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Risk Factor:
  (vitamin C, vitamin E)
Risk Factor Type: Nutrition and supplements
Current Understanding:
The tables in the Risk Factor Overview present a modest number of reports with generally null results on nutritional antioxidants (vitamins C and E)—based on dietary intake, dietary supplement use, or plasma levels— and risk of Alzheimer disease (AD) and total dementia. Apart from a possible suggestion of benefits of dietary vitamin E on AD risk, these data provide little support for a role of nutritional antioxidants in the prevention of Alzheimer disease. There are several limitations in these studies that could lead to either spurious negative or positive associations, and thus explain the mixed results. It also remains possible that specific types of exposures defined by timing (e.g., in midlife rather than late life), duration (e.g., over many years), or dietary context (e.g., with phytochemicals) might have beneficial effects that could not be detected in the studies reported to date. The collective findings from current studies do not suggest a protective effect of vitamin C on the risk of developing AD and therefore do not warrant a recommendation of increasing intake of vitamin C in the diet or through supplements to prevent AD. However, individuals might choose to increase intake of vitamin C for other reasons. For vitamin E supplementation, the body of the evidence argues against its use to prevent dementia due to lack of efficacy and potential toxicity. However, dietary vitamin E may be beneficial, and appears to carry little risk of toxicity. For a review of the putative mechanisms by which these nutritional antioxidants 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: 27 October 2016 - Last content update released on 22 Nov 2016.


Table 1:   Vitamin C supplement use (yes vs. no)
Meta-Analysis
Notes These reports examine any use of supplements that contain vitamin C in relation to AD risk. Some papers examined the associations of using vitamin C supplements in combination with or to the exclusion of multivitamin supplements. For such papers, we show only the overall association for vitamin C supplement use as defined in that paper, which generally excluded multivitamin use. The referents for comparison in these papers vary slightly. Many papers here compare vitamin C supplement users with non-users, while the referent groups in other papers comprised non-users of vitamin C supplements and vitamin E supplements, or non-users of multivitamins and vitamins C and E supplements.  
  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
Basambombo, 2016 CSHA Incidence study reporting hazard ratios (HRs) 5269
(3223%)		 5.2 y
(detail)
No vitamins: 62%
Yes (except multivitamins): 6%
(detail)		 414
20
Total: 434		 1.00
0.60		 Ref.
0.38-0.94		 Ref.
0.03
*		 600
33
Total: 633		 1.00
0.70		 Ref.
0.49-0.99		 Ref.
0.05
*		 Caucasian
(detail)		 76 (6)
(65 - )		 Screening: 3MSE

AD Diagnosis: DSM IIIR, NINCDS ADRDA
(detail)		 A, E, G, ALC, AIM, DM, SMHX, PA, VD‡
(detail)		 Basambombo, 2016
Gray, 2008 ACT-GHC Incidence study reporting hazard ratios (HRs) 2969
(60%)		 5.5 y
*
(detail)
No vitamins: 35%
Yes (except multivitamins): 38%
(detail)		 106
105
Total: 289		 1.00
0.95		 Ref.
0.72-1.25		 Ref.
0.72
*		 156
143
Total: 405		 1.00
0.90		 Ref.
0.71-1.13		 Ref.
0.37
*		 Caucasian, Other
(detail)		 76 (-)
(65 - )		 Screening: CASI

AD Diagnosis: NINCDS ADRDA
(detail)		 A, E, G, CHD, HS, PA, SM‡
(detail)		 Gray, 2008
Luchsinger, 2003 WHICAP Incidence study reporting hazard ratios (HRs) 980
(67%)		 4.0 y
No vitamin C: 64%
Yes (includes multivitamins): 36%
(detail)		 -
-
Total: 242		 1.00
0.85		 Ref.
0.64-1.13		 Ref.
0.26
*		  
 		       Caucasian, Hispanic, African-American (Black)
 75 (6)
(65 - )		 AD Diagnosis: NINCDS ADRDA
(detail)		 A, E, G, APOE4, RE, SM‡
(detail)		 Luchsinger, 2003
Masaki, 2000 HAAS Cumulative incidence study reporting odds ratios (ORs) 3385
(0%)		 -
(detail)
No supplemental vitamin C or E: 51%
Yes (except multivitamins): 15%
(detail)		 26
7
Total: 47		 1.00
1.73		 Ref.
0.82-3.64		 Ref.
0.15
*		  
 		       Japanese-American
(detail)		 74 (-)
(71 - 93)
(detail)		 Screening: CASI, CERAD, Informant interview

