (categorical)
Notes These studies evaluated the association between total folate intake (dietary plus supplemental) and risk of Alzheimer disease. The majority of studies measured intake of folate using food frequency questionnaires. One study used a a 7-day food diary.  
  Alzheimer Disease Total Dementia  
Paper Cohort Study Type # Subjects
(% Female)
Average Follow-up Time Exposure Distribution
# of Cases Effect Size 95% CI P-value # of Cases Effect Size 95% CI P-value Ethnicity Age at Start of Follow-up:
Mean (SD)
(Range)
Diagnostic Assessment Covariates & Analysis Comment Paper
Corrada, 2005 BLSA Incidence study reporting hazard ratios (HRs) 579
(38%)
9.3 y
Lowest tertile (median: 200.0 µg/day): 33%
Second tertile (median: 317.8 µg/day): 33%
Highest tertile (median: 627.8 µg/day): 33%
(detail)
21
21
15
Total: 57
1.00
0.98
0.32
Ref.
0.48-2.01
0.11-0.92
Ref.
0.96
0.03
 
 
 
       (detail) 70 (-)
(49 - 93)
AD Diagnosis: NINCDS ADRDA
(detail)
A, E, G, Kcal, VTB6, VitE‡
(detail)
Corrada, 2005
Corrada, 2005 BLSA Incidence study reporting hazard ratios (HRs) 579
(38%)
9.3 y
79.0-398.9 µg/day: 65%
403.1–1,457.0 µg/day: 35%
(detail)
42
15
Total: 57
1.00
0.45
Ref.
0.21-0.97
Ref.
0.04
 
 
       (detail) 70 (-)
(49 - 93)
AD Diagnosis: NINCDS ADRDA
(detail)
A, E, G, Kcal, VTB6, VitE‡
(detail)
Corrada, 2005
Luchsinger, 2007 WHICAP Incidence study reporting hazard ratios (HRs) 965
(70%)
6.1 y
Lowest quartile (≤292.9 µg/day): 25%
Second quartile (293.0-365.0 µg/day): 25%
Third quartile (365.1-487.8 µg/day): 25%
Highest quartile (≥487.9 µg/day): 25%
(detail)
-
-
-
-
Total: 192
1.00
0.90
0.70
0.50
Ref.
0.60-1.30
0.50-1.10
0.30-0.90
Ref.
0.59
0.08
0.01
*
 
 
 
 
      Caucasian, Hispanic, African-American (Black)
(detail)
76 (6)
(65 - )
AD Diagnosis: DSM IV, NINCDS ADRDA
(detail)
A, E, G, APOE4, CHD, DM, HTN, SM, SH, VTB, VTB6‡
(detail)
Luchsinger, 2007
Morris, 2006 CHAP Cohort study reporting odds ratios (ORs) 1041
(62%)
3.9 y
Lowest quintile (median: 202.8 µg/day): 20%
Second quintile (median: 275.2 µg/day): 20%
Third quintile (median: 338.2 µg/day): 20%
Fourth quintile (median: 474.5 µg/day): 20%
Highest quintile (median: 752.7 µg/day): 20%
(detail)
-
-
-
-
-
Total: 161
1.00
1.00
1.90
2.70
1.60
Ref.
0.40-2.30
0.70-5.00
1.00-7.10
0.50-5.20
Ref.
0.99
0.2
0.05
0.43
*
 
 
 
 
 
      Caucasian, African-American (Black)
(detail)
73 (-)
(65 - )
Screening: CERAD

AD Diagnosis: NINCDS ADRDA
(detail)
A, E, G, APOE4, VITED, FUT, CA-Past, RE, NCNTOTL‡
(detail)
Morris, 2006
Nelson, 2009 Cache County Study Incidence study reporting hazard ratios (HRs) 3634
(57%)
9.0 y
Lowest quintile (mean: 333 μg/day): 20%
Second quintile (mean: 430 μg/day): 20%
Third quintile (mean: 476 μg/day): 20%
Fourth quintile (mean: 524 μg/day): 20%
Highest quintile (mean: 698 μg/day): 20%
(detail)
-
-
-
-
-
Total: 212
1.00
1.14
0.95
1.36
1.75
Ref.
0.71-1.84
0.54-1.66
0.68-2.72
0.80-3.83
Ref.
0.59
0.86
0.38
0.16
*
-
-
-
-
-
Total: 353
1.00
1.02
0.87
1.13
1.42
Ref.
0.67-1.57
0.53-1.45
0.60-2.12
0.69-2.88
Ref.
0.96
0.59
0.7
0.34
*
Caucasian
(detail)
75 (-)
(65 - )
Screening: 3MSE

