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Risk Factor:
Risk Factor Type: Chronic disease, Metabolic
Current Understanding:
The tables below summarize results from observational studies of the relationship between diabetes mellitus and measures of pre-clinical diabetes with AD and total dementia. Overall, the evidence is consistent with an association between diabetes diagnosis and increased risk of AD, suggesting that measures to prevent diabetes -- such as exercise, weight reduction and diet control -- will likely provide some protective benefit. Preliminary studies examining the risk of AD in association with measures of pre-clinical diabetes seem to specifically link impaired glucose tolerance with increased AD risk, but further research is needed to better characterize the relationship between these measures and AD. While standard glucose control is critical to prevent microvascular and macrovascular complications of diabetes, and may also be beneficial for cognitive outcomes, the effects of tighter glucose control regimens on AD require further study. For a review of the putative mechanisms by which diabetes 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: 26 June 2012 - Last content update released on 1 Nov 2012


Table 1:   Diabetes mellitus diagnosis (yes vs. no)
Meta-Analysis
Notes These reports examine diabetes mellitus in relation to AD risk. Although very few reports distinguished persons with type 1 (previously called "juvenille onset") from persons with type 2 (previously called "adult onset") diabetes, the latter condition is far more common among older adults.  
  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
Ahtiluoto, 2010 V85+S Incidence study reporting hazard ratios (HRs) 355
(-)		 3.7 y
*
(detail)
No DM: 75%
DM: 25%
(detail)		 -
-		 1.00
2.45		 Ref.
1.33-4.53		 Ref.
0.004
*		 75
31
Total: 106		 1.00
2.09		 Ref.
1.34-3.25		 Ref.
0.001		  (detail) - (-)
(85 - )		 AD Diagnosis: DSM IIIR, NINCDS ADRDA
(detail)		 A, E, G, APOE4‡
(detail)		 Ahtiluoto, 2010
Akomolafe, 2006 Framingham Heart Study Incidence study reporting hazard ratios (HRs) 1594
(60%)		 13 y
No DM: 91%
DM: 9%
(detail)		 -
-
Total: 176		 1.00
1.15		 Ref.
0.65-2.05		 Ref.
0.63
*		 -
-
Total: 233		 1.00
1.20		 Ref.
0.74-1.96		 Ref.
0.46
*		 Caucasian
(detail)		 70 (7)
( - )
(detail)		 Screening: MMSE

AD Diagnosis: NINCDS ADRDA
(detail)		 A, E, G, ALC, BMI, CVD, HCY, SM, SH, SBP‡
(detail)		 Akomolafe, 2006
Arvanitakis, 2004 ROS Incidence study reporting hazard ratios (HRs) 824
(69%)		 5.5 y
No DM: 85%
DM: 15%
(detail)		 120
31
Total: 151		 1.00
1.58		 Ref.
1.05-2.38		 Ref.
0.03
*		  
 		       Caucasian
(detail)		 75 (-)
(55 - )		 Screening: CERAD

AD Diagnosis: NINCDS ADRDA
(detail)		 A, E, G, SH‡ Arvanitakis, 2004
Cheng, 2011 WHICAP Incidence study reporting hazard ratios (HRs) 1488
(67%)		 3.9 y
*
(detail)
No DM: 83%
DM: 17%
(detail)		 113
36
Total: 149		 1.00
1.60		 Ref.
1.00-2.60		 Ref.
0.05
*		 121
40
Total: 161		 1.00
1.70		 Ref.
1.10-2.70		 Ref.
0.02
*		 Caucasian, Hispanic, African-American (Black)
 76 (6)
(65 - )		 AD Diagnosis: NINCDS ADRDA
(detail)		 A, E, G, APOE4, RE‡
(detail)		 Cheng, 2011
Curb, 1999 HAAS Cumulative incidence study reporting odds ratios (ORs) 3742
(0%)		 -
(detail)
No midlife DM:         
Midlife DM:         
(detail)		 -
-		 1.00
0.98		 Ref.
0.48-1.99		 Ref.
0.96
*		 -
-		 1.00
1.10		 Ref.
0.69-1.76		 Ref.
0.69
*		 Japanese-American
(detail)		 - (-)
(45 - 68)
(detail)		 Screening: CASI

AD Diagnosis: CERAD, NINCDS ADRDA, Neurologic examination
(detail)		 A, E‡ Curb, 1999
Hassing, 2002 OCTO-TWIN Incidence study reporting hazard ratios (HRs) 621
(-)		 -
No DM:         
DM:         
(detail)		 -
-		 1.00
0.85		 Ref.
0.36-2.02		 Ref.
0.71
*		  
 		        (detail) - (-)
(80 - )		 Screening: MMSE