AD Diagnosis: NINCDS ADRDA
(detail)		 A, E, APOE4, O, SH, VITES‡
(detail)		 Masaki, 2000
Morris, 2002 CHAP Cumulative incidence study reporting odds ratios (ORs) 815
(62%)		 3.9 y
No supplemental vitamin C: 84%
Yes (except multivitamins): 16%
(detail)		 -
-
Total: 131		 1.00
0.51		 Ref.
0.23-1.12		 Ref.
0.09		  
 		       Caucasian, African-American (Black)
 73 (10)
(65 - )
(detail)		 AD Diagnosis: NINCDS ADRDA
(detail)		 A, E, G, APOE4, FUT, MV, RE, SS, VITES, VITCD‡
(detail)		 Morris, 2002
Zandi, 2004 Cache County Study Incidence study reporting hazard ratios (HRs) 3227
(56%)		 3.1 y
*
No vitamin C: 85%
Yes (includes multivitamins): 15%
(detail)		 88
11
Total: 99		 1.00
0.74		 Ref.
0.37-1.35		 Ref.
0.36
*		  
 		       Caucasian
(detail)		 72 (-)
(65 - )
(detail)		 Screening: DQ, 3MSE

AD Diagnosis: NINCDS ADRDA
(detail)		 A, E, G, APOE4, HS‡
(detail)		 Zandi, 2004
* Derived value.
 ‡ Covariates: "A" (age), "E" (education), "G" (gender), "ALC" (alcohol intake), "AIM" (anti-inflammatory medication), "APOE4" (APOE e4 genotype), "CHD" (coronary heart disease), "DM" (diabetes mellitus), "FUT" (follow up time), "HS" (health status), "SMHX" (history of smoking), "MV" (multivitamins), "O" (other), "PA" (physical activity), "RE" (race/ethnicity), "SM" (smoking status), "SS" (stratified sampling), "SH" (stroke history), "VITES" (supplemental vitamin E), "VD" (vascular disease), "VITCD" (vitamin C dietary)
 
Table 2:   Vitamin E supplement use (yes vs. no)
Meta-Analysis
Notes These reports examine any use of supplements that contain vitamin E in relation to AD risk. Some papers examined the associations of using vitamin E supplements in combination with or to the exclusion of other vitamin supplements. For such papers, we show only the overall association for vitamin E supplement use. The referents for comparison in these papers vary slightly. Many papers here compare vitamin E supplement users with non-users, while the referent groups in other papers comprised non-users of vitamin E supplements and vitamin C supplements, or non-users of multivitamins and vitamins E and C supplements.  
  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
Gray, 2008 ACT-GHC Incidence study reporting hazard ratios (HRs) 2969
(60%)		 5.5 y
(detail)
No vitamins: 35%
Yes: 32%
(detail)		 106
89
Total: 195		 1.00
1.04		 Ref.
0.78-1.39		 Ref.
0.79
*		 156
122
Total: 278		 1.00
0.98		 Ref.
0.77-1.25		 Ref.
0.87
*		 Caucasian, Other
(detail)		 76 (-)
(65 - )		 Screening: CASI

AD Diagnosis: NINCDS ADRDA
(detail)		 A, E, G, CHD, HS, PA, SM‡
(detail)		 Gray, 2008
Luchsinger, 2003 WHICAP Incidence study reporting hazard ratios (HRs) 980
(67%)		 4.0 y
No E: 66%
Yes: 34%
(detail)		 -
-
Total: 242		 1.00
0.91		 Ref.
0.68-1.22		 Ref.
0.53
*		  
 		       Caucasian, Hispanic, African-American (Black)
 75 (6)
(65 - )		 AD Diagnosis: NINCDS ADRDA
(detail)		 A, E, G, APOE4, SM‡
(detail)		 Luchsinger, 2003
Masaki, 2000 HAAS Cumulative incidence study reporting odds ratios (ORs) 3385
(0%)		 -
(detail)
No E or C: 62%
Yes: 27%
(detail)		 31
16
Total: 47		 1.00
1.03		 Ref.
0.47-2.25		 Ref.
0.94
*		  
 		       Japanese
(detail)		 74 (-)
(71 - 93)
(detail)		 Screening: CASI, CERAD, Informant interview

AD Diagnosis: NINCDS ADRDA
(detail)		 A, E, APOE4, O, SH‡ Masaki, 2000
Morris, 2002 CHAP Cumulative incidence study reporting odds ratios (ORs) 815
(62%)		 3.9 y
No E: 83%
Yes: 17%
(detail)		 -
-
Total: 131		 1.00
1.11		 Ref.
0.58-2.15		 Ref.
0.75
*		  
 		       Caucasian, African-American (Black)
 73 (10)
(65 - )
(detail)		 AD Diagnosis: NINCDS ADRDA, Other
(detail)		 A, E, G, APOE4, VITED, O, RE, SS‡
(detail)		 Morris, 2002
Zandi, 2004 Cache County Study Incidence study reporting hazard ratios (HRs) 3227
(56%)		 3.1 y
*
No E: 88%
Yes: 12%
(detail)		 93
6
Total: 99		 1.00
0.53		 Ref.
0.20-1.12		 Ref.
0.15
*		  
 		       Caucasian
(detail)		 72 (-)
(65 - )
(detail)		 Screening: DQ, 3MSE