AD Diagnosis: NINCDS ADRDA
(detail)
A, E, G, ALC, APOE4, BMI, Kcal, DM, MI, PA, SM, SH, VTB, VTB6‡
(detail)
Nelson, 2009
* Derived value.
‡ Covariates: "A" (age), "E" (education), "G" (gender), "ALC" (alcohol intake), "APOE4" (APOE e4 genotype), "BMI" (body mass index), "Kcal" (caloric intake), "CHD" (coronary heart disease), "DM" (diabetes mellitus), "VITED" (dietary vitamin E), "FUT" (follow up time), "HTN" (hypertension), "MI" (mycardial infarction history), "CA-Past" (Past Cognitive Activity ), "PA" (physical activity), "RE" (race/ethnicity), "SM" (smoking status), "SH" (stroke history), "NCNTOTL" (total niacin), "VTB" (vitamin B12), "VTB6" (vitamin B6), "VitE" (vitamin E)
 
Table 8:   Total vitamin B6 intake (categorical)
Notes These studies evaluated the association between total vitamin B6 intake (dietary plus supplemental) and risk of Alzheimer disease. The majority of studies measured intake of vitamin B6 using food frequency questionnaires. One study used a a 7-day food diary.  
  Alzheimer Disease Total Dementia  
Paper Cohort Study Type # Subjects
(% Female)
Average Follow-up Time Exposure Distribution
# of Cases Effect Size 95% CI P-value # of Cases Effect Size 95% CI P-value Ethnicity Age at Start of Follow-up:
Mean (SD)
(Range)
Diagnostic Assessment Covariates & Analysis Comment Paper
Corrada, 2005 BLSA Incidence study reporting hazard ratios (HRs) 579
(38%)
9.3 y
Lowest tertile (median: 1.4 mg/day): 33%
Second tertile (median: 2.2 mg/day): 33%
Highest tertile (median: 4.9 mg/day): 33%
(detail)
20
18
19
Total: 57
1.00
0.80
2.02
Ref.
0.37-1.71
0.78-5.26
Ref.
0.56
0.15
 
 
 
       (detail) 70 (-)
(49 - 93)
AD Diagnosis: NINCDS ADRDA
(detail)
A, E, G, Kcal, FOLTOTL, VitE‡
(detail)
Corrada, 2005
Corrada, 2005 BLSA Incidence study reporting hazard ratios (HRs) 579
(38%)
9.3 y
0.5-1.3 mg/day: 12%
1.3-254.6 mg/day: 88%
(detail)
10
47
Total: 57
1.00
0.55
Ref.
0.26-1.15
Ref.
0.11
 
 
       (detail) 70 (-)
(49 - 93)
AD Diagnosis: NINCDS ADRDA
(detail)
A, E, G, Kcal, FOLTOTL, VitE‡
(detail)
Corrada, 2005
Luchsinger, 2007 WHICAP Incidence study reporting hazard ratios (HRs) 965
(70%)
6.1 y
Lowest quartile (<2.3 mg/day): 25%
Second quartile (2.3-2.7 mg/day): 25%
Third quartile (2.8-4.5 mg/day): 25%
Highest quartile (>4.5 mg/day): 25%
(detail)
-
-
-
-
Total: 192
1.00
1.10
1.30
1.30
Ref.
0.70-1.70
0.80-2.10
0.70-2.30
Ref.
0.67
0.29
0.39
*
 
 
 