AD Diagnosis: NINCDS ADRDA
(detail)		 A, E, G, ANG, CHF, HTN, HYPOTN, MI, SMKH, SH, TIA‡
(detail)		 Hassing, 2002
Hayden, 2006 Cache County Study Incidence study reporting hazard ratios (HRs) 3123
(58%)		 3.2 y
No DM: 89%
DM: 11%
(detail)		 -
-
Total: 104		 1.00
1.33		 Ref.
0.66-2.46		 Ref.
0.4
*		 120
21
Total: 141		 1.00
1.56		 Ref.
0.90-2.56		 Ref.
0.1
*		 Caucasian
(detail)		 74 (6)
(65 - )		 Screening: "Modified" 3MSE, DQ, IQ-CODE

AD Diagnosis: DSM IIIR, NINCDS ADRDA
(detail)		 A, E, G, APOE4, CABG, CHD, HC, HTN, OB, SH‡
(detail)		 Hayden, 2006
Leibson, 1997 Rochester Epidemiology Project Incidence study reporting standardized morbidity ratios (SMRs) 33000
(59%)		 6.9 y
*
(detail)
No DM: 96%
DM: 4%
(detail)		 725
77
Total: 802		 1.00
1.59		 Ref.
1.25-1.98		 Ref.
< 0.0001
*		 912
101
Total: 1013		 1.00
1.60		 Ref.
1.30-1.95		 Ref.
< 0.0001
*		 Caucasian
(detail)		 - (-)
(45 - 99)
(detail)		 AD Diagnosis: Autopsy, DSM IIIR, Other
(detail)		 A, G‡
(detail)		 Leibson, 1997
Luchsinger, 2001 WHICAP Incidence study reporting hazard ratios (HRs) 1262
(69%)		 4.3 y
(detail)
No DM: 80%
DM: 20%
(detail)		 122
35
Total: 157		 1.00
1.30		 Ref.
0.84-1.88		 Ref.
0.2
*		  
 		       Caucasian, Hispanic, African-American (Black)
(detail)		 76 (6)
(65 - )		 AD Diagnosis: CDR, NINCDS ADRDA
(detail)		 A, E, G, APOE4, RE‡
(detail)		 Luchsinger, 2001
MacKnight, 2002 CSHA Cumulative incidence study reporting odds ratios (ORs) 5574
(61%)		 5.0 y
No DM: 91%
DM: 9%
(detail)		 -
-
Total: 267		 1.00
1.16		 Ref.
0.75-1.80		 Ref.
0.51
*		 -
-
Total: 467		 1.00
1.23		 Ref.
0.89-1.72		 Ref.
0.22
*		  (detail) 74 (6)
(65 - )		 Screening: 3MSE

AD Diagnosis: NINCDS ADRDA
(detail)		 A, E, G‡ MacKnight, 2002
Ott, 1999 Rotterdam Study Incidence study reporting hazard ratios (HRs) 6370
(59%)		 2.1 y
No DM: 89%
DM: 11%
(detail)		 -
-
Total: 89		 1.00
1.90		 Ref.
1.20-3.10		 Ref.
0.008
*		 92
34
Total: 126		 1.00
1.90		 Ref.
1.30-2.80		 Ref.
0.001
*		  (detail) 69 (-)
( - )		 Screening: GMS, MMSE, Other

AD Diagnosis: NINCDS ADRDA
(detail)		 A, G‡ Ott, 1999
Peila, 2002 HAAS Cumulative incidence study reporting odds ratios (ORs) 2574
(0%)		 2.9 y
(detail)
No DM: 65%
DM: 35%
(detail)		 37
32
Total: 69		 1.00
1.70		 Ref.
1.01-2.80		 Ref.
0.04
*		 75
53
Total: 128		 1.00
1.50		 Ref.
1.00-2.20		 Ref.
0.04
*		 Japanese-American
(detail)		 77 (4)
( - )
(detail)		 Screening: CASI

AD Diagnosis: NINCDS ADRDA
(detail)		 A, E, ALC, APOE4, O, SM‡
(detail)		 Peila, 2002
Tyas, 2001 MSHA Cumulative incidence study reporting odds ratios (ORs) 694
(62%)		 5.0 y
*
(detail)
No DM: 93%
DM: 7%
(detail)		 31
4
Total: 35		 1.00
2.70†		 Ref.
0.85-8.52		 Ref.
0.09
*		  
 		        (detail) 74 (6)
(65 - 93)
(detail)		 Screening: 3MSE

