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Risk Factor:
Risk Factor Type: Metabolic
Current Understanding:
The tables below present a modest number of reports whose results, considered collectively, do not provide consistent support for an association between elevated peripheral blood levels of inflammatory markers (C-reactive protein [CRP], interleukin-6 [IL-6], alpha-1-antichymotrypsin [ACT], fibrinogen, lipoprotein-associated phospholipase A2 [Lp-PLA2], interleukin-1β [IL-1β] ) and risk for Alzheimer disease (AD). Associations between higher levels of these markers and total dementia risk are more suggestive, consistent with a reported link between vascular inflammation and vascular dementia. Individual markers were significantly associated with AD in some studies, but the evidence overall was inconsistent. The ability of peripheral inflammatory markers to represent inflammation in the central nervous system (CNS) is limited, and future studies may provide more clarity on the distinction between the roles of peripheral and CNS inflammation by identifying and measuring brain-specific markers of inflammation. In addition, it is possible that measurement of an overall inflammatory profile, particularly as it unfolds over time, may provide a much better test of the inflammatory hypothesis than individual markers measured on a single occasion. In the meantime, inflammatory responses might have an impact on disease progression, and could be the basis for developing and monitoring therapeutic treatments. For a review of the putative mechanisms by which inflammatory biomarkers may be related to AD risk and detailed commentary on interpreting the findings below in a broader context, please view the Discussion.
Last Search Completed: 10 May 2011


Table 1:   Serum C-reactive protein (CRP) - categorical
Notes The reports in this table examine categories of serum levels of C-reactive protein (CRP) in relation to AD risk. Higher levels of CRP indicate a higher degree of inflammatory response. To measure CRP, most investigations used a high-sensitivity laboratory assay, which better distinguishes among lower levels of CRP than standard assays do. Sensitivity at low CRP levels may be important, because very modest elevations in CRP (>1 mg/L) are associated with increased cardiovascular risk, which may have implications for AD risk. The strategy for categorizing CRP levels varied across the papers, with some using quantiles and others using pre-established cutpoints.  
  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, 2007 CSBA Incidence study reporting hazard ratios (HRs) 804
(53%)
3.7 y
(detail)
< 3.0 mg/L: 50%
> 3.0 mg/L: 50%
(detail)
34
34
Total: 68
1.00
1.10
*
Ref.
0.62-2.00
*
Ref.
0.75
*
50
59
Total: 109
1.00
1.40
*
Ref.
0.90-2.10
*
Ref.
0.12
*
 (detail) 74 (6)
( - )
(detail)
Screening: Informant interview, MMSE, Other

AD Diagnosis: NINCDS ADRDA
(detail)
A, E, G, APOE4, BMI, CVD, PA, HCY, CRT, FOL, SH, VTB‡
(detail)
Ravaglia, 2007
Schmidt, 2002 HAAS Nested case control study with cumulative incidence sampling reporting odds ratios (ORs) 1050
(0%)
25 y
*
< 0.34 mg/L: 24%
0.34-0.56 mg/L: 26%
0.57-1.00 mg/L: 25%
>1.00 mg/L: 25%
(detail)
-
-
-
-
Total: 95
1.00
2.80
5.40
2.30
Ref.
1.30-6.30
2.50-11.70
1.00-5.40
Ref.
0.01
< 0.0001
0.05
*
-
-
-
-
Total: 214
1.00
2.70
3.80
2.40
Ref.
1.50-4.90
1.30-4.30
1.30-4.30
Ref.
0.001
< 0.0001
0.004
*
Japanese-American
(detail)
55 (5)
( - )
Screening: CASI, IQ-CODE

AD Diagnosis: Brain Imaging, CERAD, DSM IIIR, Neuropsychological examination
(detail)
A, E, ABI, APOE4, AF, BMI, CHD, DM, DBP, FUT, LVH, SM, SH, SBP, TC‡
(detail)
Schmidt, 2002
Sundelof, 2009a ULSAM Incidence study reporting hazard ratios (HRs) 749
(0%)
5.3 y
(detail)
< 1.81 mg/L: 50%
> 1.81 mg/L: 50%
(detail)
-
-
Total: 46
1.00
0.77
Ref.
0.38-1.55
Ref.
0.48
-
-
Total: 70
1.00
1.21
Ref.
0.76-1.93
Ref.
0.42
Caucasian
(detail)
78 (1)
( - )
(detail)
Screening: MMSE, Other

