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Risk Factor:
Risk Factor Type: Metabolic
Current Understanding:
The evidence from observational epidemiologic studies suggests that higher levels of plasma total homocysteine (tHcy) may be associated with an increased risk of incident Alzheimer's disease (AD). This body of findings is consistent with findings from related studies of cognitive decline, of brain imaging, and of genetic polymorphisms predisposing individuals to hyperhomocysteinemia. Recent trials of the tHcy-lowering vitamins—B6, B12, and folate, however, have had mixed, predominantly null results. Further research will be required to know whether supplementation with B vitamins starting in midlife, when it could prevent chronic elevation of homocysteine over a longer span, would provide greater benefit. For a review of the putative mechanisms by which homocysteine may influence AD risk and detailed commentary on interpreting the findings below in a broader context, please view the Discussion.
Last Search Completed: 27 October 2011


Table 1:   Homocysteine - continuous, per 1 µmol/L increment
Notes This report examines the relationship between plasma level of homocysteine and AD risk. Effect sizes are per one-µmol/L increment in plasma homocysteine.  
  Alzheimer Disease Total Dementia  
Paper Cohort Study Type # Subjects
(% Female)		 Average Follow-up Time
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
(62%)		 7.4 y
(detail)
13 (-)
( - )
(detail)		 17 1.19 1.01-1.39 0.03
*		         Caucasian
 71 (4)
( - )		 Screening: MMSE

AD Diagnosis: NINCDS ADRDA
(detail)		 A, E, G, APOE4, MMSE, BMI, DBP, SM, SH, SBP‡
(detail)		 Hooshmand, 2010
Kivipelto, 2009 Kungsholmen Project Cohort study reporting odds ratios (ORs) 228
(70%)		 6.7 y
19 (11)
(5 - 130)
(detail)		 61 1.06 1.02-1.10 < 0.0001
*		 83 1.04 1.01-1.07 0.01
*		 Caucasian
(detail)		 81 (5)
(75 - 93)
(detail)		 Screening: DSM IIIR - dementia

AD Diagnosis: DSM IIIR
(detail)		 A, E, G, Albumin, APOE234, MMSE, BMI, HGB, CRT‡
(detail)		 Kivipelto, 2009
* Derived value.
 ‡ Covariates: "A" (age), "E" (education), "G" (gender), "Albumin" (albumin), "APOE234" (APOE e2 e3 e4 genotype), "APOE4" (APOE e4 genotype), "MMSE" (baseline MMSE), "BMI" (body mass index), "DBP" (diastolic blood pressure), "HGB" (hemoglobin), "CRT" (serum creatinine), "SM" (smoking status), "SH" (stroke history), "SBP" (systolic blood pressure)
 
Table 2:   Homocysteine - continuous, per 1 log(µmol/L) increase
Notes These reports examine the relationship between log-transformed level of plasma homocysteine and AD.We have converted the study results to effect size per 25% increase in plasma homocysteine, using the formula, exp[ln(effect estimate)*ln(1.25)].  
  Alzheimer Disease Total Dementia  
Paper Cohort Study Type # Subjects
(% Female)		 Average Follow-up Time
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
Luchsinger, 2004 WHICAP Incidence study reporting hazard ratios (HRs) 679
(71%)		 4.0 y
*
16 (-)
( - )
(detail)		 109 1.06
*		 0.95-1.19
*		 0.34
*		         Caucasian, Hispanic, African-American (Black)
(detail)		 76 (6)
( - )
(detail)		 AD Diagnosis: NINCDS ADRDA
(detail)		 A, E, G, APOE4‡
(detail)		 Luchsinger, 2004
Ravaglia, 2005 CSBA Incidence study reporting hazard ratios (HRs) 816
(53%)		 3.8 y
(detail)
13 (7)
( - )
(detail)		 70 1.10
*		 1.05-1.16
*		 0.001
*		 112 1.08
*		 1.04-1.12
*		 0.001
*		 Caucasian
(detail)		 74 (6)
( - )
(detail)		 Screening: MMSE

AD Diagnosis: NINCDS ADRDA
(detail)		 A, E, G, APOE4, BMI, CVD, DM, HTN, CRT, FOL, SM, SH, VTB‡
(detail)		 Ravaglia, 2005
Seshadri, 2002 Framingham Heart Study Incidence study reporting hazard ratios (HRs) 1092
(61%)		 8.0 y
(detail)
13 (7)
( - )
(detail)		 44 1.14
*		 1.06-1.22
*		 0.001
*		 60 1.06
*		 1.02-1.09
*		 0.007
*		 Caucasian
 76 (6)
(68 - 97)		 Screening: MMSE

AD Diagnosis: NINCDS ADRDA
(detail)		 A, E, G, ALC, APOE4, BMI, DM, SM, SH, SBP, VTB, VTB6‡
(detail)		 Seshadri, 2002
Seshadri, 2002 Framingham Heart Study Incidence study reporting hazard ratios (HRs) 935
(61%)		 16 y
*
(detail)
13 (7)
( - )
(detail)		 56 1.11
*		 1.04-1.18
*		 0.001
*		 72 1.07
*		 1.02-1.15
*		 0.01
*		 Caucasian
 68 (6)
( - )
(detail)		 Screening: MMSE

AD Diagnosis: NINCDS ADRDA
(detail)		 A, E, G, ALC, APOE4, BMI, DM, SM, SH, SBP‡
(detail)		 Seshadri, 2002
* Derived value.
 ‡ Covariates: "A" (age), "E" (education), "G" (gender), "ALC" (alcohol intake), "APOE4" (APOE e4 genotype), "BMI" (body mass index), "CVD" (cardiovascular disease), "DM" (diabetes mellitus), "HTN" (hypertension), "CRT" (serum creatinine), "FOL" (serum folate), "SM" (smoking status), "SH" (stroke history), "SBP" (systolic blood pressure), "VTB" (vitamin B12), "VTB6" (vitamin B6)
 