AD Diagnosis: NINCDS ADRDA
(detail)		 A, E, G, APOE4, HS‡
(detail)		 Zandi, 2004
* Derived value.
 ‡ Covariates: "A" (age), "E" (education), "G" (gender), "ALC" (alcohol intake), "AIM" (anti-inflammatory medication), "APOE4" (APOE e4 genotype), "CHD" (coronary heart disease), "DM" (diabetes mellitus), "VITED" (dietary vitamin E), "HS" (health status), "SMHX" (history of smoking), "O" (other), "PA" (physical activity), "RE" (race/ethnicity), "SM" (smoking status), "SS" (stratified sampling), "SH" (stroke history), "VD" (vascular disease)
 
Table 3:   Dietary vitamin C intake (categorical)
Notes These studies evaluated vitamin C intake from diet in relation to AD risk. The studies measured dietary intake of vitamin C using a variety of methods, including food frequency questionnaires (measuring intake over the past year) and 24-hour recall exams (measuring intake in the past 24 hours as a proxy for usual intake). In addition, one study measured midlife dietary intake, while all other studies measured dietary intake later in life.  
  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
Devore, 2010 Rotterdam Study Incidence study reporting hazard ratios (HRs) 5395
(59%)		 9.6 y
Lowest tertile (median: 80 mg/day): 33%
Second tertile (median: 121 mg/day): 33%
Highest tertile (median: 174 mg/day): 33%
(detail)		 118
129
118
Total: 365		 1.00
1.01
0.96		 Ref.
0.79-1.30
0.74-1.25		 Ref.
0.94
0.76
*		 151
158
156
Total: 465		 1.00
0.96
0.99		 Ref.
0.77-1.21
0.79-1.25		 Ref.
0.72
0.93
*		  (detail) 68 (8)
(55 - )		 Screening: CAMDEX, GMS, Informant interview, MMSE

AD Diagnosis: DSM IIIR, NINCDS ADRDA
(detail)		 A, E, G, ALC, AOS, APOE4, BMI, Kcal, SM‡
(detail)		 Devore, 2010
Engelhart, 2002 Rotterdam Study Incidence study reporting hazard ratios (HRs) 5395
(59%)		 6.0 y
Lowest tertile (<95 mg/day): 33%
Second tertile (95-133 mg/day): 33%
Highest tertile (>133 mg/day): 33%
(detail)		 57
48
41
Total: 146		 1.00
0.76
0.66		 Ref.
0.51-1.12
0.44-1.00		 Ref.
0.17
0.05
*		  
 
 		        (detail) 68 (8)
(55 - )		 Screening: CAMDEX, GMS, Informant interview, MMSE

AD Diagnosis: DSM IIIR, NINCDS ADRDA
(detail)		 A, E, G, ALC, AOS, ATH, MMSE, BMI, Kcal, SMKPY, SMKH‡
(detail)		 Engelhart, 2002
Laurin, 2004 HAAS Incidence study reporting hazard ratios (HRs) 2459
(0%)		 30 y
*
(detail)
Lowest quartile (median: 23 mg/day): 25%
Second quartile (median: 69 mg/day): 25%
Third quartile (median: 128 mg/day): 25%
Highest quartile (median: 219 mg/day): 25%
(detail)		 33
27
34
46
Total: 140		 1.00
0.73
0.93
1.24		 Ref.
0.43-1.22
0.57-1.53
0.78-1.98		 Ref.
0.24
0.77
0.37
*		 58
43
59
75
Total: 235		 1.00
0.75
0.96
1.25		 Ref.
0.50-1.12
0.66-1.40
0.87-1.78		 Ref.
0.16
0.83
0.22
*		 Japanese
(detail)		 52 (4)
( - )		 Screening: CASI, MMSE, 3MSE

AD Diagnosis: NINCDS ADRDA
(detail)		 A, E, ALC, APOE4, BMI, Kcal, CVD, DBP, PA, SM, VITS, SBP, TC, YOB‡
(detail)		 Laurin, 2004
Luchsinger, 2003 WHICAP Incidence study reporting hazard ratios (HRs) 980
(67%)		 4.0 y
Lowest quartile (mean: 66 mg/day): 25%
Second quartile (mean: 115 mg/day): 25%
Third quartile (mean: 149 mg/day): 25%
Highest quartile (mean: 232 mg/day): 25%
(detail)		 -
-
-
-
Total: 242		 1.00
0.79
1.04
0.84		 Ref.
0.54-1.17
0.71-1.52
0.56-1.26		 Ref.
0.23
0.84
0.4
*		  
 