 
      Caucasian, Hispanic, African-American (Black)
(detail)
76 (6)
(65 - )
AD Diagnosis: DSM IV, NINCDS ADRDA
(detail)
A, E, G, APOE4, CHD, DM, HTN, SM, SH, FOLTOTL, VTB‡
(detail)
Luchsinger, 2007
Morris, 2006 CHAP Cohort study reporting odds ratios (ORs) 1041
(62%)
3.9 y
Lowest quintile (median: 1.2 mg/day): 20%
Second quintile (median: 1.6 mg/day): 20%
Third quintile (median: 1.9 mg/day): 20%
Fourth quintile (median: 3.1 mg/day): 20%
Highest quintile (median: 5.5 mg/day): 20%
(detail)
-
-
-
-
-
Total: 161
1.00
0.90
1.30
1.90
0.70
Ref.
0.40-2.10
0.60-3.10
0.70-5.10
0.20-2.40
Ref.
0.8
0.53
0.21
0.57
*
 
 
 
 
 
      Caucasian, African-American (Black)
(detail)
73 (-)
(65 - )
Screening: CERAD

AD Diagnosis: NINCDS ADRDA
(detail)
A, E, G, APOE4, VITED, FUT, CA-Past, RE, NCNTOTL‡
(detail)
Morris, 2006
Nelson, 2009 Cache County Study Incidence study reporting hazard ratios (HRs) 3634
(57%)
9.0 y
Lowest quintile (mean: 1.57 μg/day): 20%
Second quintile (mean: 2.16 μg/day): 20%
Third quintile (mean: 2.96 μg/day): 20%
Fourth quintile (mean: 4.24 μg/day): 20%
Highest quintile (mean: 25.8 μg/day): 20%
(detail)
-
-
-
-
-
Total: 212
1.00
0.79
0.62
0.61
0.58
Ref.
0.49-1.27
0.36-1.07
0.30-1.27
0.27-1.21
Ref.
0.33
0.09
0.37
0.15
*
-
-
-
-
-
Total: 353
1.00
0.74
0.62
0.69
0.67
Ref.
0.48-1.14
0.38-1.03
0.36-1.34
0.34-1.30
Ref.
0.17
0.06
0.27
0.24
*
Caucasian
(detail)
75 (-)
(65 - )
Screening: 3MSE

AD Diagnosis: NINCDS ADRDA
(detail)
A, E, G, ALC, APOE4, BMI, Kcal, DM, MI, PA, SM, SH, FOLTOTL, VTB‡
(detail)
Nelson, 2009
* Derived value.
‡ Covariates: "A" (age), "E" (education), "G" (gender), "ALC" (alcohol intake), "APOE4" (APOE e4 genotype), "BMI" (body mass index), "Kcal" (caloric intake), "CHD" (coronary heart disease), "DM" (diabetes mellitus), "VITED" (dietary vitamin E), "FUT" (follow up time), "HTN" (hypertension), "MI" (mycardial infarction history), "CA-Past" (Past Cognitive Activity ), "PA" (physical activity), "RE" (race/ethnicity), "SM" (smoking status), "SH" (stroke history), "FOLTOTL" (total folate), "NCNTOTL" (total niacin), "VTB" (vitamin B12), "VitE" (vitamin E)
 
Table 9:   Total vitamin B12 intake (categorical)
Notes These studies evaluated the association between total vitamin B12 intake (dietary plus supplemental) and risk of Alzheimer disease. The majority of studies measured intake of vitamin B12 using food frequency questionnaires. One study used a a 7-day food diary.  
  Alzheimer Disease Total Dementia  
Paper Cohort Study Type # Subjects
(% Female)
Average Follow-up Time Exposure Distribution
# of Cases Effect Size 95% CI P-value # of Cases Effect Size 95% CI P-value Ethnicity Age at Start of Follow-up:
Mean (SD)
(Range)
Diagnostic Assessment Covariates & Analysis Comment Paper
Corrada, 2005 BLSA Incidence study reporting hazard ratios (HRs) 579
(38%)
9.3 y
Lowest tertile (median: 3.2 μg/day): 33%
Second tertile (median: 6.3 μg/day): 33%
Highest tertile (median: 15.4 μg/day): 33%
(detail)
20
16
21
Total: 57
1.00
0.80
0.84
Ref.
0.41-1.59
0.45-1.59
Ref.
0.53
0.6
 