AD Diagnosis: DSM IV, NINCDS ADRDA
(detail)
A, E, AIM, APOE4, ASP, BMI, DM, HTN, SCH, SM, SH‡
(detail)
Sundelof, 2009a
Sundelof, 2009a ULSAM Incidence study reporting hazard ratios (HRs) 1062
(0%)
11 y
(detail)
< 1.19 mg/L: 50%
> 1.19 mg/L: 50%
(detail)
-
-
Total: 81
1.00
1.23
Ref.
0.72-1.10
Ref.
0.43
-
-
Total: 165
1.00
1.21
Ref.
0.85-1.73
Ref.
0.3
Caucasian
(detail)
71 (1)
( - )
(detail)
Screening: MMSE, Other

AD Diagnosis: DSM IV, NINCDS ADRDA
(detail)
A, E, AIM, APOE4, ASP, BMI, DM, HTN, SCH, SM, SH‡
(detail)
Sundelof, 2009a
Tan, 2007 Framingham Heart Study Incidence study reporting hazard ratios (HRs) 691
(62%)
7.0 y
(detail)
low (0 mg/L): 69%
intermediate (1-2 mg/L): 12%
high (> 3 mg/L): 19%
(detail)
30
3
11
Total: 44
1.00
0.75†
1.68
Ref.
0.22-2.57
0.75-3.71
Ref.
0.65
0.21
 
 
 
       (detail) 79 (5)
( - )
Screening: MMSE, Other

AD Diagnosis: Autopsy, Brain Imaging, Medical History, NINCDS ADRDA, Neurologic examination, Neuropsychological examination
(detail)
A, E, G, APOE4, BMI, O, HCY, SM, SH‡
(detail)
Tan, 2007
* Derived value.
† Five or fewer cases exist.
‡ Covariates: "A" (age), "E" (education), "G" (gender), "ABI" (ankle-brachial index), "AIM" (anti-inflammatory medication), "APOE4" (APOE e4 genotype), "ASP" (aspirin ), "AF" (atrial fibrillation), "BMI" (body mass index), "CVD" (cardiovascular disease), "CHD" (coronary heart disease), "DM" (diabetes mellitus), "DBP" (diastolic blood pressure), "FUT" (follow up time), "HTN" (hypertension), "LVH" (left ventricular hypertrophy), "O" (other), "PA" (physical activity), "HCY" (plasma homocysteine), "SCH" (serum cholesterol), "CRT" (serum creatinine), "FOL" (serum folate), "SM" (smoking status), "SH" (stroke history), "SBP" (systolic blood pressure), "TC" (total cholesterol), "VTB" (vitamin B12)
 
Table 2:   C-reactive protein (CRP) - continuous, per 5-mg/L increase
Notes The report in this table examines AD risk in relation to plasma and serum C-reactive protein (CRP), modeled as a continuous variable. We report findings over a uniform interval of CRP (effect size per 5-mg/L increment in CRP), which required us to convert some results to fit this interval.  
  Alzheimer Disease Total Dementia  
Paper Cohort Study Type # Subjects
(% Female)
Average Follow-up Time mg/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
Engelhart, 2004 Rotterdam Study Case-cohort study reporting odds ratios (ORs) 727
(53%)
-
(detail)
- (6)
( - )
(detail)
140 1.08
*
0.97-1.22
*
0.19
*
188 1.10
*
1.00-1.22
*
0.06
*
 (detail) 72 (9)
( - )
Screening: CAMDEX, GMS, MMSE

AD Diagnosis: Brain Imaging, NINCDS ADRDA, Neurologic examination
(detail)
A, E, G‡
(detail)
Engelhart, 2004
Sundelof, 2009a ULSAM Incidence study reporting hazard ratios (HRs) 749
(0%)
5.3 y
(detail)
3.9 (7)
( - )
(detail)
46 0.90
*
0.69-1.17
*
0.43
*
70 1.05
*
0.89-1.25
*
0.57
*
Caucasian
(detail)
78 (1)
( - )
(detail)
Screening: 3MSE, Other

AD Diagnosis: DSM IV, NINCDS ADRDA
(detail)
A, E, AIM, APOE4, ASP, BMI, DM, HTN, SCH, SM, SH‡
(detail)
Sundelof, 2009a
Sundelof, 2009a ULSAM Incidence study reporting hazard ratios (HRs) 1062
(0%)
11 y
(detail)
3.4 (5)
( - )
(detail)
81 1.18
*
0.89-1.56
*
0.25
*
165 1.17
*
0.96-1.42
*
0.12
*
Caucasian
(detail)
71 (1)
( - )
(detail)
Screening: MMSE, Other

AD Diagnosis: DSM IV, NINCDS ADRDA
(detail)
A, E, AIM, APOE4, ASP, BMI, DM, HTN, SCH, SM, SH‡
(detail)
Sundelof, 2009a
* Derived value.
‡ Covariates: "A" (age), "E" (education), "G" (gender), "AIM" (anti-inflammatory medication), "APOE4" (APOE e4 genotype), "ASP" (aspirin ), "BMI" (body mass index), "DM" (diabetes mellitus), "HTN" (hypertension), "SCH" (serum cholesterol), "SM" (smoking status), "SH" (stroke history)
 