 
 		       Caucasian, Hispanic, African-American (Black)
 75 (6)
(65 - )		 AD Diagnosis: NINCDS ADRDA
(detail)		 A, E, G, APOE4, Kcal, SM‡
(detail)		 Luchsinger, 2003
Morris, 2002 CHAP Cumulative incidence study reporting odds ratios (ORs) 815
(62%)		 3.9 y
Lowest quintile (<72 mg/day): 20%
Second quintile (72-106 mg/day): 20%
Third quintile (106-135 mg/day): 20%
Fourth quintile (136-173 mg/day): 20%
Highest quintile (173-417 mg/day): 20%
(detail)		 -
-
-
-
-
Total: 131		 1.00
0.53
0.62
0.37
1.03		 Ref.
0.17-1.63
0.21-1.87
0.17-0.82
0.41-2.56		 Ref.
0.27
0.39
0.01
0.95
*		  
 
 
 
 		       Caucasian, African-American (Black)
 73 (10)
(65 - )
(detail)		 AD Diagnosis: NINCDS ADRDA
(detail)		 A, E, G, APOE4, Kcal, FUT, RE, SS‡
(detail)		 Morris, 2002
* Derived value.
 ‡ Covariates: "A" (age), "E" (education), "G" (gender), "ALC" (alcohol intake), "AOS" (antioxidative Supplements), "APOE4" (APOE e4 genotype), "ATH" (atherosclerosis), "MMSE" (baseline MMSE), "BMI" (body mass index), "Kcal" (caloric intake), "CVD" (cardiovascular disease), "DBP" (diastolic blood pressure), "FUT" (follow up time), "SMKPY" (pack-years of smoking), "PA" (physical activity), "RE" (race/ethnicity), "SMKH" (smoking habits), "SM" (smoking status), "SS" (stratified sampling), "VITS" (supplemental vitamin intake), "SBP" (systolic blood pressure), "TC" (total cholesterol), "YOB" (year of birth)
 
Table 4:   Dietary vitamin E intake (categorical)
Notes These studies evaluated vitamin E intake from diet in relation to AD risk. The studies measured dietary intake of vitamin E using a variety of methods, including food frequency questionnaires (measuring intake over the past year) and 24-hour recall exams (measuring intake in the past 24 hours as a proxy for usual intake). In addition, one study measured midlife dietary intake, while all other studies measured dietary intake later in life.  
  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
Devore, 2010 Rotterdam Study Incidence study reporting hazard ratios (HRs) 5395
(59%)		 9.6 y
Lowest tertile (median: 9.0 mg/day): 33%
Second tertile (median: 13.5 mg/day): 33%
Highest tertile (median: 18.5 mg/day): 33%
(detail)		 131
137
97
Total: 365		 1.00
1.12
0.74		 Ref.
0.88-1.44
0.56-0.97		 Ref.
0.37
0.03
*		 164
181
120
Total: 465		 1.00
1.20
0.75		 Ref.
0.97-1.49
0.59-0.95		 Ref.
0.1
0.02
*		  (detail) 68 (8)
(55 - )		 Screening: CAMDEX, GMS, Informant interview, MMSE

AD Diagnosis: DSM IIIR, NINCDS ADRDA
(detail)		 A, E, G, ALC, AOS, APOE4, BMI, Kcal, SM‡
(detail)		 Devore, 2010
Laurin, 2004 HAAS Incidence study reporting hazard ratios (HRs) 2459
(0%)		 30 y
*
(detail)
Lowest quartile (median: 3.8 mg/day): 25%
Second quartile (median: 10.7 mg/day): 25%
Third quartile (median: 18.0 mg/day): 25%
Highest quartile (median: 29.9 mg/day): 25%
(detail)		 25
43
30
42
Total: 140		 1.00
1.92
1.35
1.78		 Ref.
1.16-3.18
0.78-2.31
1.06-2.98		 Ref.
0.01
0.28
0.03
*		 48
67
59
61
Total: 235		 1.00
1.47
1.27
1.33		 Ref.
1.01-2.14
0.86-1.88
0.90-1.96		 Ref.
0.04
0.23
0.15
*		 Japanese-American
(detail)		 52 (4)
( - )		 Screening: CASI, MMSE, 3MSE