AD Diagnosis: NINCDS ADRDA
(detail)		 A, E, G‡ Tyas, 2001
Xu, 2004 Kungsholmen Project Incidence study reporting hazard ratios (HRs) 1301
(75%)		 4.3 y
*
No DM: 91%
DM: 9%
(detail)		 237
23
Total: 260		 1.00
1.30		 Ref.
0.80-1.90		 Ref.
0.23
*		 313
37
Total: 350		 1.00
1.50		 Ref.
1.10-2.10		 Ref.
0.01
*		  (detail) 82 (-)
(75 - )		 AD Diagnosis: NINCDS ADRDA, Other
(detail)		 A, E, G‡ Xu, 2004
Xu, 2009 HARMONY Nested case control study with cumulative incidence sampling reporting odds ratios (ORs) 13665
(56%)		 -
No DM: 90%
DM: 10%
(detail)		 236
56
Total: 292		 1.00
2.03		 Ref.
1.47-2.80		 Ref.
< 0.0001
*		 498
139
Total: 637		 1.00
2.45		 Ref.
1.97-3.03		 Ref.
< 0.0001
*		  (detail) - (-)
(65 - )		 Screening: BDRS, TELE

AD Diagnosis: CERAD, DSM IV, Medical History, NINCDS ADRDA, Neuropsychological examination
(detail)		 A, E, G‡
(detail)		 Xu, 2009
* Derived value.
 † Five or fewer cases exist.
 ‡ Covariates: "A" (age), "E" (education), "G" (gender), "ALC" (alcohol intake), "ANG" (angina), "APOE4" (APOE e4 genotype), "BMI" (body mass index), "CVD" (cardiovascular disease), "CBVD" (cerebrovascular disease), "CHF" (congestive heart failure history), "CABG" (coronary artery bypass graft), "CHD" (coronary heart disease), "HC" (high cholesterol), "HTN" (hypertension), "HYPOTN" (hypotension), "MI" (mycardial infarction history), "O" (other), "OB" (overweight/obesity), "HCY" (plasma homocysteine), "RE" (race/ethnicity), "RES" (residential township), "SMKH" (smoking habits), "SM" (smoking status), "SH" (stroke history), "SBP" (systolic blood pressure), "TIA" (transient ischemic attack history)
 
Table 2:   Prediabetes - categorical
Notes These studies examine prediabetes in relation to AD risk. Prediabetes refers to blood glucose concentrations that are above normal but lower than diagnostic thresholds for diabetes. Prediabetes is considered to be a high-risk state for eventual development of diabetes and encompasses two sub-categories, depending on the test used for diagnosis: impaired fasting glucose [IFG] and impaired glucose tolerance [IGT]. Studies included in this table vary with respect to criteria used to define prediabetes, and on the inclusion of participants with diabetes. (See exposure detail for the specific prediabetes criteria, category definitions, and participant populations used in each of the studies. See Table 3 for results from studies that evaluate categories of fasting blood glucose and/or medication use aligning with clinical definitions of metabolic syndrome. See Table 5 for studies that evaluate categories of blood glucose.)  
  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
Ohara, 2011 Hisayama Study Incidence study reporting hazard ratios (HRs) 1017
(57%)		 11 y
(detail)
Normal glucose tolerance: 55%
Impaired fasting glucose: 7%
Impaired glucose tolerance: 23%
Diabetes mellitus: 15%
(detail)		 51
5
29
20
Total: 105		 1.00
0.61†
1.60
2.05		 Ref.
0.24-1.55
0.99-2.59
1.18-3.57		 Ref.
0.29
0.05
0.01		 115
13
63
41
Total: 232		 1.00
0.63
1.35
1.74		 Ref.
0.35-1.13
0.98-1.86
1.19-2.53		 Ref.
0.12
0.07
0.04		 Japanese
(detail)		 68 (6)
(60 - )		 AD Diagnosis: Autopsy, Brain Imaging, DSM IIIR, NINCDS ADRDA
(detail)		 A, E, G, ALC, BMI, ECG, HTN, PA, SM, SH, TC, WHR‡ Ohara, 2011
Xu, 2007 Kungsholmen Project Incidence study reporting hazard ratios (HRs) 1173
(75%)		 5.0 y
(detail)
Among participants without diabetes only
No prediabetes: 96%
Prediabetes: 4%
(detail)
291
16
Total: 307
1.00
1.98
Ref.
1.12-3.50
Ref.
0.02
*
378
19
Total: 397
1.00
1.77
Ref.
1.02-3.12
Ref.
0.05
*		 Caucasian
(detail)		 81 (5)
(75 - )		 Screening: MMSE