 
 
       (detail) 70 (-)
(49 - 93)
AD Diagnosis: NINCDS ADRDA
(detail)
A, E, G, Kcal‡
(detail)
Corrada, 2005
Corrada, 2005 BLSA Incidence study reporting hazard ratios (HRs) 579
(38%)
9.3 y
0.2-2.4 μg/day: 8%
2.4-314.8 μg/day: 92%
(detail)
7
50
Total: 57
1.00
0.60
Ref.
0.26-1.36
Ref.
0.22
 
 
       (detail) 70 (-)
(49 - 93)
AD Diagnosis: NINCDS ADRDA
(detail)
A, E, G, Kcal‡
(detail)
Corrada, 2005
Luchsinger, 2007 WHICAP Incidence study reporting hazard ratios (HRs) 965
(70%)
6.1 y
Lowest quartile <3.5 μg/day): 25%
Second quartile (3.5-6.6 μg/day): 25%
Third quartile (6.7-13.5 μg/day): 25%
Highest quartile (>13.5 μg/day): 25%
(detail)
-
-
-
-
Total: 192
1.00
0.70
1.20
1.10
Ref.
0.40-1.00
0.80-1.90
0.70-1.70
Ref.
0.13
0.41
0.67
*
 
 
 
 
      Caucasian, Hispanic, African-American (Black)
(detail)
76 (6)
(65 - )
AD Diagnosis: DSM IV, NINCDS ADRDA
(detail)
A, E, G, APOE4, CHD, DM, HTN, SM, SH, FOLTOTL, VTB6‡
(detail)
Luchsinger, 2007
Morris, 2006 CHAP Cohort study reporting odds ratios (ORs) 1041
(62%)
3.9 y
Lowest quintile (median: 3.1 μg/day): 20%
Second quintile (median: 5.3 μg/day): 20%
Third quintile (median: 7.8 μg/day): 20%
Fourth quintile (median: 12.7 μg/day): 20%
Highest quintile (median: 20.6 μg/day): 20%
(detail)
-
-
-
-
-
Total: 161
1.00
1.00
0.60
1.70
0.60
Ref.
0.40-2.70
0.30-1.50
0.70-4.40
0.20-1.60
Ref.
0.99
0.21
0.26
0.34
*
 
 
 
 
 
      Caucasian, African-American (Black)
(detail)
73 (-)
(65 - )
Screening: CERAD

AD Diagnosis: NINCDS ADRDA
(detail)
A, E, G, APOE4, VITED, FUT, CA-Past, RE, NCNTOTL‡
(detail)
Morris, 2006
Nelson, 2009 Cache County Study Incidence study reporting hazard ratios (HRs) 3634
(57%)
9.0 y
Lowest quintile (mean: 3.4 μg/day): 20%
Second quintile (mean: 5.5 μg/day): 20%
Third quintile (mean: 8.1 μg/day): 20%
Fourth quintile (mean: 11.1 μg/day): 20%
Highest quintile (mean: 20.1 μg/day): 20%
(detail)
-
-
-
-
-
Total: 212
1.00
0.95
1.14
0.87
0.91
Ref.
0.58-1.54
0.71-1.81
0.50-1.53
0.52-1.60
Ref.
0.84
0.58
0.63
0.74
*
-
-
-
-
-
Total: 353
1.00
0.93
1.14
0.83
0.87
Ref.
0.60-1.46
0.74-1.74
0.49-1.39
0.52-1.46
Ref.
0.75
0.55
0.48
0.63
*
Caucasian
(detail)
75 (-)
(65 - )
Screening: 3MSE