AD Diagnosis: NINCDS ADRDA
(detail)		 A, G, ALC, APOE4, BMI, Kcal, CVD, DBP, PA, SM, VITS, SBP, TC, YOB‡
(detail)		 Laurin, 2004
Luchsinger, 2003 WHICAP Incidence study reporting hazard ratios (HRs) 680
(67%)		 4.0 y
Lowest quartile (mean: 2.68 mg/day): 25%
Second quartile (mean: 3.35 mg/day): 25%
Third quartile (mean: 4.02 mg/day): 25%
Highest quartile (mean: 4.69 mg/day): 25%
(detail)		 -
-
-
-
Total: 242		 1.00
0.88
0.82
0.98		 Ref.
0.60-1.29
0.55-1.20
0.67-1.44		 Ref.
0.2
0.36
0.92
*		  
 
 
 		       Caucasian, Hispanic, African-American (Black)
 75 (6)
(65 - )		 AD Diagnosis: NINCDS ADRDA
(detail)		 A, E, G, APOE4, Kcal, SM‡
(detail)		 Luchsinger, 2003
Morris, 2002 CHAP Cumulative incidence study reporting odds ratios (ORs) 815
(62%)		 3.9 y
Lowest quintile (<4.69 mg/day): 20%
Second quintile (4.69-5.43 mg/day): 20%
Third quintile (5.43-6.10 mg/day): 20%
Fourth quintile (6.10-6.97 mg/day): 20%
Highest quintile (6.97-28.81 mg/day): 20%
(detail)		 -
-
-
-
-
Total: 131		 1.00
0.71
0.62
0.71
0.30		 Ref.
0.24-2.07
0.26-1.45
0.27-1.88
0.10-0.92		 Ref.
0.53
0.28
0.49
0.03
*		  
 
 
 
 		       Caucasian, African-American (Black)
 73 (10)
(65 - )
(detail)		 AD Diagnosis: NINCDS ADRDA, Other
(detail)		 A, E, G, APOE4, Kcal, FUT, RE, SS‡
(detail)		 Morris, 2002
* Derived value.
 ‡ Covariates: "A" (age), "E" (education), "G" (gender), "ALC" (alcohol intake), "AOS" (antioxidative Supplements), "APOE4" (APOE e4 genotype), "BMI" (body mass index), "Kcal" (caloric intake), "CVD" (cardiovascular disease), "DBP" (diastolic blood pressure), "FUT" (follow up time), "PA" (physical activity), "RE" (race/ethnicity), "SM" (smoking status), "SS" (stratified sampling), "VITS" (supplemental vitamin intake), "SBP" (systolic blood pressure), "TC" (total cholesterol), "YOB" (year of birth)
 
Table 5:   Dietary vitamin E intake (continuous, per 5 mg/d increase)
Notes This study evaluated AD risk across a continuum of vitamin E intake from diet. The resulting effect estimate is the relative risk of AD corresponding to a 5 mg increase in daily dietary vitamin E intake  
  Alzheimer Disease Total Dementia  
Paper Cohort Study Type # Subjects
(% Female)		 Average Follow-up Time mg/d
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
Morris, 2005 CHAP Cumulative incidence study reporting odds ratios (ORs) 1041
(62%)		 3.9 y
(detail)
- (-)
( - )
(detail)		 162 0.74 0.62-0.88 0.0007
*		         Caucasian, African-American (Black)
 74 (-)
(65 - )		 AD Diagnosis: NINCDS ADRDA, Other
(detail)		 A, E, G, APOE4, FUT, OB, RE, SS‡
(detail)		 Morris, 2005
* Derived value.
 ‡ Covariates: "A" (age), "E" (education), "G" (gender), "APOE4" (APOE e4 genotype), "FUT" (follow up time), "OB" (overweight/obesity), "RE" (race/ethnicity), "SS" (stratified sampling)
 
Table 6:   Total vitamin C intake (categorical)
Notes These studies evaluated the association between total vitamin C intake (dietary plus supplemental) and risk of Alzheimer disease.  
  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: 95.1 mg/day): 34%
Second tertile (median: 167.0 mg/day): 33%
Highest tertile (median: 495.1 mg/day): 33%
(detail)		 21
17
19
Total: 57		 1.00
0.56
0.61		 Ref.
0.29-1.09
0.31-1.18		 Ref.
0.09
0.14		  
 
 		        (detail) 70 (-)
(49 - 93)		 AD Diagnosis: NINCDS ADRDA
(detail)		 A, E, G, Kcal‡
(detail)		 Corrada, 2005
Luchsinger, 2003 WHICAP Incidence study reporting hazard ratios (HRs) 980
(67%)		 4.0 y
Lowest quartile (mean 79 mg/day): 25%
Second quartile (mean 141 mg/day): 25%
Third quartile (mean 203 mg/day): 25%
Highest quartile (mean 580 mg/day): 25%
(detail)		 -
-
-
-
Total: 242		 1.00
0.70
0.85
0.71		 Ref.
0.48-1.02
0.58-1.24
0.49-1.04		 Ref.
0.06
0.4
0.07
*		  
 