AD Diagnosis: Death Records, Medical History, NINCDS ADRDA
(detail)		 A, E, G, AHD, MMSE, BMI, CHD, DBP, SVS, SH, SBP‡
(detail)		 Xu, 2007
* Derived value.
 † Five or fewer cases exist.
 ‡ Covariates: "A" (age), "E" (education), "G" (gender), "ALC" (alcohol intake), "AHD" (antihypertensive drug use), "MMSE" (baseline MMSE), "BMI" (body mass index), "CHD" (coronary heart disease), "DBP" (diastolic blood pressure), "ECG" (electrocardiogram abnormalities), "SVS" (follow-up survival status), "HTN" (hypertension), "PA" (physical activity), "SM" (smoking status), "SH" (stroke history), "SBP" (systolic blood pressure), "TC" (total cholesterol), "WHR" (waist to hip ratio)
 
Table 3:   Hyperglycemia (yes vs. no)
Notes These studies evaluate the association between hyperglycemia (elevated fasting glucose; HG) and incidence of Alzheimer disease and dementia. Their evaluations of hyperglycemia as a risk factor occurred within broader investigations of the metabolic syndrome, of which hyperglycemia is a component. Thus, the studies in this table use definitions of hyperglycemia that generally match that specified in the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria for metabolic syndrome. Hyperglycemic persons were those whose fasting blood glucose exceeded a particular threshold or who were taking anti-diabetes medications. (See exposure detail of the individual studies for their specific exposure definitions.) Hyperglycemia often overlaps with diagnosed diabetes, particularly uncontrolled diabetes, but it is also present in individuals who have undiagnosed diabetes or conditions that indicate the early stages of or elevated risks for diabetes (e.g., impaired fasting glycemia, impaired glucose tolerance). (See Table 2 for results from studies that evaluate categories of blood glucose aligning with clinical definitions of prediabetes. See Table 5 for studies that evaluate categories of blood glucose.)  
  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
Forti, 2010 CSBA Incidence study reporting hazard ratios (HRs) 466
(51%)		 3.9 y
(detail)
Ages 65-74 at baseline
No HG: 80%
HG: 20%
(detail)
12
6
Total: 18
1.00
2.40
Ref.
0.81-7.11
Ref.
0.15
25
10
Total: 35
1.00
1.83
Ref.
0.81-4.17
Ref.
0.19		  (detail) 69 (3)
(65 - 74)
(detail)		 Screening: MMSE

AD Diagnosis: DSM IV, NINCDS ADRDA
(detail)		 A, E, G, AO, APOE4, CVD, HDL, HHC, HTN, HTG, IS, SL, SH‡
(detail)		 Forti, 2010
Forti, 2010 CSBA Incidence study reporting hazard ratios (HRs) 283
(57%)		 3.9 y
(detail)
Ages 75+ at baseline
No HG: 82%
HG: 18%
(detail)
33
2
Total: 35
1.00
0.31†
Ref.
0.07-1.35
Ref.
0.12
*
44
8
Total: 52
1.00
0.79
Ref.
0.34-1.82
Ref.
0.54		  (detail) 80 (4)
(75 - )
(detail)		 Screening: MMSE

AD Diagnosis: DSM IV, NINCDS ADRDA
(detail)		 A, E, G, AO, APOE4, CVD, HDL, HHC, HTN, HTG, IS, SL, SH‡
(detail)		 Forti, 2010
Raffaitin, 2009 3C Incidence study reporting hazard ratios (HRs) 7087
(61%)		 -
(detail)
No HG: 88%
HG: 12%
(detail)		 -
-
Total: 134		 1.00
1.04		 Ref.
0.62-1.74		 Ref.
0.89		 -
-
Total: 208		 1.00
1.28		 Ref.
0.88-1.88		 Ref.
0.2		 Caucasian
(detail)		 73 (5)
(65 - )		 Screening: BVRT, IST, MMSE

AD Diagnosis: DSM IV, NINCDS ADRDA
(detail)		 A, E, G, SP‡
(detail)		 Raffaitin, 2009
* Derived value.
 † Five or fewer cases exist.
 ‡ Covariates: "A" (age), "E" (education), "G" (gender), "AO" (abdominal obeisity), "APOE4" (APOE e4 genotype), "CVD" (cardiovascular disease), "HDL" (HDL cholesterol), "HHC" (hyperhomocysteinemia), "HTN" (hypertension), "HTG" (hypertriglyceridemia), "IS" (inflammation status), "SL" (sedentary lifestyle), "SH" (stroke history), "SP" (study population)
 