Table 3:   Interleukin 6 (IL-6) - categorical
Notes The reports in this table examine serum or plasma levels of interleukin 6 (IL-6) in relation to AD risk. They evaluate IL-6 in categories, where higher categories of IL-6 reflect a higher degree of inflammatory response.  
  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, 2007 CSBA Incidence study reporting hazard ratios (HRs) 804
(53%)
3.7 y
(detail)
< 1.17 pg/mL: 50%
> 1.17 pg/mL: 50%
(detail)
28
40
Total: 68
1.00
1.20
*
Ref.
0.68-2.00
*
Ref.
0.51
*
45
64
Total: 109
1.00
1.10
*
Ref.
0.75-1.70
*
Ref.
0.65
*
 (detail) 74 (6)
( - )
(detail)
Screening: Informant interview, MMSE, Other

AD Diagnosis: NINCDS ADRDA
(detail)
A, E, G, APOE4, BMI, CVD, PA, HCY, CRT, FOL, SH, VTB‡
(detail)
Ravaglia, 2007
Sundelof, 2009a ULSAM Incidence study reporting hazard ratios (HRs) 749
(0%)
5.3 y
(detail)
< 3.47 pg/mL: 50%
> 3.47 pg/mL: 50%
(detail)
-
-
Total: 46
1.00
0.86
Ref.
0.43-1.70
Ref.
0.66
-
-
Total: 70
1.00
1.28
Ref.
0.80-2.07
Ref.
0.3
Caucasian
(detail)
78 (1)
(≤ - )
(detail)
Screening: MMSE, Other

AD Diagnosis: DSM IV, NINCDS ADRDA
(detail)
A, E, AIM, APOE4, ASP, BMI, DM, HTN, SCH, SM, SH‡
(detail)
Sundelof, 2009a
Sundelof, 2009a ULSAM Incidence study reporting hazard ratios (HRs) 1062
(0%)
11 y
(detail)
< 3.47 pg/mL: 50%
> 3.47 pg/mL: 50%
(detail)
-
-
Total: 81
1.00
1.31
Ref.
0.78-2.21
Ref.
0.31
-
-
Total: 165
1.00
1.45
Ref.
1.06-2.07
Ref.
0.04
Caucasian
(detail)
71 (1)
( - )
(detail)
Screening: 3MSE, Other

AD Diagnosis: DSM IV, NINCDS ADRDA
(detail)
A, E, AIM, APOE4, ASP, BMI, DM, HTN, SCH, SM, SH‡
(detail)
Sundelof, 2009a
Tan, 2007 Framingham Heart Study Incidence study reporting hazard ratios (HRs) 540
(-)
7.0 y
(detail)
Lowest tertile: 36%
2nd tertile: 31%
Highest tertile: 33%
(detail)
9
11
13
Total: 33
1.00
1.22
1.27
Ref.
0.14-3.34
0.46-3.53
Ref.
0.7
0.64
 
 
 
       (detail) 79 (5)
( - )
(detail)
Screening: MMSE, Other

AD Diagnosis: Autopsy, Brain Imaging, Medical History, NINCDS ADRDA, Neurologic examination, Neuropsychological examination
(detail)
A, E, G, APOE4, BMI, O, HCY, SM, SH‡ Tan, 2007
* Derived value.
‡ Covariates: "A" (age), "E" (education), "G" (gender), "AIM" (anti-inflammatory medication), "APOE4" (APOE e4 genotype), "ASP" (aspirin ), "BMI" (body mass index), "CVD" (cardiovascular disease), "DM" (diabetes mellitus), "HTN" (hypertension), "IL-B" (interleukin-1ß), "O" (other), "OAS" (Overt Aggression Scale), "PA" (physical activity), "HCY" (plasma homocysteine), "SCH" (serum cholesterol), "CRT" (serum creatinine), "FOL" (serum folate), "SM" (smoking status), "SH" (stroke history), "VTB" (vitamin B12)
 
Table 4:   Plasma interleukin-6 (IL-6) - continuous, per 5-pg/mL increase
Notes The report in this table examines AD risk in relation to plasma interleukin-6 (IL-6), modeled as a continuous variable. We report findings over a uniform interval of IL-6 (effect size per 5-mg/L increment in IL-6), which required us to convert some results to fit this interval.  
  Alzheimer Disease Total Dementia  
Paper Cohort Study Type # Subjects
(% Female)
Average Follow-up Time pg/mL
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
Engelhart, 2004 Rotterdam Study Case-cohort study reporting odds ratios (ORs) 727
(53%)
-
(detail)
- (5)
( - )
(detail)
140
140
1.30
-
*
1.05-1.62
-
*
0.02
-
*
188 1.28
*
1.06-1.56
*
0.01
*
  72 (9)
( - )
Screening: CAMDEX, GMS, MMSE