 
 		       Caucasian, Hispanic, African-American (Black)
 75 (6)
(65 - )		 AD Diagnosis: NINCDS ADRDA
(detail)		 A, E, G, APOE4, Kcal, SM‡
(detail)		 Luchsinger, 2003
Morris, 2002 CHAP Cumulative incidence study reporting odds ratios (ORs) 815
(62%)		 3.9 y
Lowest quintile (<93 mg/day): 20%
Second quintile (93-134 mg/day): 20%
Third quintile (135-185 mg/day): 20%
Fourth quintile (185-308 mg/day): 20%
Highest quintile (310-2530 mg/day): 20%
(detail)		 -
-
-
-
-
Total: 131		 1.00
0.68
0.79
1.11
0.79		 Ref.
0.24-1.97
0.34-1.87
0.47-2.65
0.33-1.91		 Ref.
0.47
0.59
0.81
0.6
*		  
 
 
 
 		       Caucasian, African-American (Black)
 73 (10)
(65 - )
(detail)		 AD Diagnosis: NINCDS ADRDA, Other
(detail)		 A, E, G, APOE4, Kcal, FUT, RE, SS‡
(detail)		 Morris, 2002
* Derived value.
 ‡ Covariates: "A" (age), "E" (education), "G" (gender), "APOE4" (APOE e4 genotype), "Kcal" (caloric intake), "FUT" (follow up time), "RE" (race/ethnicity), "SM" (smoking status), "SS" (stratified sampling)
 
Table 7:   Total vitamin E intake (categorical)
Notes These studies evaluated the association between total vitamin E intake (dietary plus supplemental) and risk of Alzheimer disease.  
  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: 3.3 mg/day): 34%
Second Tertile (median: 6.3 mg/day): 33%
Highest Tertile (median: 26.5 mg/day): 33%
(detail)		 23
17
17
Total: 57		 1.00
1.25
0.62		 Ref.
0.63-2.48
0.32-1.20		 Ref.
0.53
0.15		  
 
 		        (detail) 70 (-)
(49 - 93)		 AD Diagnosis: NINCDS ADRDA
(detail)		 A, E, G, Kcal‡
(detail)		 Corrada, 2005
Luchsinger, 2003 WHICAP Incidence study reporting hazard ratios (HRs) 980
(67%)		 4.0 y
Lowest quartile (mean 2.68 mg/day): 25%
Second quartile (mean 4.02 mg/day): 25%
Third quartile (mean 8.04 mg/day): 25%
Highest quartile (mean 171.52 mg/day): 25%
(detail)		 -
-
-
-
Total: 242		 1.00
0.75
0.97
0.76		 Ref.
0.51-1.10
0.66-1.41
0.52-1.13		 Ref.
0.14
0.88
0.17
*		  
 
 
 		       Caucasian, Hispanic, African-American (Black)
 75 (6)
(65 - )		 AD Diagnosis: NINCDS ADRDA
(detail)		 A, E, G, APOE4, Kcal, SM‡
(detail)		 Luchsinger, 2003
Morris, 2002 CHAP Cumulative incidence study reporting odds ratios (ORs) 815
(62%)		 3.9 y
Lowest quintile (<5.29 mg/day): 20%
Second quintile (5.29-6.50 mg/day): 20%
Third quintile (6.50 -11.66 mg/day): 20%
Fourth quintile (11.66-33.90 mg/day): 20%
Highest quintile (33.90-1112.20 mg/day): 20%
(detail)		 -
-
-
-
-
Total: 131		 1.00
0.82
0.50
0.84
0.81		 Ref.
0.42-1.59
0.21-1.21
0.33-2.09
0.37-1.81		 Ref.
0.56
0.45
0.71
0.41
*		  
 
 
 
 		       Caucasian, African-American (Black)
 73 (10)
(65 - )
(detail)		 AD Diagnosis: NINCDS ADRDA, Other
(detail)		 A, E, G, APOE4, Kcal, FUT, RE, SS‡
(detail)		 Morris, 2002
* Derived value.
 ‡ Covariates: "A" (age), "E" (education), "G" (gender), "APOE4" (APOE e4 genotype), "Kcal" (caloric intake), "FUT" (follow up time), "RE" (race/ethnicity), "SM" (smoking status), "SS" (stratified sampling)
 
Table 8:   Plasma or serum vitamin E (categorical)
Notes These studies evaluated plasma or serum vitamin E 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
Helmer, 2003 PAQUID Nested case control study with cumulative incidence sampling reporting odds ratios (ORs) 182
(63%)		 -
(detail)
µmol/L
Lowest tertile (11.0-21.0): 33%
Second tertile (21.01-25.52): 33%
Highest tertile (25.53-54.61): 33%
(detail)
-
-
-
Total: 39
1.00
1.53
0.33
Ref.
0.47-4.98
0.11-1.02
Ref.
0.47
0.05
*
-
-
-
Total: 46
1.00
0.82
0.32
Ref.
0.27-2.50
0.11-0.92
Ref.
0.73
0.03
*		  (detail) 77 (6)
(65 - )		 Screening: Informant interview