Table 4:   Fasting blood glucose - continuous, per 1 mmol/L increment
Notes These studies evaluate the relationship between AD risk and fasting blood glucose level, considered as a continuous variable. Such reports assume an exponential (i.e., log-linear) relationship between fasting blood glucose level and AD risk. The studies varied in whether their analyses included or excluded participants with diabetes.  
  Alzheimer Disease Total Dementia  
Paper Cohort Study Type # Subjects
(% Female)		 Average Follow-up Time mmol/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
Ronnemaa, 2008 ULSAM Incidence study reporting hazard ratios (HRs) 2269
(0%)		 32 y
(detail)
5 (1)
( - )
(detail)		 102 0.94
*		 0.67-1.34
*		 0.73
*		 394 0.96
*		 0.81-1.13 0.63
*		 Caucasian
(detail)		 50 (1)
( - )		 Screening: 7MS, MMSE, TMT

AD Diagnosis: DSM IV, NINCDS ADRDA
(detail)		 A, E, BMI, SM, SBP, TC‡ Ronnemaa, 2008
Ronnemaa, 2009 ULSAM Incidence study reporting hazard ratios (HRs) 1125
(0%)		 12 y
(detail)
5.8 (2)
( - )
(detail)		 81 0.93
*		 0.72-1.21
*		 0.58
*		 257 1.11
*		 0.98-1.26
*		 0.1
*		 Caucasian
(detail)		 71 (1)
( - )		 Screening: 7MS, MMSE, TMT

AD Diagnosis: DSM IV, NINCDS ADRDA
(detail)		 A, E, BMI, DM, SM, SBP, TC‡
(detail)		 Ronnemaa, 2009
Schrijvers, 2010 Rotterdam Study Incidence study reporting hazard ratios (HRs) 3139
(58%)		 -
(detail)
No DM hx, up to 3 y of follow-up
5.7 (1)
( - )
(detail)
71
1.18
*
0.92-1.50
*
0.18
*
 
 
 
 		  (detail) 72 (7)
( - )		 Screening: CAMDEX, GMS, MMSE

AD Diagnosis: NINCDS ADRDA
(detail)		 A, E, G, APOE4, DBP, HDL, SBP, TG, WC‡
(detail)		 Schrijvers, 2010
Schrijvers, 2010 Rotterdam Study Incidence study reporting hazard ratios (HRs) 2881
(-)		 -
(detail)
No DM hx, 3-5.5 y of follow-up
- (-)
( - )
(detail)
72
0.84
*
0.58-1.20
*
0.35
*
 
 
 
 		  (detail) - (-)
( - )		 Screening: CAMDEX, GMS, MMSE

AD Diagnosis: NINCDS ADRDA
(detail)		 A, E, G, APOE4, DBP, HDL, SBP, TG, WC‡
(detail)		 Schrijvers, 2010
Schrijvers, 2010 Rotterdam Study Incidence study reporting hazard ratios (HRs) 2566
(-)		 -
(detail)
No DM hx, 5.5-9.7 y of follow-up
- (-)
( - )
(detail)
68
0.58
*
0.38-0.89
*
0.01
*
 
 
 
 		  (detail) - (-)
( - )		 Screening: CAMDEX, GMS, MMSE

AD Diagnosis: NINCDS ADRDA
(detail)		 A, E, G, APOE4, DBP, HDL, SBP, TG, WC‡
(detail)		 Schrijvers, 2010
* Derived value.
 ‡ Covariates: "A" (age), "E" (education), "G" (gender), "APOE4" (APOE e4 genotype), "BMI" (body mass index), "DM" (diabetes mellitus), "DBP" (diastolic blood pressure), "HDL" (HDL cholesterol), "SM" (smoking status), "SBP" (systolic blood pressure), "TC" (total cholesterol), "TG" (triglycerides), "WC" (waist circumference)
 