AD Diagnosis: NINCDS ADRDA
(detail)
A, E, G, ALC, APOE4, BMI, Kcal, DM, MI, PA, SM, SH, FOLTOTL, VTB6‡
(detail)
Nelson, 2009
* Derived value.
‡ Covariates: "A" (age), "E" (education), "G" (gender), "ALC" (alcohol intake), "APOE4" (APOE e4 genotype), "BMI" (body mass index), "Kcal" (caloric intake), "CHD" (coronary heart disease), "DM" (diabetes mellitus), "VITED" (dietary vitamin E), "FUT" (follow up time), "HTN" (hypertension), "MI" (mycardial infarction history), "CA-Past" (Past Cognitive Activity ), "PA" (physical activity), "RE" (race/ethnicity), "SM" (smoking status), "SH" (stroke history), "FOLTOTL" (total folate), "NCNTOTL" (total niacin), "VTB6" (vitamin B6)
 
Table 10:   Serum folate (categorical)
Notes These studies evaluated serum folate concentrations in relation to AD risk.  
  Alzheimer Disease Total Dementia  
Paper Cohort Study Type # Subjects
(% Female)
Average Follow-up Time Exposure Distribution
# of Cases Effect Size 95% CI P-value # of Cases Effect Size 95% CI P-value Ethnicity Age at Start of Follow-up:
Mean (SD)
(Range)
Diagnostic Assessment Covariates & Analysis Comment Paper
Middleton, 2007 CSHA Cohort study reporting odds ratios (ORs) 318
(63%)
5.0 y
Below median: 50%
Above median: 50%
-
-
Total: 45
1.91
1.00
0.89-4.11
Ref.
0.1
Ref.
*
-
-
Total: 62
1.62
1.00
0.84-3.15
Ref.
0.15
Ref.
*
 (detail) 79 (-)
(65 - )
Screening: 3MSE

AD Diagnosis: DSM IIIR
(detail)
A, E, G, PA, VARS, VTB‡ Middleton, 2007
Ravaglia, 2005 CSBA Incidence study reporting hazard ratios (HRs) 816
(53%)
3.8 y
Lowest quartile (<8.9 nmol/L): 25%
Second quartile (8.9-11.8 nmol/L): 25%
Third quartile (11.9-15.2 nmol/L): 25%
Highest quartile (>15.2 nmol/L): 25%
(detail)
-
-
-
-
Total: 70
2.04
1.30
0.66
1.00
1.02-4.09
0.62-2.72
0.29-1.54
Ref.
0.05
0.48
0.34
Ref.
-
-
-
-
Total: 112
2.22
1.83
1.16
1.00
1.21-4.05
1.00-3.34
0.60-2.24
Ref.
0.01
0.05
0.66
Ref.
Caucasian
(detail)
74 (6)
(65 - )
Screening: MMSE

AD Diagnosis: DSM IV, NINCDS ADRDA
(detail)
A, E, G, APOE4, HCY, CRT, SH, VTB‡ Ravaglia, 2005
Ravaglia, 2005 CSBA Incidence study reporting hazard ratios (HRs) 816
(53%)
3.8 y
Below median (≤11.8 nmol/L): 50%
Above median (>11.8 nmol/L): 50%
(detail)
-
-
Total: 70
1.98
1.00
1.15-3.40
Ref.
0.01
Ref.
-
-
Total: 112
1.87
1.00
1.21-2.89
Ref.
0.005
Ref.
Caucasian
(detail)
74 (6)
(65 - )
Screening: MMSE

AD Diagnosis: DSM IV, NINCDS ADRDA
(detail)
A, E, G, APOE4, HCY, CRT, SH, VTB‡ Ravaglia, 2005
Wang, 2001 Kungsholmen Project Incidence study reporting hazard ratios (HRs) 370
(81%)
3.0 y
≤10 nmol/L: 15%
>10 nmol/L: 85%
(detail)
12
47
Total: 59
1.70
1.00
0.90-3.20
Ref.
0.1
Ref.
*
15
62
Total: 77
1.60
1.00
0.90-2.90
Ref.
0.12
Ref.
*
Caucasian
(detail)
- (-)
(75 - )
AD Diagnosis: DSM IIIR
(detail)
A, E, G‡ Wang, 2001
Wang, 2001 Kungsholmen Project Incidence study reporting hazard ratios (HRs) 370
(81%)
3.0 y
≤12 nmol/L: 28%
>12 nmol/L: 72%
(detail)
22
37
Total: 59
1.60
1.00
0.90-2.70
Ref.
0.09
Ref.
*
28
49
Total: 77
1.50
1.00
0.90-2.40
Ref.
0.11
Ref.
*
Caucasian
(detail)
- (-)
(75 - )
AD Diagnosis: DSM IIIR
(detail)
A, E, G‡ Wang, 2001
* Derived value.
‡ Covariates: "A" (age), "E" (education), "G" (gender), "APOE4" (APOE e4 genotype), "PA" (physical activity), "HCY" (plasma homocysteine), "CRT" (serum creatinine), "SH" (stroke history), "VARS" (vascular risk score), "VTB" (vitamin B12)
 