Table 3:   Homocysteine - categorical
Notes These reports examine the relationship between categories of plasma homocysteine level and AD.  
  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 Cohort study reporting odds ratios (ORs) 228
(70%)		 6.7 y
Lowest quartile: 25%
2nd quartile: 25%
3rd quartile: 25%
Highest quartile: 25%
(detail)		 13
8
12
28
Total: 61		 1.00
0.71
1.45
2.57		 Ref.
0.26-1.91
0.57-3.69
1.06-6.24		 Ref.
0.5
0.42
0.04		 19
14
15
35
Total: 83		 1.00
0.83
1.12
1.79		 Ref.
0.39-1.77
0.51-2.42
0.86-3.74		 Ref.
0.64
0.77
0.12		 Caucasian
(detail)		 81 (5)
(75 - 93)
(detail)		 Screening: DSM IIIR - dementia

AD Diagnosis: DSM IIIR
(detail)		 A, E, G, Albumin, APOE234, MMSE, BMI, HGB, HTC, CRT, FOL, VTB‡
(detail)		 Kivipelto, 2009
Luchsinger, 2004 WHICAP Incidence study reporting hazard ratios (HRs) 679
(71%)		 4.0 y
*
≤10.5 µmol/L (mean, 10.8): 26%
10.6-15.6 µmol/L (mean, 14.1): 27%
15.7-19.7 µmol/L (mean, 17.5): 24%
>19.75 µmol/L (mean, 27.4): 23%
(detail)		 25
27
25
32
Total: 109		 1.00
1.10
0.90
1.40		 Ref.
0.60-1.90
0.60-1.80
0.80-2.40		 Ref.
0.75
0.71
0.23
*		  
 
 
 		       Caucasian, Hispanic, African-American (Black)
(detail)		 76 (6)
( - )
(detail)		 AD Diagnosis: NINCDS ADRDA
(detail)		 A, E, G, APOE4‡
(detail)		 Luchsinger, 2004
Ravaglia, 2005 CSBA Incidence study reporting hazard ratios (HRs) 816
(53%)		 3.8 y
(detail)
<10.1 µmol/L: 26%
10.1 -12.5 µmol/L: 25%
12.6 -15.0 µmol/L: 23%
>15.0 µmol/L: 27%
(detail)		 8
17
14
31
Total: 70		 1.00
2.43
2.50
4.20
*		 Ref.
0.95-6.20
0.95-5.90
1.75-11.07
*		 Ref.
0.06
0.06
0.002		 13
23
21
55
Total: 112		 1.00
1.75
2.00
3.50
*		 Ref.
0.75-3.50
0.50-4.10
1.75-7.67
*		 Ref.
0.12
0.06
0.001		 Caucasian
(detail)		 74 (6)
( - )		 Screening: MMSE

AD Diagnosis: NINCDS ADRDA
(detail)		 A, E, G, APOE234, CRT, FOL, SH, VTB‡
(detail)		 Ravaglia, 2005
Ravaglia, 2005 CSBA Incidence study reporting hazard ratios (HRs) 816
(53%)		 3.8 y
(detail)
≤15 µmol/L: 73%
>15 µmol/L: 27%
(detail)		 39
53
Total: 92		 1.00
1.96		 Ref.
1.09-3.50		 Ref.
0.02		 57
55
Total: 112		 1.00
2.16		 Ref.
1.37-4.00		 Ref.
0.001		 Caucasian
(detail)		 74 (6)
( - )
(detail)		 Screening: MMSE

AD Diagnosis: NINCDS ADRDA
(detail)		 A, E, G, APOE4, CRT, FOL, VTB‡
(detail)		 Ravaglia, 2005
Seshadri, 2002 Framingham Heart Study Incidence study reporting hazard ratios (HRs) 1092
(61%)		 8.0 y
(detail)
Lowest three quartiles: 75%
Highest quartile: 25%
(detail)		 -
54
Total: 54		 1.00
2.80		 Ref.
1.40-5.40		 Ref.
0.003		 -
77
Total: 77		 1.00
2.50		 Ref.
1.50-4.40		 Ref.
0.001		 Caucasian
 76 (6)
(68 - 97)		 Screening: MMSE

AD Diagnosis: NINCDS ADRDA
(detail)		 A, G, APOE4, FOL, VTB, VTB6‡
(detail)		 Seshadri, 2002
Seshadri, 2002 Framingham Heart Study Incidence study reporting hazard ratios (HRs) 1092
(61%)		 16 y
*
(detail)
Lowest three quartiles: 75%
Highest quartile: 25%
(detail)		 38
63
Total: 101		 1.00
1.70		 Ref.
1.00-3.10		 Ref.
0.06		 48
82
Total: 130		 1.00
1.70		 Ref.
1.00-2.80		 Ref.
0.04		 Caucasian
 68 (6)
( - )		 Screening: MMSE

AD Diagnosis: NINCDS ADRDA
(detail)		 A, G, APOE4‡
(detail)		 Seshadri, 2002
* Derived value.
 ‡ Covariates: "A" (age), "E" (education), "G" (gender), "Albumin" (albumin), "APOE234" (APOE e2 e3 e4 genotype), "APOE4" (APOE e4 genotype), "MMSE" (baseline MMSE), "BMI" (body mass index), "HGB" (hemoglobin), "HTC" (holo-transcobalamin), "CRT" (serum creatinine), "FOL" (serum folate), "SH" (stroke history), "VTB" (vitamin B12), "VTB6" (vitamin B6)
 
 
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