Participants

The Adult Changes in Thought (ACT) study6 initially included 2581 randomly selected dementia-free members of the Group Health Cooperative (hereafter referred to as Group Health), a health care system in Washington State. Participants had to be 65 years of age or older at the time of enrollment, which occurred from 1994 through 1996. An additional 811 participants were enrolled between 2000 and 2002. Participants were invited to return at 2-year intervals for the purpose of identifying incident cases of dementia. The sample for the current study was limited to 2067 participants who had at least one follow-up visit, had been enrolled in Group Health for at least 5 years before study entry, and had at least five measurements of glucose or glycated hemoglobin (measured as hemoglobin A 1c or as total glycated hemoglobin, with the latter measurement reflecting an older hemoglobin assay) over the course of 2 or more years before study entry. The demographic characteristics of the ACT study participants who were included in the current study and those who were excluded were similar, although several clinical characteristics were more common among participants in the current study (see Table S1 in the Supplementary Appendix, available with the full text of this article at NEJM.org).

Study Oversight

The study procedures were approved by the institutional review boards of Group Health and the University of Washington, and participants provided written informed consent. The first three authors vouch for the accuracy of the study and the completeness of the data and analysis. Author responsibilities are discussed in the Methods S7 section in the Supplementary Appendix.

Identification of Dementia

Study participants were assessed for dementia every 2 years with the use of the Cognitive Abilities Screening Instrument, for which scores range from 0 to 100 and higher scores indicate better cognitive functioning.7 Patients with scores of 85 or less underwent further clinical and psychometric evaluation, including a battery of neuropsychological tests (see the Methods S1 section in the Supplementary Appendix). The results of these evaluations and laboratory testing and imaging records were then reviewed in a consensus conference. Diagnoses of dementia8 and of probable or possible Alzheimer's disease9 were made on the basis of research criteria. Dementia-free participants continued with scheduled follow-up visits. The incidence date for dementia was recorded as the halfway point between the study visit at which dementia was diagnosed and the previous visit.6

Risk Factors Assessed

Glucose Levels

Clinical data, including measurements of fasting glucose, random measurements of glucose, and measurements of glycated hemoglobin, were captured as computerized laboratory data from 1988 onward. We transformed values for total glycated hemoglobin to hemoglobin A 1c values using this formula: hemoglobin A 1c =(0.6×total glycated hemoglobin)+1.7. We then transformed the calculated hemoglobin A 1c values to daily average glucose values with this formula: daily average glucose=(28.7×hemoglobin A 1c )–46.7.10 We combined the recorded glucose values and daily average glucose values derived from glycated hemoglobin values using a hierarchical Bayesian framework (see the Methods S2 section in the Supplementary Appendix) to compute a time-varying estimate of the average glucose level for each participant. This approach creates an estimate of glucose level, weighted by the precision of the measures for glucose and glycated hemoglobin and stabilized with the use of a shrinkage factor to account for the instability of the estimation for participants with relatively few observations. We computed average glucose levels for each participant at study baseline and subsequently in 5-year rolling windows. Our approach to measurement was closely correlated with a simpler way of estimating glucose exposure (see the Methods S3 section and Fig. S6 in the Supplementary Appendix). The analysis included data from study participants for all time frames in which at least one measurement of glucose or glycated hemoglobin was available. Our secondary analyses explicitly considered more recent exposure (average glucose level in the preceding 5 years) as compared with more distant exposure (average glucose level in the period between 5 and 8 years earlier).

Diabetes

We classified participants as having treated diabetes on the basis of diabetes-related medication data from Group Health pharmacy records (Table S2 in the Supplementary Appendix). At least two filled prescriptions per year were required for the classification, with the onset date for treated diabetes defined as the date when the second prescription was filled. Once a participant was classified as having treated diabetes, the classification was retained for the remainder of the study.

Apolipoprotein E Genotype

Data on apolipoprotein E (APOE) genotype were available for 1818 participants (88%). APOE status was determined with the use of published methods11,12 and categorized as the presence or absence of any ε4 alleles.

Other Risk Factors

Risk factors with the potential to confound the relation between glucose levels and dementia were defined with the use of ACT study and Group Health data sources (see the Methods S4 section in the Supplementary Appendix). Exercise level was assessed with the use of questions about types of physical activity and the number of times each was performed in a week. These numbers were totaled, and those who exercised 3 or more days per week were categorized as having regular exercise, as previously reported.13 At each study visit, a research staff member administered a questionnaire that asked participants about their smoking status and whether a doctor had told them they had coronary artery disease, cerebrovascular disease, or hypertension. Blood pressure, measured while the participant was seated, was determined as the average of two measurements on the left arm, with a 5-minute rest period between measurements. Atrial fibrillation was determined with the use of codes 427.3, 427.31, and 427.32 from the International Classification of Diseases, 9th Revision, in accordance with procedures at Group Health. Treatment for hypertension was determined on the basis of Group Health pharmacy data (Table S3 in the Supplementary Appendix).

Statistical Analysis

We used stratified Cox regression models with empirical standard errors to examine the relation between glucose level and incidence of dementia. Age was used as the time axis. Stratification was based on status with respect to diabetes and cerebrovascular disease, which allowed for different baseline hazard functions across these strata in the estimation of model parameters. We controlled for age at study entry, study cohort, sex, educational level, exercise level, blood pressure, and status with respect to coronary artery disease, atrial fibrillation, smoking, and treatment for hypertension.

Glucose levels were incorporated in models with the use of natural cubic splines14 (see the Methods S8 section in the Supplementary Appendix) to allow for a nonlinear association between glycemia and risk of dementia as measured by the log hazard. Separate splines were used in accordance with diabetes status. The statistical significance (at the 0.05 level) of the association between glycemia and risk of dementia was estimated with the use of two-sided Wald tests of the composite hypotheses that all model parameters associated with the splines were equal to 0 (omnibus tests; α=0.05). We assessed the proportional hazards of covariate effects by testing for interactions with (log) time and plotting Schoenfeld residuals.15 All statistical analyses were performed with the use of SAS software, version 9.2 (SAS Institute), and R, version 2.15.1 (R Foundation for Statistical Computing).

We performed several sensitivity analyses, testing for interactions with glucose levels according to sex and age at study entry, investigating clinical data from participants whose data were particularly influential on model results, contracting or expanding the window for calculating the average glucose level (2 or 8 years rather than 5 years), adjusting for the presence of one or more APOE ε4 alleles, changing the parameters of the prior distribution within the Bayesian framework for exposure computation (see the Methods S5 section in the Supplementary Appendix), and making additional modifications to our glucose exposure model to account for prandial status when that was indicated (see the Methods S6 section in the Supplementary Appendix).