Table 11:   Serum folate (continuous, per decreasing ordinal category)
Notes These studies evaluated serum folate concentrations in relation to AD risk. Quantiles of serum folate concentrations were analyzed as a continuous variable.  
  Alzheimer Disease Total Dementia  
Paper Cohort Study Type # Subjects
(% Female)
Average Follow-up Time nmol/L
Mean (SD)
(Range)
# of Cases Effect Size 95% CI P-value # of Cases Effect Size 95% CI P-value Ethnicity Age at Start of Follow-up:
Mean (SD)
(Range)
Diagnostic Assessment Covariates & Analysis Comment Paper
Kim, 2008 Older adults in Kwangju, South Korea Cohort study reporting odds ratios (ORs) 518
(57%)
2.4 y
24.9 (13)
(7.8 - 88.4)
(detail)
34 1.32 1.00-1.75 0.05
*
45 1.41 1.08-1.82 0.01
*
Korean
72 (5)
(65 - )
Screening: CDR, MMSE, Neuropsych Testing, Other

AD Diagnosis: NINCDS ADRDA
(detail)
A, E, G, ALC, bsln wt, DEP, DISAB, PA, CRT, SM, VITS, VARS‡
(detail)
Kim, 2008
* Derived value.
‡ Covariates: "A" (age), "E" (education), "G" (gender), "ALC" (alcohol intake), "bsln wt" (baseline body weight), "DEP" (depression), "DISAB" (disability), "PA" (physical activity), "CRT" (serum creatinine), "SM" (smoking status), "VITS" (supplemental vitamin intake), "VARS" (vascular risk score)
 
Table 12:   Serum folate (continuous, per 1 nmol/L increase)
Notes These studies evaluated plasma or serum folate concentrations in relation to AD risk. The resulting effect estimate is the relative risk of AD corresponding to a 1 nmol/L increase in serum folate concentration.  
  Alzheimer Disease Total Dementia  
Paper Cohort Study Type # Subjects
(% Female)
Average Follow-up Time nmol/L
Mean (SD)
(Range)
# of Cases Effect Size 95% CI P-value # of Cases Effect Size 95% CI P-value Ethnicity Age at Start of Follow-up:
Mean (SD)
(Range)
Diagnostic Assessment Covariates & Analysis Comment Paper
Hooshmand, 2010 NKP-FINMONICA-CAIDE Cohort study reporting odds ratios (ORs) 271
(65%)
7.4 y
7.2 (4)
( - )
(detail)
17 1.03 0.91-1.16 0.63
*
        Caucasian
(detail)
71 (4)
( - )
Screening: MMSE

AD Diagnosis: NINCDS ADRDA
(detail)
A, E, G, APOE4, MMSE, BMI, DBP, FUT, SM, SH, SBP‡
(detail)
Hooshmand, 2010
* Derived value.
‡ Covariates: "A" (age), "E" (education), "G" (gender), "APOE4" (APOE e4 genotype), "MMSE" (baseline MMSE), "BMI" (body mass index), "DBP" (diastolic blood pressure), "FUT" (follow up time), "SM" (smoking status), "SH" (stroke history), "SBP" (systolic blood pressure)
 