Table 5:   Blood glucose - categorical
Notes These studies evaluate the risk of AD across categories of blood glucose. The studies varied with respect to the specific blood glucose measure (fasting, random, post-load, or a combination) used to form the basis for the categories, and on the inclusion of participants with diabetes. (See Table 2 for results from studies that evaluate categories of blood glucose aligning with clinical definitions of prediabetes. See Table 3 for results from studies that evaluate categories of fasting blood glucose and/or medication use aligning with clinical definitions of metabolic syndrome.)  
  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
Ohara, 2011 Hisayama Study Incidence study reporting hazard ratios (HRs) 1017
(57%)		 11 y
(detail)
Fasting blood glucose (FG)
<100 mg/dl:         
100-109 mg/dl:         
110-125 mg/dl:         
>126 mg/dl:         
(detail)
48
30
16
11
Total: 105
1.00
1.11
0.99
1.41
Ref.
0.69-1.77
0.49-1.64
0.72-2.76
Ref.
0.67
0.97
0.32
101
71
39
21
Total: 232
1.00
1.18
0.96
1.21
Ref.
0.86-1.61
0.65-1.41
0.75-1.96
Ref.
0.3
0.84
0.44		 Japanese
(detail)		 68 (6)
(60 - )		 AD Diagnosis: Autopsy, Brain Imaging, DSM IIIR, NINCDS ADRDA
(detail)		 A, E, G, ALC, BMI, ECG, HTN, PA, SM, SH, TC, WHR‡ Ohara, 2011
Ohara, 2011 Hisayama Study Incidence study reporting hazard ratios (HRs) 1017
(57%)		 11 y
(detail)
2-hr blood glucose (2hG)
<120 mg/dl:         
121-139 mg/dl:         
140-199 mg/dl:         
> 200 mg/dl:         
(detail)
37
20
30
18
Total: 105
1.00
1.49
1.87
3.42
Ref.
0.83-2.67
1.13-3.12
1.83-6.40
Ref.
0.17
0.02
0.0001
85
44
67
36
Total: 232
1.00
1.16
1.50
2.47
Ref.
0.78-1.71
1.07-2.11
1.62-3.77
Ref.
0.47
0.02
< 0.0001		 Japanese
(detail)		 68 (6)
(60 - )		 AD Diagnosis: Autopsy, Brain Imaging, DSM IIIR, NINCDS ADRDA
(detail)		 A, E, G, ALC, BMI, ECG, HTN, PA, SM, SH, TC, WHR‡ Ohara, 2011
Peila, 2002 HAAS Cumulative incidence study reporting odds ratios (ORs) 1729
(0%)		 -
Fasting (FG) or 2-hr (2hG) blood glucose, no DM hx
FG<126 mg/dl or 2hG<200 mg/dl:         
FG>126 mg/dl or 2hG>200 mg/dl:         
(detail)
-
-
1.00
1.40
Ref.
0.70-2.90
Ref.
0.35
*
-
-
1.00
1.40
Ref.
0.80-2.40
Ref.
0.23
*		 Japanese-American
(detail)		 - (-)
( - )		 Screening: CASI

AD Diagnosis: NINCDS ADRDA
(detail)		 A, E, ABI, APOE4, BMI, O, SH, SBP, TC‡ Peila, 2002
Xu, 2004 Kungsholmen Project Incidence study reporting hazard ratios (HRs) 1301
(75%)		 4.7 y
(detail)
Random blood glucose
≤11 mmol/L:         
>11 mmol/L:         
(detail)
246
7
Total: 253
1.00
1.20
Ref.
0.50-2.50
Ref.
0.66
*
323
13
Total: 336
1.00
1.60
Ref.
0.90-2.80
Ref.
0.1
*		 Caucasian
(detail)		 82 (5)
(75 - )		 AD Diagnosis: Death Records, Medical History, NINCDS ADRDA
(detail)		 A, E, G, AHD, BMI, CHD, DBP, SH, SBP‡ Xu, 2004
* Derived value.
 ‡ Covariates: "A" (age), "E" (education), "G" (gender), "ALC" (alcohol intake), "ABI" (ankle-brachial index), "AHD" (antihypertensive drug use), "APOE4" (APOE e4 genotype), "BMI" (body mass index), "CHD" (coronary heart disease), "DBP" (diastolic blood pressure), "ECG" (electrocardiogram abnormalities), "HTN" (hypertension), "O" (other), "PA" (physical activity), "SM" (smoking status), "SH" (stroke history), "SBP" (systolic blood pressure), "TC" (total cholesterol), "WHR" (waist to hip ratio)
 