AD Diagnosis: DSM IIIR
(detail)		 A, E, G, APOE4, MMSE, BMI, HTN, O, SM, WINE‡§
(detail)		 Helmer, 2003
Mangialasche, 2010 Kungsholmen Project Incidence study reporting hazard ratios (HRs) 232
(80%)		 3.6 y
(detail)
µmol/mmol of cholesterol
Lowest tertile (≤6.87): 33%
Highest tertile (≥8.81): 33%
(detail)
18
11
Total: 29
1.00
0.55
Ref.
0.32-0.94
Ref.
0.03
*
 
 
 
 
 		  (detail) 85 (-)
(80 - )		 Screening: DSM IIIR - dementia, MMSE

AD Diagnosis: DSM IIIR, Medical History, NINCDS ADRDA
(detail)		 A, E, G, ALC, APOE4, MMSE, BMI, SVS, SM‡ Mangialasche, 2010
Sundelof, 2009b ULSAM Incidence study reporting hazard ratios (HRs) 761
(0%)		 5.5 y
*
(detail)
alpha-tocopherol (mg/mmol of cholesterol)
≤ 1.53: 50%
> 1.53: 50%
(detail)
-
-
Total: 45
1.00
0.67
Ref.
0.34-1.33
Ref.
0.25
-
-
Total: 80
1.00
0.90
Ref.
0.57-1.44
Ref.
0.25		 Caucasian
(detail)		 78 (1)
( - )		 Screening: MMSE

AD Diagnosis: DSM IV, NINCDS ADRDA
(detail)		 A, E, AIM, APOE4, ASP, BMI, DM, VITED, SM, SH, TC, VITCD‡ Sundelof, 2009b
Sundelof, 2009b ULSAM Incidence study reporting hazard ratios (HRs) 761
(0%)		 5.5 y
*
(detail)
gamma-tocopherol (mg/mmol of cholesterol)
≤ 0.09: 50%
> 0.09: 50%
(detail)
-
-
Total: 45
1.00
1.07
Ref.
0.58-1.58
Ref.
0.52
-
-
Total: 80
1.00
1.13
Ref.
0.71-1.78
Ref.
0.61		 Caucasian
(detail)		 78 (1)
( - )		 Screening: MMSE

AD Diagnosis: DSM IV, NINCDS ADRDA
(detail)		 A, E, AIM, APOE4, ASP, BMI, DM, VITED, SM, SH, TC, VITCD‡ Sundelof, 2009b
Sundelof, 2009b ULSAM Incidence study reporting hazard ratios (HRs) 616
(0%)		 9.0 y
*
(detail)
alpha-tocopherol (mg/mmol of cholesterol)
≤ 1.60: 50%
> 1.60: 50%
(detail)
-
-
Total: 36
1.00
1.26
Ref.
0.52-3.05
Ref.
0.6
-
-
Total: 86
1.00
1.28
Ref.
0.76-2.16
Ref.
0.35		 Caucasian
(detail)		 71 (1)
( - )		 Screening: MMSE

AD Diagnosis: DSM IV, NINCDS ADRDA
(detail)		 A, E, AIM, APOE4, ASP, BMI, DM, VITED, SM, SH, TC, VITCD‡ Sundelof, 2009b
Sundelof, 2009b ULSAM Incidence study reporting hazard ratios (HRs) 616
(0%)		 9.0 y
*
(detail)
gamma-tocopherol (mg/mmol of cholesterol)
≤ 0.18: 50%
> 0.18: 50%
(detail)
-
-
Total: 36
1.00
2.03
Ref.
0.82-5.04
Ref.
0.12
-
-
Total: 86
1.00
1.87
Ref.
1.10-3.18
Ref.
0.02		 Caucasian
(detail)		 71 (1)
( - )		 Screening: MMSE

AD Diagnosis: DSM IV, NINCDS ADRDA
(detail)		 A, E, AIM, APOE4, ASP, BMI, DM, VITED, SM, SH, TC, VITCD‡ Sundelof, 2009b
* Derived value.
 ‡ Covariates: "A" (age), "E" (education), "G" (gender), "ALC" (alcohol intake), "AIM" (anti-inflammatory medication), "APOE4" (APOE e4 genotype), "ASP" (aspirin ), "MMSE" (baseline MMSE), "BMI" (body mass index), "DM" (diabetes mellitus), "VITED" (dietary vitamin E), "SVS" (follow-up survival status), "HTN" (hypertension), "O" (other), "SM" (smoking status), "SH" (stroke history), "TC" (total cholesterol), "VITCD" (vitamin C dietary), "WINE" (wine consumption)
 § Covariates for total dementia are different.
 