Table 13:   Serum vitamin B12 (categorical)
Notes These studies evaluated serum vitamin B12 concentrations in relation to AD risk.  
  Alzheimer Disease Total Dementia  
Paper Cohort Study Type # Subjects
(% Female)
Average Follow-up Time Exposure Distribution
# of Cases Effect Size 95% CI P-value # of Cases Effect Size 95% CI P-value Ethnicity Age at Start of Follow-up:
Mean (SD)
(Range)
Diagnostic Assessment Covariates & Analysis Comment Paper
Ravaglia, 2005 CSBA Incidence study reporting hazard ratios (HRs) 816
(53%)
3.8 y
Below median (≤251 pmol/L): 50%
Above median (>251 pmol/L): 50%
(detail)
-
-
Total: 70
0.66
1.00
0.40-1.09
Ref.
0.1
Ref.
-
-
Total: 112
0.83
1.00
0.56-1.24
Ref.
0.37
Ref.
Caucasian
(detail)
74 (6)
(65 - )
Screening: MMSE

AD Diagnosis: DSM IV, NINCDS ADRDA
(detail)
A, E, G, APOE4, HCY, CRT, SH, VTB‡ Ravaglia, 2005
Wang, 2001 Kungsholmen Project Incidence study reporting hazard ratios (HRs) 370
(81%)
3.0 y
≤150 pmol/L: 16%
>150 pmol/L: 84%
(detail)
14
46
Total: 60
1.60
1.00
0.90-2.80
Ref.
0.1
Ref.
*
15
63
Total: 78
1.30
1.00
0.70-2.30
Ref.
0.39
Ref.
*
Caucasian
(detail)
- (-)
(75 - )
AD Diagnosis: DSM IIIR
(detail)
A, E, G‡ Wang, 2001
Wang, 2001 Kungsholmen Project Incidence study reporting hazard ratios (HRs) 370
(81%)
3.0 y
≤250 pmol/L: 47%
>250 pmol/L: 53%
(detail)
37
23
Total: 60
1.80
1.00
1.00-3.00
Ref.
0.04
Ref.
*
42
36
Total: 78
0.30
1.00
0.80-2.10
Ref.
0.29
Ref.
*
Caucasian
(detail)
- (-)
(75 - )
AD Diagnosis: DSM IIIR
(detail)
A, E, G‡ Wang, 2001
* Derived value.
‡ Covariates: "A" (age), "E" (education), "G" (gender), "APOE4" (APOE e4 genotype), "HCY" (plasma homocysteine), "CRT" (serum creatinine), "SH" (stroke history), "VTB" (vitamin B12)
 
Table 14:   Serum vitamin B12 (continuous, per decreasing ordinal category)
Notes These studies evaluated serum vitamin B12 concentrations in relation to AD risk. Quantiles of serum folate concentrations were analyzed as a continuous variable.  
  Alzheimer Disease Total Dementia  
Paper Cohort Study Type # Subjects
(% Female)
Average Follow-up Time pmol/L
Mean (SD)
(Range)
# of Cases Effect Size 95% CI P-value # of Cases Effect Size 95% CI P-value Ethnicity Age at Start of Follow-up:
Mean (SD)
(Range)
Diagnostic Assessment Covariates & Analysis Comment Paper
Kim, 2008 Older adults in Kwangju, South Korea Cohort study reporting odds ratios (ORs) 518
(57%)
2.4 y
380.7 (149)
(104 - 1334)
(detail)
34 0.93 0.71-1.21 0.59
*
45 1.06 0.83-1.34 0.63
*
Korean
- (-)
(65 - )
Screening: CDR, MMSE, Neuropsych Testing, Other

AD Diagnosis: NINCDS ADRDA
(detail)
A, E, G, ALC, bsln wt, DEP, DISAB, PA, CRT, SM, VITS, VARS‡
(detail)
Kim, 2008
* Derived value.
‡ Covariates: "A" (age), "E" (education), "G" (gender), "ALC" (alcohol intake), "bsln wt" (baseline body weight), "DEP" (depression), "DISAB" (disability), "PA" (physical activity), "CRT" (serum creatinine), "SM" (smoking status), "VITS" (supplemental vitamin intake), "VARS" (vascular risk score)
 