Table 6:   Fasting insulin - categorical
Notes These studies evaluate the association between categories of fasting serum insulin and incidence of Alzheimer disease. For this table, we have converted all reported insulin units to micro-international units per milliliter (μIU/ml).  
  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, 2004 WHICAP Incidence study reporting hazard ratios (HRs) 683
(71%)		 5.4 y
*
(detail)
No hyperinsulinemia (< 27 μIU/mL): 61%
Hyperinsulinemia (> 27 μIU/mL): 39%
(detail)		 -
-
Total: 137		 1.00
2.10		 Ref.
1.50-2.90		 Ref.
< 0.0001
*		 -
-
Total: 149		 1.00
1.90		 Ref.
1.40-2.70		 Ref.
0.0001
*		 Caucasian, Hispanic, African-American (Black)
(detail)		 76 (6)
(65 - )		 AD Diagnosis: NINCDS ADRDA
(detail)		 A, E, G, APOE4‡
(detail)		 Luchsinger, 2004
Luchsinger, 2004 WHICAP Incidence study reporting hazard ratios (HRs) 683
(71%)		 5.4 y
*
(detail)
Lowest quartile (mean: 7.9 μIU/mL): 25%
Second quartile (mean:15.6 μIU/mL): 25%
Third quartile (mean: 28.7 μIU/mL): 25%
Highest quartile (mean: 71.1 μIU/mL): 25%
(detail)		 -
-
-
-
Total: 137		 1.00
0.90
1.50
1.70		 Ref.
0.50-1.60
0.90-2.40
1.05-2.70		 Ref.
0.72
0.11
0.03
*		  
 
 
 		       Caucasian, Hispanic, African-American (Black)
(detail)		 76 (6)
(65 - )		 AD Diagnosis: NINCDS ADRDA
(detail)		 A, E, G, APOE4‡
(detail)		 Luchsinger, 2004
Muller, 2007 WHICAP Incidence study reporting hazard ratios (HRs) 542
(-)		 -
(detail)
Lowest 3 quartiles: 75%
Highest quartile: 25%
(detail)		 -
-
Total: 58		 1.00
1.40		 Ref.
0.90-2.70		 Ref.
0.23
*		 -
-
Total: 99		 1.00
1.60		 Ref.
1.00-2.50		 Ref.
0.04
*		 Caucasian, Hispanic, African-American (Black)
(detail)		 - (-)
( - )		 AD Diagnosis: DSM IV, NINCDS ADRDA
(detail)		 A, E, G, APOE4, RE, SM‡
(detail)		 Muller, 2007
Peila, 2004 HAAS Incidence study reporting hazard ratios (HRs) 2568
(0%)		 5.1 y
(detail)
Low (< 7.2 μIU/mL): 15%
Medium (7.2 - 23.0 μIU/mL): 68%
High (> 23 μIU/ml): 17%
(detail)		 -
-
-
Total: 148		 1.41
1.00
1.38		 0.92-2.16
Ref.
0.84-2.90		 0.12
Ref.
0.32
*		 -
-
-
Total: 244		 1.54
1.00
1.54		 1.11-2.11
Ref.
1.05-2.26		 0.008
Ref.
0.03
*		 Japanese-American
(detail)		 77 (-)
( - )		 Screening: CASI

AD Diagnosis: NINCDS ADRDA
(detail)		 A, E, APOE4, FGLU‡
(detail)		 Peila, 2004
* Derived value.
 ‡ Covariates: "A" (age), "E" (education), "G" (gender), "APOE4" (APOE e4 genotype), "FGLU" (fasting glucose), "RE" (race/ethnicity), "SM" (smoking status)
 
Table 7:   Fasting insulin - continuous, per 1 mU/L increment
Notes These studies evaluate the relationship between AD risk and fasting blood insulin level, considered as a continuous variable. Such reports assume an exponential (i.e., log-linear) relationship between fasting blood insulin level and AD risk.  
  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
Ronnemaa, 2008 ULSAM Incidence study reporting hazard ratios (HRs) 2269
(0%)		 32 y
(detail)
13 (8)
( - )
(detail)		 102 1.01
*		 0.98-1.04
*		 0.51
*		 394 1.01
*		 0.99-1.02
*		 0.19
*		 Caucasian
(detail)		 50 (1)
( - )		 Screening: 7MS, MMSE, TMT

AD Diagnosis: DSM IV, NINCDS ADRDA
(detail)		 A, E, BMI, SM, SBP, TC‡ Ronnemaa, 2008
Ronnemaa, 2009 ULSAM Incidence study reporting hazard ratios (HRs) 1125
(0%)		 12 y
(detail)
7.6 (7)
( - )
(detail)		 81 0.99
*		 0.95-1.03
*		 0.55
*		 257 1.00
*		 0.98-1.02
*		 1.0
*		 Caucasian
(detail)		 71 (1)
( - )		 Screening: 7MS, MMSE, TMT