Table 9:   Vitamin C and E supplement use (yes vs. no)
Meta-Analysis
Notes These reports examine any use of multiple supplements that contain vitamins C and E in relation to AD risk. Most papers examined the associations of using individual vitamin C and E supplements in combination with or to the exclusion of multivitamin supplements. For such papers, we show only the overall association for vitamin C and E supplement use as defined in that paper, which generally excluded multivitamin use. The referents for comparison in these papers are neither vitamin C nor E use. One paper reported separate effect estimates for joint vitamin C and E use when both were only parts of multivitamins.  
  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
Gray, 2008 ACT-GHC Incidence study reporting hazard ratios (HRs) 2969
(60%)		 5.5 y
*
(detail)
No vitamins: 35%
Yes (except multivitamins): 25%
(detail)		 106
70
Total: 289		 1.00
1.00		 Ref.
0.73-1.35		 Ref.
1.0
*		 156
95
Total: 405		 1.00
0.93		 Ref.
0.72-1.20		 Ref.
0.58
*		 Caucasian, Other
(detail)		 76 (-)
(65 - )		 Screening: CASI

AD Diagnosis: NINCDS ADRDA
(detail)		 A, E, G, CHD, HS, PA, SM‡
(detail)		 Gray, 2008
Laurin 2002 HAAS Incidence study reporting hazard ratios (HRs) 2369
(0%)		 5.2 y
long-term use (at 2 of 2 visits)
No vitamins: 48%
Yes (except multivitamins): 12%
(detail)
77
16
Total: 93
1.00
0.80
Ref.
0.45-1.42
Ref.
0.45
*
130
26
Total: 156
1.00
0.88
Ref.
0.56-1.37
Ref.
0.58
*		 Japanese-American
 - (-)
(71 - 92)		 AD Diagnosis: DSM IIIR, NINCDS ADRDA
(detail)		 A, E, ALC, APOE4, BMI, CVD, SM‡
(detail)		 Laurin 2002
Laurin 2002 HAAS Incidence study reporting hazard ratios (HRs) 2369
(0%)		 5.2 y
short-term use (at 1 of 2 visits)
No vitamins: 48%
Yes (except multivitamins): 6%
(detail)
77
7
Total: 84
1.00
0.61
Ref.
0.27-1.37
Ref.
0.23
*
130
15
Total: 145
1.00
0.80
Ref.
0.46-1.41
Ref.
0.43
*		 Japanese-American
 - (-)
(71 - 92)		 AD Diagnosis: DSM IIIR, NINCDS ADRDA
(detail)		 A, E, ALC, APOE4, BMI, CVD, SM‡
(detail)		 Laurin 2002
Masaki, 2000 HAAS Cumulative incidence study reporting odds ratios (ORs) 3385
(0%)		 -
(detail)
No supplemental vitamin C or E: 51%
Yes (except multivitamins): 21%
(detail)		 26
14
Total: 47		 1.00
1.81		 Ref.
0.91-3.62		 Ref.
0.09
*		  
 		       Japanese-American
(detail)		 74 (-)
(71 - 93)		 Screening: CASI, CERAD, Informant interview

AD Diagnosis: NINCDS ADRDA
(detail)		 A, E, APOE4, O, SH, VITES‡ Masaki, 2000
Maxwell, 2005 CSHA Cumulative incidence study reporting odds ratios (ORs) 894
(64%)		 5.0 y
(detail)
No vitamins: 86%
Yes (includes multivitamins): 10%
(detail)		 -
-
Total: 107		 1.00
0.79		 Ref.
0.48-1.32		 Ref.
0.36
*		 -
-
Total: 230		 1.00
1.00		 Ref.
0.53-1.87		 Ref.
1.0
*		 Caucasian
(detail)		 78 (7)
(65 - )		 Screening: 3MSE

AD Diagnosis: DSM IIIR, NINCDS ADRDA
(detail)		 A, G‡ Maxwell, 2005
Zandi, 2004 Cache County Study Incidence study reporting hazard ratios (HRs) 3227
(56%)		 3.1 y
*
(detail)
No vitamins: 60%
Yes (includes multivitamins): 8%
(detail)		 64
3
Total: 99		 1.00
0.36†		 Ref.
0.09-0.99		 Ref.
0.09
*		  
 		       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), "ALC" (alcohol intake), "APOE4" (APOE e4 genotype), "BMI" (body mass index), "CVD" (cardiovascular disease), "CHD" (coronary heart disease), "HS" (health status), "O" (other), "PA" (physical activity), "SM" (smoking status), "SH" (stroke history), "VITES" (supplemental vitamin E)