Table 15:   Plasma holotranscobalamin (categorical)
Notes These studies evaluated plasma holotranscobalamin concentrations (the active form of vitamin B12) in relation to AD risk.  
  Alzheimer Disease Total Dementia  
Paper Cohort Study Type # Subjects
(% Female)
Average Follow-up Time Exposure Distribution
# of Cases Effect Size 95% CI P-value # of Cases Effect Size 95% CI P-value Ethnicity Age at Start of Follow-up:
Mean (SD)
(Range)
Diagnostic Assessment Covariates & Analysis Comment Paper
Kivipelto, 2009 Kungsholmen Project Incidence study reporting hazard ratios (HRs) 228
(70%)
6.7 y
Lowest quartile: 25%
Second quartile: 25%
Third quartile: 25%
Highest quartile: 25%
(detail)
22
16
8
15
Total: 61
1.00
0.81
0.38
0.82
Ref.
0.39-1.69
0.15-0.94
0.36-1.87
Ref.
0.58
0.04
0.65
27
21
14
21
Total: 83
1.00
0.85
0.47
0.85
Ref.
0.45-1.61
0.23-0.96
0.43-1.67
Ref.
0.63
0.04
0.64
Caucasian
(detail)
81 (5)
(75 - 93)
Screening: DSM IIIR - dementia

AD Diagnosis: DSM IIIR
(detail)
A, E, G, albumin, APOE4, MMSE, BMI, HGB, HCY, CRT, FOL‡
(detail)
Kivipelto, 2009
‡ Covariates: "A" (age), "E" (education), "G" (gender), "albumin" (albumin), "APOE4" (APOE e4 genotype), "MMSE" (baseline MMSE), "BMI" (body mass index), "HGB" (hemoglobin), "HCY" (plasma homocysteine), "CRT" (serum creatinine), "FOL" (serum folate)
 
Table 16:   Plasma or serum holotranscobalamin (continuous, per 5 pmol/L increase)
Notes These studies evaluated plasma or serum holotranscobalamin concentrations in relation to AD risk. The resulting effect estimate is the relative risk of AD corresponding to a 5 pmol/L increase in plasma or serum holotranscobalamin concentration.  
  Alzheimer Disease Total Dementia  
Paper Cohort Study Type # Subjects
(% Female)
Average Follow-up Time pmol/L
Mean (SD)
(Range)
# of Cases Effect Size 95% CI P-value # of Cases Effect Size 95% CI P-value Ethnicity Age at Start of Follow-up:
Mean (SD)
(Range)
Diagnostic Assessment Covariates & Analysis Comment Paper
Hooshmand, 2010 NKP-FINMONICA-CAIDE Cohort study reporting odds ratios (ORs) 271
(65%)
7.4 y
Serum
91.3 (50)
( - )
(detail)

17

0.90
*

0.83-0.99
*

0.02
*

 

 

 

 
Caucasian
(detail)
71 (4)
( - )
Screening: MMSE

AD Diagnosis: NINCDS ADRDA
(detail)
A, E, G, APOE4, MMSE, BMI, DBP, FUT, SM, SH, SBP‡
(detail)
Hooshmand, 2010
Kivipelto, 2009 Kungsholmen Project Incidence study reporting hazard ratios (HRs) 228
(70%)
6.7 y
Plasma
105 (88)
(18 - 685)
(detail)

83

1.00
*

0.98-1.03
*

0.99
*

130

1.00
*

0.98-1.03
*

0.99
*
Caucasian
(detail)
81 (5)
(75 - 93)
Screening: DSM IIIR - dementia

AD Diagnosis: DSM IIIR
(detail)
A, E, G‡
(detail)
Kivipelto, 2009
* Derived value.
‡ Covariates: "A" (age), "E" (education), "G" (gender), "APOE4" (APOE e4 genotype), "MMSE" (baseline MMSE), "BMI" (body mass index), "DBP" (diastolic blood pressure), "FUT" (follow up time), "SM" (smoking status), "SH" (stroke history), "SBP" (systolic blood pressure)