AD Diagnosis: DSM IV, NINCDS ADRDA
(detail)		 A, E, BMI, DM, SM, SBP, TC‡
(detail)		 Ronnemaa, 2009
* Derived value.
 ‡ Covariates: "A" (age), "E" (education), "BMI" (body mass index), "DM" (diabetes mellitus), "SM" (smoking status), "SBP" (systolic blood pressure), "TC" (total cholesterol)
 
Table 8:   Fasting insulin - continuous, per 25% increment
Notes These studies evaluate the association between fasting insulin and risk of AD. For their analyses, these studies log-transformed insulin. The effect estimates in this table represent the relative risk corresponding to a 25% increase in insulin. To fit this interval, we converted some reported results.  
  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
Schrijvers, 2010 Rotterdam Study Incidence study reporting hazard ratios (HRs) 3139
(58%)		 -
(detail)
No DM hx, up to 3 y of follow-up
9.3 (-)
( - )
(detail)
71
1.12
*
1.01-1.24
*
0.04
*
 
 
 
 		  (detail) 72 (7)
( - )		 Screening: CAMDEX, GMS, MMSE

AD Diagnosis: NINCDS ADRDA
(detail)		 A, E, G, APOE4, DBP, HDL, SBP, TG, WC‡
(detail)		 Schrijvers, 2010
Schrijvers, 2010 Rotterdam Study Incidence study reporting hazard ratios (HRs) 2881
(-)		 -
(detail)
No DM hx, 3-5.5 y of follow-up
- (-)
( - )
(detail)
72
0.90
*
0.79-1.01
*
0.07
*
 
 
 
 		  (detail) - (-)
( - )		 Screening: CAMDEX, GMS, MMSE

AD Diagnosis: NINCDS ADRDA
(detail)		 A, E, G, APOE4, DBP, HDL, SBP, TG, WC‡
(detail)		 Schrijvers, 2010
* Derived value.
 ‡ Covariates: "A" (age), "E" (education), "G" (gender), "APOE4" (APOE e4 genotype), "DBP" (diastolic blood pressure), "HDL" (HDL cholesterol), "SBP" (systolic blood pressure), "TG" (triglycerides), "WC" (waist circumference)
 
Table 9:   Insulin resistance - continuous, per 25% increment
Notes These studies evaluate the association between insulin resistance as measured by the homeostatic model assessment (HOMA) technique, and risk of AD. The HOMA uses a mathematical model derived from human and experimental data to estimate insulin resistance from measures of fasting plasma glucose and plasma insulin. For their analyses, these studies log-transformed insulin resistance. The effect estimates in this table represent the relative risk corresponding to a 25% increase in insulin resistance. To fit this interval, we converted some reported results.  
  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
Schrijvers, 2010 Rotterdam Study Incidence study reporting hazard ratios (HRs) 3139
(58%)		 -
(detail)
No DM hx, up to 3 y of follow-up
2.3 (-)
( - )
(detail)
71
1.11
*
1.01-1.22
*
0.03
*
 
 
 
 		  (detail) 72 (7)
( - )		 Screening: CAMDEX, GMS, MMSE

AD Diagnosis: NINCDS ADRDA
(detail)		 A, E, G, APOE4, DBP, HDL, SBP, TG, WC‡
(detail)		 Schrijvers, 2010
Schrijvers, 2010 Rotterdam Study Incidence study reporting hazard ratios (HRs) 2881
(-)		 -
(detail)
No DM hx, 3-5.5 y of follow-up
- (-)
( - )
(detail)
72
0.90
*
0.81-1.00
*
0.05
*
 
 
 
 		  (detail) - (-)
( - )		 Screening: CAMDEX, GMS, MMSE

AD Diagnosis: NINCDS ADRDA
(detail)		 A, E, G, APOE4, DBP, HDL, SBP, TG, WC‡
(detail)		 Schrijvers, 2010
Schrijvers, 2010 Rotterdam Study Incidence study reporting hazard ratios (HRs) 2566
(-)		 -
(detail)
No DM hx, 5.5-9.7 years of follow-up
- (-)
( - )
(detail)
68
0.89
*
0.80-1.00
*
0.04
*
 
 
 
 		  (detail) - (-)
( - )		 Screening: CAMDEX, GMS, MMSE

AD Diagnosis: NINCDS ADRDA
(detail)		 A, E, G, APOE4, DBP, HDL, SBP, TG, WC‡
(detail)		 Schrijvers, 2010
* Derived value.
 ‡ Covariates: "A" (age), "E" (education), "G" (gender), "APOE4" (APOE e4 genotype), "DBP" (diastolic blood pressure), "HDL" (HDL cholesterol), "SBP" (systolic blood pressure), "TG" (triglycerides), "WC" (waist circumference)