AD Diagnosis: Brain Imaging, NINCDS ADRDA, Neurologic examination
(detail)
A, E, GठEngelhart, 2004
Sundelof, 2009a ULSAM Incidence study reporting hazard ratios (HRs) 749
(0%)
5.3 y
(detail)
3.9 (7)
( - )
(detail)
46 0.82
*
0.42-1.60
*
0.56
*
70 1.23
*
0.81-1.89
*
0.34
*
Caucasian
(detail)
- (-)
( - )
(detail)
Screening: MMSE, Other

AD Diagnosis: DSM IV, NINCDS ADRDA
(detail)
A, E, AIM, APOE4, ASP, BMI, DM, HTN, SCH, SM, SH‡
(detail)
Sundelof, 2009a
Sundelof, 2009a ULSAM Incidence study reporting hazard ratios (HRs) 1062
(0%)
11 y
(detail)
5.9 (9)
( - )
(detail)
81 1.03
*
0.90-1.19
*
0.68
*
165 1.23
*
1.12-1.35
*
< 0.0001
*
 (detail) 71 (1)
( - )
(detail)
Screening: MMSE, Other

AD Diagnosis: DSM IV, NINCDS ADRDA
(detail)
A, E, AIM, APOE4, ASP, BMI, DM, HTN, SCH, SM, SH‡
(detail)
Sundelof, 2009a
* Derived value.
‡ Covariates: "A" (age), "E" (education), "G" (gender), "AIM" (anti-inflammatory medication), "APOE4" (APOE e4 genotype), "ASP" (aspirin ), "BMI" (body mass index), "DM" (diabetes mellitus), "HTN" (hypertension), "SCH" (serum cholesterol), "SM" (smoking status), "SH" (stroke history)
§ Covariates for total dementia are different.
 
Table 5:   Plasma alpha-1-antichymotrypsin (ACT) - categorical
Notes The reports in this table examine plasma levels of alpha-1-antichymotrypsin (ACT) in relation to AD risk. They evaluate ACT in categories, where higher categories of ACT reflect a higher degree of inflammatory response.  
  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, 2007 CSBA Incidence study reporting hazard ratios (HRs) 804
(53%)
3.7 y
(detail)
< 369 mg/dL: 50%
> 369 mg/dL: 50%
(detail)
29
39
Total: 68
1.00
1.30
*
Ref.
0.74-2.20
*
Ref.
0.35
*
41
68
Total: 109
1.00
1.50
*
Ref.
0.96-2.20
*
Ref.
0.06
*
 (detail) 74 (6)
( - )
(detail)
Screening: Informant interview, MMSE, Other

AD Diagnosis: NINCDS ADRDA
(detail)
A, E, G, APOE4, BMI, CVD, PA, HCY, CRT, FOL, SH, VTB‡
(detail)
Ravaglia, 2007
* Derived value.
‡ Covariates: "A" (age), "E" (education), "G" (gender), "APOE4" (APOE e4 genotype), "BMI" (body mass index), "CVD" (cardiovascular disease), "PA" (physical activity), "HCY" (plasma homocysteine), "CRT" (serum creatinine), "FOL" (serum folate), "SH" (stroke history), "VTB" (vitamin B12)
 
Table 6:   Plasma alpha-1-antichymotrypsin (ACT) - continuous, per 15-mg/dL increase
Notes The report in this table examines AD risk in relation to plasma alpha-1-antichymotrypsin (ACT), modeled as a continuous variable. We report findings over a uniform interval of ACT (effect size per 15-mg/dL increment in ACT), which required us to convert some results to fit this interval.  
  Alzheimer Disease Total Dementia  
Paper Cohort Study Type # Subjects
(% Female)
Average Follow-up Time mg/dL
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
Engelhart, 2004 Rotterdam Study Case-cohort study reporting odds ratios (ORs) 727
(53%)
-
(detail)
- (16)
( - )
(detail)
140 1.32
*
1.08-1.61
*
0.01
*
188 1.45
*
1.21-1.73
*
< 0.0001
*
 (detail) 72 (9)
( - )
Screening: CAMDEX, GMS, MMSE

AD Diagnosis: Brain Imaging, NINCDS ADRDA, Neurologic examination
(detail)
A, E, G‡ Engelhart, 2004
* Derived value.
‡ Covariates: "A" (age), "E" (education), "G" (gender)